Enhanced structural variety of nonplanar N-oxyl radical catalysts and their application to the aerobic oxidation of benzylic C-H bonds

Article abstract of DOI:10.1248/cpb.c16-00083

The design and synthesis of structurally variable, nonplanar N-oxyl radical catalysts and their application to the aerobic oxidation, etherification, and acetoamidation of benzylic C-H bonds are described. The catalytic oxidation of C-H bonds represents a powerful tool to synthesize oxygenated functional molecules from simple hydrocarbons in a straightforward way. Electron-deficient N-oxyl radical catalysts, such as phthalimidoyl N-oxyl (PINO) radical, generated from N-hydroxyphthalimide (1), have attracted much attention because of their applications in the oxidation of C-H bonds with high bond dissociation energy (BDE). However, a few sites in 1 are available for structural modifications and improvements of the catalytic performance. By replacing one carbonyl group in 1 with a trifluoromethyl (CF₃)-substituted sp³-carbon, we generated an additional tunable site and a nonplanar backbone, while retaining the desirable electron-withdrawing properties and increasing the lipophilicity with respect to 1. We synthesized a variety of N-hydroxy pre catalysts containing such a CF₃ moiety, and investigated their utility in the aerobic oxidation of benzylic C-H bonds. Precatalysts with electron-withdrawing substituents, such as trifluoroethoxy and the acetophenone moieties, afforded higher yields than a corresponding methoxy-substituted analogue. The introduction of substituents at the aromatic ring was also effective, as evident from the performance of 7-CF₃ and 4,5,6,7-tetrafluoro precatalysts. Especially the combination of trifluoroethoxy- and 4,5,6,7-tetrafluoro substitution afforded a superior performance. These catalyst systems exhibited high functional group tolerance during the aerobic oxidation of C-H bonds, and benzylic etherification and Ritter-type reactions could be carried out at room temperature when a selected precatalyst and N-bromosuccinimide (NBS) were used.

Full text of DOI:10.1248/cpb.c16-00083

Vol. 64, No. 7
Chem. Pharm. Bull. 64, 737–753 (2016)
737
Special Collection of Papers
This article is dedicated to Professor Satoshi Ōmura in celebration of his 2015 Nobel Prize.
Regular Article
Enhanced Structural Variety of Nonplanar N-Oxyl Radical Catalysts and
Their Application to the Aerobic Oxidation of Benzylic C–H Bonds
,a
,a,c
Yoichi Kadoh,a,b Kounosuke Oisaki,* and Motomu Kanai*
a Graduate School of Pharmaceutical Sciences, The University of Tokyo; 7–3–1 Hongo,
b
Bunkyo-ku, Tokyo 113–0033, Japan: Research B Unit, Sohyaku Innovative Research
Division, Mitsubishi Tanabe Pharma Corporation; 1000 Kamoshida-cho, Aoba-ku,
c
Yokohama 227–0033, Japan: and Kanai Life Science Catalysis Project, ERATO,
Japan Science Technology Agency; 7–3–1 Hongo, Bunkyo-ku, Tokyo 113–0033, Japan.
Received January 26, 2016; accepted February 3, 2016
The design and synthesis of structurally variable, nonplanar N-oxyl radical catalysts and their applica-
tion to the aerobic oxidation, etherification, and acetoamidation of benzylic C–H bonds are described. The
catalytic oxidation of C–H bonds represents a powerful tool to synthesize oxygenated functional molecules
from simple hydrocarbons in a straightforward way. Electron-deficient N-oxyl radical catalysts, such as
phthalimidoyl N-oxyl (PINO) radical, generated from N-hydroxyphthalimide (1), have attracted much at-
tention because of their applications in the oxidation of C–H bonds with high bond dissociation energy
(BDE). However, a few sites in 1 are available for structural modifications and improvements of the catalytic
performance. By replacing one carbonyl group in 1 with a trifluoromethyl (CF3)-substituted sp3-carbon, we
generated an additional tunable site and a nonplanar backbone, while retaining the desirable electron-
withdrawing properties and increasing the lipophilicity with respect to 1. We synthesized a variety of N-
hydroxy precatalysts containing such a CF3 moiety, and investigated their utility in the aerobic oxidation of
benzylic C–H bonds. Precatalysts with electron-withdrawing substituents, such as trifluoroethoxy and the
acetophenone moieties, afforded higher yields than a corresponding methoxy-substituted analogue. The in-
troduction of substituents at the aromatic ring was also effective, as evident from the performance of 7-CF3
and 4,5,6,7-tetrafluoro precatalysts. Especially the combination of trifluoroethoxy- and 4,5,6,7-tetrafluoro
substitution afforded a superior performance. These catalyst systems exhibited high functional group toler-
ance during the aerobic oxidation of C–H bonds, and benzylic etherification and Ritter-type reactions could
be carried out at room temperature when a selected precatalyst and N-bromosuccinimide (NBS) were used.
Key words N-oxyl radical; aerobic oxidation; organocatalyst; C–H oxidation
The catalytic oxidation of C–H bonds is a valuable trans- reported to enhance its solubility and stability (Fig. 1). Thus,
formation in organic chemistry that leads to medicinally at- the group of Ishii was able to develop a lipophilic derivative
tractive oxygenated functional molecules in a small number of 1 (A), which is soluble in alkanes,10) as well as derivatives
of synthetic steps.1–3) In the context of green chemistry, the B and C, which contain long fluorinated alkyl chains and
use of molecular oxygen (O2) for this conversion has recently are thus soluble in trifluorotoluene.11) The group of Einhorn
attracted much attention, as it minimizes both the use of po- synthesized tetraphenyl- (D)12) and silyl-substituted13) (E) ana-
tentially hazardous oxidants and the generation of byproducts. logues with enhanced stability, and the group of Xu reported
However, C–H oxidations using O2 are challenging, as the for- the synthesis of tetrahalogenated derivatives of 1, whereby tet-
mation of reactive oxygen species from triplet O2 is kinetically rachloro analogue F showed the best catalytic performance.14)
unfavorable. Therefore, bespoke initiators/catalysts that acti- Nevertheless, the backbone of 1 remains characterized by its
vate C–H bonds and/or O2 are required, in order to perform inherent planarity and its limited number of modification sites,
aerobic C–H oxidations efficiently.3,4)
Electron-deficient N-oxyl radicals, which are generated mance and the introduction of additional functional groups.
from the oxidation of N-hydroxy compounds, have been used Herein, we report an unprecedented approach towards
which restrict a further improvement of the catalytic perfor-
to homolytically cleave the inert C(sp3)–H bonds of alkanes. nonplanar, electron-deficient N-oxyl radicals, containing an
The phthalimidoyl N-oxyl (PINO) radical, derived from N- additional tunable site, which provides these compounds with
hydroxyphthalimide (1), is a representative example that has enhanced solubility, stability, and structural diversity. We fur-
been applied to various aerobic or non-aerobic C–H oxida- thermore explored the utility of these compounds in the cata-
tions.5–7) However, 1 suffers from serious limitations in such lytic oxidation, etherification, and acetoamidation of benzylic
reactions, e.g. poor solubility in common organic solvents and C(sp3)–H bonds.
rapid autodecomposition.8,9)
Introducing substituents at the aromatic ring of 1 has been
*To whom correspondence should be addressed. e-mail: oisaki@mol.f.u-tokyo.ac.jp; kanai@mol.f.u-tokyo.ac.jp
© 2016 The Pharmaceutical Society of Japan

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Fig. 1. Chemical Structure of 1 and Previously Reported Derivatives
Results and Discussion
Structural Design of a Nonplanar, CF3-Substituted N-
Oxyl Radical Precursor
The high bond dissociation energy (BDE) of the NO–H
bond in 1 (88.1kcal/mol in t-BuOH), which is sufficient for
cleaving benzylic, tertiary, and even secondary C(sp3)–H
bonds, is due to the presence of two carbonyl groups adjacent
to the N-OH moiety. These electron-withdrawing groups de-
stabilize the resulting oxyl radical by rendering the delocaliza-
tion of the nitrogen-lone pair inefficient therein.15)
Due to the structural simplicity of 1, modifiable sites are
Fig. 2. Structural Design of a Novel N-Oxyl Radical Precursor Based
on 1
limited, except for those of the aromatic ring. To overcome trifluoromethylation17) afforded the 7- and 4-iodo isomers
this limitation, we envisaged that the transformation of one 14a (46%) and b (36%), which were separated after tritura-
carbonyl group into an sp3 carbon should provide a feasible tion with Et2O and column chromatography.18) Treatment of
route to an additional tunable site in close proximity to the alcohol 14a with methanesulfonyl chloride (MsCl) furnished
N-hydroxy moiety, which would simultaneously afford a chloride 15, whose chloro group was removed by reaction
nonplanar structure. This strategy should allow access to with methanol or 2,2,2-trifluoroethanol (TFE) to afford ethers
unprecedented structural tuning in order to improve catalytic 16 and 17, respectively. The iodo group of these compounds
performance, even though the elimination of a carbonyl group was substituted with a CF3 group using (Ph3P)3CuCF3,19) and
should lower the BDE.
deprotection eventually afforded CF3-substituted N-hydroxy
The substitution of the carbonyl group at the R5 position in precatalysts 20 and 21.
1 with the lipophilic and electron-withdrawing trifluoromethyl
Acetophenone-substituted 7-trifluoromethyl analogue 28
(CF3) group should not only counterbalance such a decreased was prepared following a similar synthetic route, starting from
BDE, but also enhance the solubility of the resulting deriva- 22.20) As the removal of the benzyl group was unsuccessful in
tive.16) Simultaneous modifications of the aromatic substituents this case, the p-methoxybenzyl (PMB) group was selected as
(R1–R4) should further improve these properties (Fig. 2).
a protecting group for the N-hydroxy moiety (Chart 3). The
Preparation of N-Hydroxy Precatalysts
PMB group could be removed successfully in the last step
N-Hydroxy precatalysts 5, 6, and 9 were synthesized from under trifluoroacetic acid (TFA)/C6Me5H conditions16,21) to af-
1 in five steps (Chart 1). Initially, 1 was converted into inter- ford 28.
mediate 2 in three steps, following our previously reported
Next, we tackled the synthesis of tetrafluoro analogues 34
procedure.16) Then, the chloro group of 2 was substituted and 35, starting from 29, i.e., the 4,5,6,7-tetrafluoro derivative
with methoxy, 2,2,2-trifluoroethoxy, or acetophenone moieties of 122) as shown in Chart 4. As expected, protection of the N-
under silver-mediated SN1 conditions, using the corresponding hydroxy moiety in 29 as a PMBether, followed by nucleophilic
alcohols or a silyl enol ether (7). The ensuing removal of the trifluoromethylation successfully furnished alcohol 31. How-
protecting benzyl group under hydrogenolysis conditions af- ever, our general protocol (Chart 1), consisting of chlorination
forded N-hydroxy precatalysts 5, 6, and 9.
(Et3N–MsCl) followed by silver-mediated SN1 substitution,16)
We also synthesized N-oxyl radical precursors containing a did not afford 32 or 33 from 30, most likely on account of
CF3 group at position 7 of the aromatic ring (20 and 21; Chart the low reactivity of the chlorinated intermediate towards the
2). For this purpose, commercially available 3-nitrophthalic silver salt. As an alternative, we chose to carry out a one-
anhydride (10) was reacted with H2NOBn·HCl to afford 11, pot mesylation-substitution reaction. After 31 was mesylated
whose nitro group was reduced with iron powder to yield using Ms2O–Et3N at −78°C, methanol or TFE was added to
amine 12. Subsequently, 12 was converted into iodide 13 the mixture, which was then warmed to room temperature.
by a Sandmeyer reaction, and an ensuing Ruppert–Prakash This protocol successfully furnished ethers 32 and 33, and

Vol. 64, No. 7 (2016)
Chem. Pharm. Bull.
739
Chart 1. Preparation of N-Hydroxy Precatalysts 5, 6, and 9
Chart 2. Preparation of 7-Trifluoromethyl N-Hydroxy Precatalysts 20 and 21
their PMB groups could be removed with TFA–C6Me5H to oxidation of benzylic C–H bonds. The results obtained are
afford 4,5,6,7-tetrafluoro N-hydroxy precatalysts 34 and 35. summarized in Table 1.
Unfortunately, an acetophenone-substituted analogue could
The oxygenation of the benzylic C–H bonds in 36a was in-
not be synthesized, presumably due to the low reactivity of vestigated using 5mol% of the N-hydroxy precatalyst, 1mol%
the silyl enol ether towards the mesylated or chlorinated in- of Co(OAc)2, and 1mol% of Mn(OAc)3·2H2O in CH3CN under
termediates.
Aerobic Oxidation of Benzylic C–H Bonds with N-Oxyl control catalyst, ketone 37a was obtained in 92% yield after
Radical Catalysts 12h (entry 1). Precatalyst 5, containing a CF3 and a methoxy
an atmosphere of O2 (1atm) at 60°C. When 1 was used as a
As a part of our ongoing research program directed towards substituent instead of a carbonyl group, afforded 37a in lower
N-oxyl radical-catalyzed aerobic oxidations,23–25) we applied yield (23%, entry 2). We found that substituting the methoxy
the newly synthesized N-hydroxy precatalysts to the aerobic group with more electron-deficient 2,2,2-trifluoroethoxy (6)

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Vol. 64, No. 7 (2016)
Chart 3. Preparation of 7-Trifluoromethyl N-Hydroxy Precatalyst 28
Chart 4. Preparation of 4,5,6,7-Tetrafluoro N-Hydroxy Precatalysts 34 and 35
or acetophenone (9) moieties led to improved yields of 45% (Table 2). When 3-phenylpropyl benzoate (36b) was used as
and 39%, respectively (entries 3, 4). 7-Trifluoromethyl- and the substrate, the corresponding ketone 37b was obtained in
4,5,6,7-tetrafluoro-substituted precatalysts 20 and 34 also 78% yield. p-Substituted alkylarenes, bearing either electron-
afforded improved yields (entries 2 vs. 5, 8), probably on donating or withdrawing substituents such as OMe (36c), CF3
account of their increased electron-withdrawing properties. (36d), or F (36e), all reacted under these conditions to afford
Whereas the combination of the 7-trifluoromethyl and the ace- ketones 37c–e in moderate to high yields (42–69%). The high
tophenone moieties in 28 proved to be mismatched (entries 4 functional group tolerance of the present system is evident
vs. 7), the combination of a 7-trifluoromethyl substitution pat- from the successful transformation of a variety of alkylben-
tern with a 2,2,2-trifluoroethoxy group (21) displayed an ad- zenes that bear different functional groups, e.g. a carboxylic
ditive effect, resulting in the formation of ketone 37a in 66% acid (36f), a methyl ester (36g), a carboxamide (36h), an al-
yield (entries 3, 5 vs. 6). The best performance (71% yield, kylbromide (36i), a nitrile (36j), or a methyl imidate (36k),
entry 9) was obtained with N-hydroxy precatalyst 35, which into the corresponding ketones 37f–k in a chemoselective
contained a 4,5,6,7-tetrafluoro-substituted aromatic ring and a manner (39–80% yield). Interestingly, tetralin (36l), xanthene
2,2,2-trifluoroethoxy group.
(36m), or isochromane (36n) were oxidized more readily than
Subsequently, we examined the scope and limitations of alkylarenes, furnishing the corresponding ketones 37l–n in
the oxidation of benzylic C–H bonds using precatalyst 35 41–78% yield even at room temperature.

Vol. 64, No. 7 (2016)
Chem. Pharm. Bull.
741
Table 1. Aerobic Oxidation of Benzylic C–H Bonds in 36a Using N-Oxyl Catalysts
Entry
1b)
Catalyst
Yield (%)a)
Entry
6
Catalyst
Yield (%)a)
92
66
2
3
23
45
7
8
9
28
46
71
4
5
39
46
1
a) H-NMR yield. b) The reaction time was 12h.
Benzylic Etherification and Acetoamidation Using ence of a strong oxidant such as N-fluoro-N′-(chloromethyl)-
N-Oxyl Radical Catalyst 35 and N-Bromosuccinimide triethylenediamine pentafluoro phosphate (F-TEDA-PF6) or
(NBS)
ceric ammonium nitrate.30–33) We found that 36b could be suc-
During our investigations on the utility of N-hydroxy prec- cessfully aminated under mild conditions in CH3CN to afford
atalyst 35, we discovered novel conditions for the intermolecu- 2,2,2-trifluoroethylether 39 in 49% yield using 35. These reac-
lar benzylic etherification and a Ritter-type reaction that uses tions may proceed via a carbocation intermediate generated by
NBS as the oxidant (Chart 5). We were thus able to synthesize a two-electron oxidation process.33)
2,2,2-trifluoroethylethers, whose preparation via the classical
Williamson ether procedure is limited by their low nucleophi-
licity. The conventional synthetic method for the generation
Conclusion
We have developed a synthetic procedure to prepare highly
of benzylic 2,2,2-trifluoroethylethers involves the nucleophilic tunable, nonplanar, and electron-deficient N-oxyl radical spe-
attack of TFE to the corresponding benzylic cation, which is cies that can be used for the catalytic aerobic oxidation of
generated from a prefunctionalized benzylic compound.26–28) benzylic C–H bonds. This method is based on the introduction
To the best of our knowledge, the direct transformation of a of a CF3-substituted sp3-carbon as an additional functional-
benzylic sp3 C–H bond into a C–OCH2CF3 moiety has not ization site in close proximity to the N-hydroxy moiety of 1.
been reported so far. For that purpose, 36b was treated with a Subsequently, modulation of the catalyst activity was accom-
catalytic amount of 35 to mediate this 2,2,2-trifluoroetherifica- plished by changing the substituents at both the aromatic ring
tion, which afforded 38 in modest yield (54%).29)
and at the α-position with respect to the CF3 group. In general,
Ritter-type aminations of benzylic sp3 C–H bonds usu- the introduction of more electron-withdrawing groups led to
ally require harsh conditions, i.e. heating and/or the pres- a significant improvement of the catalyst activity, which is in

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Table 2. Substrate Scope of the Oxidation of Benzylic C–H Bonds with N-Hydroxy Precatalyst 35a)
a) Percentage values in parentheses refer to isolated yields.
good agreement with previously reported results.34) Although or Wako Pure Chemical Industries, Ltd.). Other reagents of
the best precatalyst performance still remains inferior to that which preparation is not described in this manuscript were
of 1 itself, these investigations provide fundamental informa- purchased from Aldrich, Tokyo Chemical Industry Co., Ltd.
tion on the design of novel N-oxyl radical catalysts and ef- (TCI), Kanto Chemical Co., Inc., and Wako Pure Chemical
fective radical directing activators.16) Further studies on the Industries, Ltd., and used without further purification. NMR
1
functionalization of these compounds that may eventually lead yield was calculated by H-NMR of crude product using an
to more active and selective catalysts are ongoing in our labo- internal standard (1,3,5-trioxane).
ratory and results will be reported elsewhere in due course.
Preparation of N-Hydroxy Precatalysts Full spectro-
scopic data were described for new compounds. Compound
2,16) 22,20) and 2922) were prepared following the reported
Experimental
General Method NMR spectra were recorded on JEOL procedures.
JNM-LA500, JEOL ECX500 (500MHz for 1H-NMR and
125MHz for 13C-NMR), and JEOL ECS400 (400MHz for
1H-NMR, 100MHz for 13C-NMR, and 368MHz for 19F-NMR)
spectrometer. Chemical shifts were reported downfield
from tetramethylsilane (TMS) (δ=0ppm) for 1H-NMR. For
13C-NMR, chemical shifts were reported in the scale relative
to the solvent used as an internal reference. For 19F-NMR,
chemical shifts were reported downfield from hexafluoroben-
zene (δ=−164.9ppm). IR spectra were recorded on a JASCO
General Procedure for Etherification (Procedure A)
2-Benzyloxy-3-methoxy-3-trifluoromethylisoindolin-1-one (3)
To a suspension of silver trifluoromethanesulfonate (AgOTf)
FT/IR 410 Fourier transform IR spectrophotometer. Electro- (2.18g, 8.50mmol) in toluene (5mL), chloride 2 (1.71g,
spray ionization (ESI)-MS spectra were measured on a Waters 5.00mmol) in toluene (5mL) and MeOH (243µL, 6.00mmol)
ZQ4000 spectrometer (for low resolution (LR)-MS), and a were added at 0°C. The reaction mixture was stirred for 1h
JEOL JMS-T100LC AccuTOF spectrometer (for high resolu- at 0°C, and for 3h at room temperature (rt). Brine was added
tion (HR)-MS). Column chromatographies were performed to the mixture, and the suspension was filtered over Celite.
with silica gel Merck 60 (230–400 mesh ASTM). All reac- The filtered organic layer was separated, washed with H2O
tions other than substrates synthesis were carried out in dry and brine, dried over Na2SO4, filtered, and evaporated under
solvents (purchased from Aldrich, Kanto Chemical Co., Inc. reduced pressure. The residue was purified with flash col-

Vol. 64, No. 7 (2016)
Chem. Pharm. Bull.
743
1
a) Percentage values refer to H-NMR yields using 2,4,6-trioxane as an internal standard. Percentage values in parentheses refer to isolated yields.
Chart 5. Benzylic Etherification and Acetoamidation with N-Hydroxy Precatalyst 35
umn chromatography (SiO2, n-hexane–EtOAc=9:1→4:1) to
1
afford methylether 3 (1.60g, 95%). White powder; H-NMR
(400MHz, CDCl3) δ: 7.89 (d, J=7.2Hz, 1H), 7.51–7.72 (m 5H),
7.32–7.42 (m, 3H), 5.30 (d, J=9.9Hz, 1H), 5.13 (d, J=9.9Hz,
1H), 2.99 (s, 3H); 13C-NMR (100MHz, CDCl3) δ: 165.56,
134.55, 134.47, 133.52, 131.75, 130.10, 129.45 (2C), 128.86,
128.41 (2C), 124.28, 124.19, 122.07 (q, J=285.6Hz), 91.37
(q, J=32.9Hz), 79.09, 51.28; 19F-NMR (368MHz, CDCl3) δ:
2-Benzyloxy-3-(2,2,2-trifluoroethoxy)-3-trifluoromethyl-
−77.92 (s, 3F); IR (KBr, cm−1) ν: 3586, 3443, 2939, 1742, isoindolin-1-one (4)
1654, 1559, 1541, 1185, 671; LR-MS (ESI): m/z 360 [M+Na]+;
According to the procedure A in which 2,2,2-trifluoroentha-
HR-MS (ESI): m/z Calcd for C17H14F3NO3Na [M+Na]+ nol was used as the alcohol instead, chloride 2 (1.71g,
360.0818. Found 360.0831.
5.00mmol) was converted into ether 4 (1.57g, 78%). Colorless
1
General Procedure for Hydrogenolysis of Benzyl Ether oil; H-NMR (500MHz, CDCl3) δ: 7.92 (d, J=7.5Hz, 1H), 7.74
(Procedure B)
(dd, J=7.4, 7.4Hz, 1H), 7.69 (dd, J=7.4, 7.4Hz, 1H), 7.60 (d,
J=6.9Hz, 1H), 7.54 (d, J=7.4Hz, 2H), 7.35–7.44 (m, 3H), 5.30
(d, J=9.8Hz, 1H), 5.16 (d, J=9.8Hz, 1H), 3.40–3.50 (m, 1H),
3.19–3.29 (m, 1H); 13C-NMR (125MHz, CDCl3) δ: 165.63,
134.37, 134.23 (2C), 133.53, 132.54 (2C), 129.78, 129.42,
129.07, 128.56, 124.62, 124.58, 122.72 (q, J=277.1Hz), 121.57
(q, J=286.7Hz), 91.0 (q, J=33.6Hz), 79.31, 61.3 (q, J=36.0Hz);
19F-NMR (368MHz, CDCl3) δ: −74.02 (s, 3F), −77.52 (s, 3F);
2-Hydroxy-3-methoxy-3-trifluoromethylisoindolin-1-one (5)
A suspension of benzylether 3 (1.48g, 4.39mmol) and IR (neat, cm−1) ν: 3433, 2917, 2848, 1750, 1470, 1293, 1190,
10wt% Pd/C (319mg, 0.300mmol) in EtOH (12.0mL) was 984, 766, 635; LR-MS (ESI): m/z 428 [M+Na]+; HR-MS
stirred for 2h under H2 atmosphere (1atm, balloon). The mix- (ESI): m/z Calcd for C18H13F6NO3Na [M+Na]+ 428.0692.
ture was purged with Ar and filtered over Celite. The filtrate Found 428.0690.
was evaporated under reduced pressure. The residue was puri-
fied with flash column chromatography (SiO2, n-hexane–
EtOAc=2:1→1:1) to afford 5 (1.02g, 94%). White powder;
1H-NMR (500MHz, CDCl3) δ: 7.82 (d, J=7.6Hz, 1H),
7.57–7.70 (m, 3H), 3.13 (s, 3H); 13C-NMR (125MHz, CDCl3) δ:
165.92, 134.58, 131.69, 130.06, 124.16, 124.05, 121.88 (q,
J=286.2Hz), 91.40 (q, J=33.1Hz), 51.58; 19F-NMR (368MHz,
CDCl3) δ: −78.41 (s, 3F); IR (KBr, cm−1) ν: 3136, 2952, 2887,
2-Hydroxy-3-(2,2,2-trifluoroethoxy)-3-trifluoromethyl-
1711, 1471, 1315, 1195, 1124, 1086, 1007, 878, 731; LR-MS isoindolin-1-one (6)
(ESI): m/z 270 [M+Na]+; HR-MS (ESI): m/z Calcd for
C10H8F3NO3Na [M+Na]+ 270.0348. Found 270.0341.
According to the procedure B, benzyl ether 4 (1.45g,
3.58mmol) was converted into 6 (1.07g, 95%). White powder;
1H-NMR (400MHz, acetone-d6) δ: 7.71–7.90 (m, 4H),

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3.97–4.10 (m, 1H), 3.64–3.78 (m, 1H); 13C-NMR (125MHz, 2926, 1696, 1643, 1278, 1185, 754; LR-MS (ESI): m/z 358
acetone-d6) δ: 164.68, 134.69, 134.11, 133.45, 131.47, 125.54, [M+Na]+; HR-MS (ESI): m/z Calcd for C17H12F3NO3Na
124.73, 124.43 (q, J=277.1Hz), 122.59 (q, J=285.5Hz), 91.49 [M+Na]+ 358.0661. Found 358.0677.
(q, J=33.6Hz), 61.95 (q, J=36.0Hz); 19F-NMR (368MHz, ace-
tone-d6) δ: −74.80 (s, 3F), −78.38 (s, 3F); IR (KBr, cm−1) ν:
3426, 3137, 2942, 1719, 1616, 1508, 1473, 1427, 1378, 1305,
1172, 1125, 1087, 1038, 993, 968, 882, 766; LR-MS (ESI): m/z
338 [M+Na]+; HR-MS (ESI): m/z Calcd for C11H7F6NO3Na
[M+Na]+ 338.0222. Found 338.0223.
2-Benzyloxy-4-nitroisoindoline-1,3-dione (11)
A suspension of 3-nitrophthalic anhydride 10 (1.00g,
5.18mmol) and H2NOBn·HCl (827mg, 5.18mmol) in xylene
(19mL) was heated to reflux for 3h with Dean–Stark appara-
tus. The mixture was evaporated under reduced pressure. The
residue was triturated with EtOH to afford 11 (1.39g, 90%).
1
Pale yellow powder; H-NMR (500MHz, DMSO-d6) δ: 8.30
(d, J=8.0Hz, 1H), 8.15 (d, J=8.0Hz, 1H), 8.06 (dd, J=8.0,
8.0Hz, 1H), 7.50–7.55 (m, 2H), 7.38–7.45 (m, 3H), 5.17 (s, 2H);
2-Benzyloxy-3-(2-oxo-2-phenylethyl)-3-trifluoromethyl- 13C-NMR (125MHz, DMSO-d6) δ: 161.17, 158.81, 144.11,
isoindolin-1-one (8)
136.42, 134.02, 130.53, 129.66 (2C), 129.18, 128.69, 128.52
To a suspension of AgOTf (437mg, 1.70mmol) in toluene (2C), 127.03, 120.62, 79.48; IR (KBr, cm−1) ν: 3449, 3109,
(1.0mL), chloride 2 (342mg, 1.00mmol), Et3N (279µL, 3048, 2952, 2896, 1793, 1732, 1545, 1350, 1144, 1005, 865,
2.00mmol) and [(1-phenyl-1-ethenyl)oxy]trimethylsilane (7) 699; LR-MS (ESI): m/z 321 [M+Na]+; HR-MS (ESI): m/z
(385mg, 2.00mmol) in toluene (1.0mL) were added at 0°C. Calcd for C15H11N2O5Na [M+Na]+ 321.0482. Found 321.0497.
The reaction mixture was stirred for 1h at 0°C, and for 35h at
rt. Brine was added to the mixture and the suspension was
filtered over Celite. The organic layer was separated, washed
with H2O and brine, dried over Na2SO4, filtered, and evapo-
rated under reduced pressure. The residue was purified with
flash column chromatography (SiO2, n-hexane–EtOAc=
1
9:1→4:1) to afford 8 (264mg, 62%). White powder; H-NMR
4-Amino-2-benzyloxyisoindoline-1,3-dione (12)
A suspension of 11 (34.0g, 0.114mol), Fe powder (63.7g,
(400MHz, CDCl3) δ: 7.90–7.96 (m, 1H), 7.72 (dd, J=7.2,
1.3Hz, 2H), 7.71–7.59 (m 6H), 7.27–7.37 (m, 5H), 5.43 (d, 1.14mol), and NH4Cl (3.66g, 0.0684mol) in H2O (380mL) was
J=9.9Hz, 1H), 5.05 (d, J=9.9Hz, 1H), 4.00 (d, J=17.5Hz, heated to reflux for 2h. The mixture was diluted with H2O
1H), 3.74 (d, J=17.5Hz, 1H); 13C-NMR (100MHz, CDCl3) δ: and CH2Cl2, and filtered over Celite. The organic layer was
195.56, 168.49, 137.90, 136.05, 134.61, 133.46, 132.91, 130.56, separated. The aqueous layer was extracted with CH2Cl2. The
130.12, 129.43 (2C), 128.65, 128.45 (2C), 128.30 (2C), 127.80, combined organic layer was washed with H2O and brine, dried
124.58 (q, J=284.7Hz), 124.15 (2C), 122.31, 79.20, 67.20 (q, over Na2SO4, filtered, and evaporated under reduced pressure.
J=29.1Hz), 34.31; 19F-NMR (368MHz, CDCl3) δ: −76.46 (s, The residue was triturated with Et2O to afford amine 12
1
3F); IR (KBr, cm−1) ν: 3450, 3061, 3035, 2968, 2926, 1733, (15.4g, 51%). Yellow powder; H-NMR (400MHz, DMSO-d6)
1698, 1594, 1469, 1374, 1275, 1185, 991, 751; LR-MS (ESI): δ: 7.32–7.57 (m, 6H), 6.89–7.04 (m, 2H), 6.50 (brs, 2H), 5.11
m/z 448 [M+Na]+; HR-MS (ESI): m/z Calcd for (s, 2H); 13C-NMR (125MHz, DMSO-d6) δ: 164.58, 163.36,
C24H18F3NO3Na [M+Na]+ 448.1131. Found 448.1140.
146.56, 135.43, 134.32, 129.56 (2C), 128.98 (2C), 128.41 (2C),
122.14, 111.05, 105.05, 79.07; IR (KBr, cm−1) ν: 3479, 3336,
3032, 1759, 1715, 1630, 1481, 1385, 1181, 1026, 903, 730;
LR-MS (ESI): m/z 291 [M+Na]+; HR-MS (ESI): m/z Calcd for
C15H12N2O3Na [M+Na]+ 291.0740. Found 291.0732.
2-Hydroxy-3-(2-oxo-2-phenylethyl)-3-trifluoromethyl-
isoindolin-1-one (9)
According to the procedure B, benzyl ether 8 (740mg,
1.74mmol) was converted into 9 (530mg, 91%). Colorless oil;
1H-NMR (500MHz, CDCl3) δ: 7.77 (d, J=7.4Hz, 2H), 7.70 (d,
J=7.5Hz, 1H), 7.42–7.55 (m, 4H), 7.38 (dd, J=7.5, 7.5Hz, 2H),
2-Benzyloxy-4-iodoisoindoline-1,3-dione (13)
To a suspension of amine 12 (15.4g, 57.4mmol) and 3N HCl
4.02–4.21 (m, 1H), 3.75–3.93 (m, 1H); 13C-NMR (125MHz, aq. (165mL) in CH3CN (674mL), NaNO2 (4.75g, 68.9mmol) in
CDCl3) δ: 193.39, 168.14, 137.61, 136.23, 133.71, 132.66, H2O (57.4mmol) was added dropwise at 0°C, and the mixture
130.41, 130.07 (2C), 128.62 (2C), 128.01, 124.14, 124.13 (q, was stirred for 0.5h at the same temperature. To the mixture,
J=285.5Hz), 122.41, 67.98 (q, J=34.8Hz), 34.21; 19F-NMR KI (14.3g, 86.1mmol) in H2O (57.4mL) was added at 0°C, and
(368MHz, CDCl3) δ: −76.68 (s, 3F); IR (KBr, cm−1) ν: 3422, the mixture was stirred for 1h at the same temperature. To the

Vol. 64, No. 7 (2016)
Chem. Pharm. Bull.
745
mixture, CH2Cl2 was added, and the phases were separated.
The aqueous layer was extracted with CH2Cl2. The combined
organic layer was washed with 20% Na2S2O3 aq., H2O, and
brine, dried over Na2SO4, filtered, and evaporated under re-
duced pressure. The residue was triturated with n-hexane–
EtOAc=2:1 to afford iodide 13 (16.1g, 74%). white powder;
1H-NMR (400MHz, CDCl3) δ: 8.09 (d, J=8.1Hz, 1H), 7.78 (d,
2-Benzyloxy-3-chloro-7-iodo-3-trifluoromethylisoindolin-1-
J=7.2Hz, 2H), 7.49–7.54 (m, 2H), 7.32–7.42 (m, 3H), 5.19 (s, one (15)
2H); 13C-NMR (100MHz, CDCl3) δ: 162.34, 161.39, 145.55,
To a suspension of alcohol 14a (8.64g, 19.2mmol) in
134.94, 133.44, 130.82, 129.80 (2C), 129.53, 129.33, 128.52 CH2Cl2 (192mL), Et3N (4.26mL, 28.8mmol) and MsCl
(2C), 123.21, 88.76, 79.94; IR (KBr, cm−1) ν: 3501, 3079, 3033, (2.23mL, 30.7mmol) were added at 0°C, and the mixture was
1790, 1742, 1455, 1391, 1146, 984, 876, 718; LR-MS (ESI): m/z stirred for 0.5h at 0°C, then for 13h at rt. To the mixture,
402 [M+Na]+; HR-MS (ESI): m/z Calcd for C16H11F3INO3Na Et3N (798µL, 5.76mmol) and MsCl (446µL, 5.76mmol) were
[M+Na]+ 401.9598. Found 401.9590.
added at rt, and the mixture was stirred for 1h at rt. To the
mixture, H2O was added and the phases were separated. The
aqueous layer was extracted with CH2Cl2. The combined or-
ganic layer was washed with brine, dried over Na2SO4, fil-
tered, and evaporated under reduced pressure. The residue
was purified with flash column chromatography (SiO2, n-hex-
ane–EtOAc=19:1→9:1) to afford chloride 15 (8.46g, 94%).
1
2-Benzyloxy-3-hydroxy-7-iodo-3-trifluoromethylisoindo- white powder; H-NMR (400MHz, acetone-d6) δ: 8.28 (dd,
lin-1-one (14a) and 4-Iodo Isomer (14b)
J=9.3, 0.9Hz, 1H), 7.93 (dd, J=7.7, 0.9Hz, 1H), 7.67 (dd,
To a solution of phthalimide 13 (16.0g, 42.2mmol) and CsF J=7.6, 7.6Hz, 1H), 7.57–7.62 (m, 2H), 7.41–7.49 (m, 3H), 5.42
(8.34g, 54.9mmol) in N,N-dimethylformamide (DMF) (d, J=9.4Hz, 1H), 5.27 (d, J=9.4Hz, 1H); 13C-NMR
(422mL), trimethyl(trifluoromethyl)silane3 (TMSCF3) (8.13mL, (100MHz, acetone-d6) δ: 163.85, 144.63, 140.68, 136.46,
54.9mmol) was added dropwise at 0°C. The mixture was 135.07, 130.46 (2C), 129.93, 129.33 (2C), 128.34, 125.13 (q,
stirred for 0.5h at 0°C, then for 12h at rt. To the mixture, H2O J=1.9Hz), 122.46 (q, J=283.8Hz), 90.85, 80.48, 79.00 (q,
was added at 0°C, and the whole was extracted with EtOAc J=36.6Hz); 19F-NMR (368MHz, acetone-d6) δ: −76.34 (s, 3F);
for 3 times. The combined organic layer was washed with 1N IR (KBr, cm−1) ν: 3484, 3069, 3033, 2960, 2897, 1752, 1456,
HCl aq., H2O for 3 times, and brine, dried over Na2SO4, fil- 1264, 1171, 977, 903, 713; LR-MS (ESI): m/z 490 [M+Na]+;
tered, and evaporated under reduced pressure. The residue HR-MS (ESI): m/z Calcd for C16H10ClF3INO2Na [M+Na]+
was triturated with Et2O to afford alcohol 14a (6.54g, 35%). 489.9289. Found 489.9300.
The mother liquor was evaporated under reduced pressure,
and the residue was purified with flash column chromatogra-
phy (SiO2, n-hexane–EtOAc=9:1→1:1) to afford alcohol 14a
(2.11g, 11%) and 14b (6.86g, 36%). Compound 14a: White
1
powder; H-NMR (400MHz, acetone-d6) δ: 8.16 (dd, J=7.6,
0.9Hz, 1H), 7.81 (dd, J=7.6, 0.9Hz, 1H), 7.51–7.60 (m, 3H),
7.35–7.46 (m, 3H), 5.31 (d, J=9.4Hz, 2H), 5.19 (d, J=9.4Hz,
2-Benzyloxy-7-iodo-3-methoxy-3-(trif luoromethyl)-
2H); 13C-NMR (100MHz, acetone-d6) δ: 163.88, 143.81, isoindolin-1-one (16)
141.61, 135.89, 135.52, 130.22 (2C), 129.57 (2C), 129.19 (2C),
According to the procedure A, the chloride 15 (4.09g,
124.96 (q, J=1.9Hz), 123.57 (q, J=286.6Hz), 89.65, 86.33 (q, 8.75mmol) was converted into ether 16 (2.09g, 52%). white
1
J=33.8Hz), 80.52; 19F-NMR (368MHz, acetone-d6) δ: −79.43 powder; H-NMR (400MHz, acetone-d6) δ: 8.23 (d, J=8.1Hz,
(s, 3F); IR (KBr, cm−1) ν: 3254, 3031, 1717, 1460, 1376, 1198, 1H), 7.76 (d, J=7.6Hz, 1H), 7.56–7.63 (m, 3H), 7.35–7.46 (m,
989, 946, 794, 714; LR-MS (ESI): m/z 472 [M+Na]+; HR-MS 3H), 5.29 (d, J=10.0Hz, 1H), 5.20 (d, J=10.0Hz, 1H), 3.13 (s,
(ESI): m/z Calcd for C16H11F3INO3Na [M+Na]+ 471.9628. 3H); 13C-NMR (100MHz, acetone-d6) δ: 164.68, 144.40,
Found 471.9618. Compound 14b: white powder; 1H-NMR 137.53, 135.84, 135.68, 131.27, 130.16 (2C), 129.65, 129.24
(400MHz, acetone-d6) δ: 8.25 (d, J=7.6Hz, 1H), 7.85 (d, (2C), 125.44, 122.93 (q, J=285.6Hz), 90.82 (q, J=32.9Hz),
J=7.6Hz, 1H), 7.56 (d, J=7.2Hz, 2H), 7.34–7.49 (m 4H), 5.29 90.32, 79.88, 51.83; 19F-NMR (368MHz, acetone-d6) δ: −78.29
(d, J=9.9Hz, 1H), 5.22 (d, J=9.9Hz); 13C-NMR (100MHz, (s, 3F); IR (KBr, cm−1) ν: 3466, 3077, 3029, 2965, 2898, 1742,
acetone-d6) δ: 162.90, 146.79, 139.73, 136.00, 133.77, 132.91, 1456, 1276, 1187, 986, 869, 724, 697; LR-MS (ESI): m/z 486
130.10 (2C), 129.49, 129.12 (2C), 124.14, 123.93 (q, [M+Na]+; HR-MS (ESI): m/z Calcd for C17H13F3INO3Na
J=290.3Hz), 90.14 (q, J=32.9Hz), 90.10, 80.84; 19F-NMR [M+Na]+ 485.9784. Found 485.9781.
(368MHz, acetone-d6) δ: −75.41 (s, 3F); IR (KBr, cm−1) ν:
3169, 2956, 2885, 1702, 1574, 1461, 1372, 1251, 1191, 1092,
870, 760, 700; LR-MS (ESI): m/z 472 [M+Na]+; HR-MS
(ESI): m/z Calcd for C16H11F3INO3Na [M+Na]+ 471.9628.
Found 471.9624.

746
Chem. Pharm. Bull.
Vol. 64, No. 7 (2016)
2-Benzyloxy-3-methoxy-3,7-bistrifluoromethylisoindolin-1- (100MHz, acetone-d6) δ: 164.82, 145.00, 136.40, 136.08,
one (18)
135.67, 131.28, 130.14, 129.77, 129.34, 125.76 (q, J=1.9Hz),
The mixture of iodide 16 (100mg, 0.216mmol), 124.36 (q, J=276.3Hz), 122.50 (q, J=286.6Hz), 90.86, 90.59
(PPh3)3CuCF3 (218mg, 0.237mmol) and 4,4′-di-tert-butyl-2,2′- (q, J=32.9Hz), 80.23, 62.20 (q, J=35.7Hz); 19F-NMR
bipyridyl (4,4′-dtbpy) (63.6mg, 0.237mmol) in toluene (368MHz, acetone-d6) δ: −74.61 (s, 3F), −77.85 (s, 3F); IR
(2.2mL) was stirred for 20h at 80°C. To the mixture, (KBr, cm−1) ν: 3482, 3034, 2941, 2873, 1754, 1584, 1463, 1283,
(PPh3)3CuCF3 (39.7mg, 0.0432mmol) and 4,4′-di-tert- 1190, 1002, 953, 874, 798, 727; LR-MS (ESI): m/z 554
butyl-2,2′-bipyridyl (11.6mg, 0.0432mmol) were added and the [M+Na]+; HR-MS (ESI): m/z Calcd for C18H12F6INO3Na
mixture was stirred for 4h at 80°C. The mixture was diluted [M+Na]+ 553.9658. Found 553.9634.
with EtOAc, washed with H2O, 28% NH3 aq., H2O and brine,
dried over Na2SO4, filtered and evaporated under reduced
pressure. The residue was purified with flash column chroma-
tography (SiO2, n-hexane–EtOAc=19:1→9:1) to afford triflu-
oromehylated compound 18 (41.7mg, 48%). White powder;
1H-NMR (400MHz, CDCl3) δ: 7.94 (dd, J=4.3Hz, 1H), 7.81
(d, J=4.3Hz, 2H), 7.54 (d, J=5.9Hz, 2H), 7.32–7.44 (m, 3H),
5.32 (d, J=9.7Hz, 1H), 5.13 (d, J=9.7Hz, 1H); 13C-NMR
2-Benzyloxy-3-(2,2,2-trifluoroethoxy)-3,7-bistrifluoromethyl-
(100MHz, CDCl3) δ: 162.44, 137.00, 134.30, 133.52, 129.63 isoindolin-1-one (19)
(2C), 129.23 (q, J=4.8Hz), 129.04 (2C), 128.53, 127.74, 127.83,
According to the procedure described for the preparation of
(q, J=28.8Hz), 127.81, 122.00 (q, J=274.8Hz), 121.86 (q, the trifluoromehyl compound 18 from iodide 16, the iodide 17
J=286.7Hz), 97.78 (q, J=36.0Hz), 79.20, 51.49; 19F-NMR (444mg, 0.837mmol) was converted into trifluoromethyl com-
1
(368MHz, CDCl3) δ: −60.96 (s, 3F), −77.67 (s, 3F); IR (KBr, pound 19 (346mg, 87%). White powder; H-NMR (400MHz,
cm−1) ν: 3584, 3388, 2918, 2847, 1755, 1604, 1325, 1173, 989, CDCl3) δ: 7.98 (d, J=4.5Hz, 1H), 7.86 (d, J=4.5Hz, 1H), 7.52
760, 641; LR-MS (ESI): m/z 428 [M+Na]+; HR-MS (ESI): m/z (d, J=5.4Hz, 2H), 7.37–7.41 (m, 3H), 5.32 (d, J=9.9Hz, 1H),
Calcd for C18H13F6NO3Na [M+Na]+ 428.0692. Found 428.0701. 5.16 (d, J=9.9Hz, 1H), 3.40–3.52 (m, 1H), 3.13–3.24 (m, 1H);
13C-NMR (125MHz, CDCl3) δ: 162.45, 136.03, 134.25, 134.15,
129.98 (q, J=6.0Hz), 129.56 (2C), 129.23 (2C), 128.65 (2C),
128.3 (q, J=34.8Hz), 128.04, 122.59 (q, J=277.1Hz), 121.85
(q, J=274.7Hz), 121.38 (q, J=286.7Hz), 90.18 (q, J=34.8Hz),
79.40, 61.51 (q, J=36.0Hz); 19F-NMR (368MHz, CDCl3) δ:
−61.05 (s, 3F), −74.06 (s, 3F), −77.24 (s, 3F); IR (KBr, cm−1)
ν: 3512, 3439, 3043, 2967, 2898, 1770, 1611, 1330, 1182, 980,
2-Hydroxy-3-methoxy-3,7-bistrifluoromethylisoindolin-1-one 873, 820, 693; LR-MS (ESI): m/z 496 [M+Na]+; HR-MS
(20)
(ESI): m/z Calcd for C19H12F9NO3Na [M+Na]+ 496.0566.
According to the procedure B, the benzyl ether 18 (38.0mg, Found 496.0546.
0.0938mmol) was converted into 20 (29.4mg, 99%). White
powder; 1H-NMR (400MHz, CDCl3) δ: 7.76–7.92 (m, 3H),
3.17 (s, 3H); 13C-NMR (125MHz, CDCl3) δ: 162.91, 137.07,
133.36, 129.11, 127.78 (q, J=36.0Hz), 127.61, 127.56, 121.89 (q,
J=273.5Hz), 121.55 (q, J=286.7Hz), 90.60 (q, J=33.6Hz),
51.65; 19F-NMR (368MHz, CDCl3) δ: −60.86 (s, 3F), −78.04
(s, 3F); IR (KBr, cm−1) ν: 3426, 3178, 2954, 1734, 1610, 1509,
1329, 1195, 1135, 1016, 983, 878, 812, 704; LR-MS (ESI): m/z
338 [M+Na]+; HR-MS (ESI): m/z Calcd for C11H7F6NO3Na
[M+Na]+ 338.0222. Found 338.0226.
2-Hydroxy-3-(2,2,2-trifluoroethoxy)-3,7-bistrifluoromethyl-
isoindolin-1-one (21)
According to the procedure B, the benzyl ether 19 (300mg,
0.634mmol) was converted into 21 (233mg, 95%). White pow-
der; 1H-NMR (500MHz, CDCl3) δ: 7.94 (d, J=8.0Hz, 1H),
7.83–7.91 (m, 2H), 4.01–4.12 (m, 1H), 3.31–3.38 (m, 1H);
13C-NMR (125MHz, CDCl3) δ: 163.18, 136.15, 134.12, 129.82 (q,
J=6.0Hz), 128.07 (q, J=36.0Hz), 127.96, 127.15, 122.71 (q,
J=277.1Hz), 121.73 (q, J=273.5Hz), 121.10 (q, J=286.7Hz),
2-Benzyloxy-7-iodo-3-(2,2,2-trifluoroethoxy)-3-trifluoro- 90.13 (q, J=33.6Hz), 61.86 (q, J=37.2Hz); 19F-NMR (368MHz,
methylisoindolin-1-one (17)
CDCl3) δ: −61.14 (s, 3F), −74.33 (s, 3F), −77.55 (s, 3F); IR
According to the procedure A in which 2,2,2-trifluoroentha- (KBr, cm−1) ν: 3419, 3207, 2968, 1724, 1332, 1296, 1178, 984,
nol was used as the alcohol instead, the chloride 15 (0.935g, 885, 811, 689; LR-MS (ESI): m/z 406 [M+Na]+; HR-MS (ESI):
2.00mmol) was converted into ether 17 (1.04g, 98%). White m/z Calcd for C12H6F9NO3Na [M+Na]+ 406.0096. Found
1
powder; H-NMR (400MHz, acetone-d6) δ: 8.27 (dd, J=7.6, 406.0103.
0.9Hz, 1H), 7.84 (d, J=8.1Hz, 1H), 7.64 (dd, J=7.6, 7.6Hz,
1H), 7.63 (dd, J=7.6, 1.8Hz, 2H), 7.37–7.48 (m, 3H), 5.26–5.33
(m, 2H), 4.00–4.11 (m, 1H), 3.82–3.94 (m, 1H); 13C-NMR

Vol. 64, No. 7 (2016)
Chem. Pharm. Bull.
747
brine, dried over Na2SO4, filtered and evaporated under reduced
pressure. The residue was purified with flash column chromatog-
raphy (SiO2, n-hexane–EtOAc=19:1 9:1) to afford compound
→
1
41 (217mg, 87%). Colorless oil; H-NMR (400MHz, CDCl3) δ:
7.72 (d, J=7.2Hz, 1H), 7.30–7.56 (m, 7H), 5.26 (d, J=10.3Hz,
1H), 5.18 (d, J=10.3Hz, 1H), 3.05 (s, 3H), 2.46 (s, 3H); 13C-NMR
2-Benzyloxy-3-chloro-4-iodo-3-trifluoromethylisoindolin-1- (125MHz, CDCl3) δ: 165.83, 136.41, 136.30, 134.95, 131.56,
one (40a) and 2-Benzyloxy-4-iodo-3-methoxy-3-trifluorometh- 131.52, 130.86, 129.26, 128.79, 128.44, 122.55 (q, J=287.9Hz),
ylisoindolin-1-one (40b)
121.97, 93.59 (q, J=32.4Hz), 78.92, 51.05, 17.80 (q, J=3.6Hz);
To a solution of alcohol 14b (1.00g, 2.23mmol) in CH2Cl2 19F-NMR (368MHz, CDCl3) δ: −75.41 (s, 3F); IR (neat, cm−1) ν:
(22mL), MsCl (259µL, 3.35mmol) and Et3N (495µL, 3426, 2916, 1746, 1637, 1282, 1193, 1114, 1020, 735; LR-MS
3.57mmol) were added dropwise at 0°C, and the mixture was (ESI): m/z 374 [M+Na]+; HR-MS (ESI): m/z Calcd for
stirred for 1h at 0°C, then for 24h at rt. To the mixture, MsCl C18H16F3NO3Na [M+Na]+ 374.0974. Found 374.0978.
(173 µL, 2.23mmol) and Et3N (340µL, 2.45mmol) were added
at rt and stirred for 3h at the same temperature. To the mix-
ture, LiCl (189mg, 4.46mmol) was added, and stirred for 12h
at rt. To the mixture, MeOH (5.0mL) was added, stirred for
12h at rt, then H2O was added. The phases were separated.
The aqueous layer was extracted with CH2Cl2. The combined
organic layer was washed with H2O, and brine, dried over
Na2SO4, filtered, and evaporated under reduced pressure. The
4-Iodo-2-(4-methoxybenzyloxy)isoindoline-1,3-dione (23)
To a solution of 4-iodo-NHPI (22) (5.03g, 17.4mmol) in DMF
residue was purified with flash column chromatography (SiO2, (35mL), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (2.60mL,
n-hexane–EtOAc=19:1→9:1) to afford chloride 40a (630mg, 19.1mmol) and PMBCl (2.80mL, 19.1mmol) were added at 0°C
59%) and ether 40b (335mg, 32%). Chloride 40a: White pow- and the mixture was stirred for 2h at the same temperature.
der; 1H-NMR (400MHz, acetone-d6) δ: 8.44 (dd, J=8.1, H2O was added to the mixture and the resulted suspension was
1.4Hz, 1H), 7.99 (dd, J=8.1, 0.9Hz, 1H), 7.53–7.63 (m, 3H), filtered. The collected precipitate was triturated with iPr2O to
7.40–7.48 (m, 3H), 5.42 (d, J=9.4Hz, 1H), 5.35 (d, J=9.4Hz, afford ether 23 (6.88g, 97%). Brown powder; 1H-NMR
1H); 13C-NMR (100MHz, acetone-d6) δ: 162.90, 146.79, (500MHz, acetone-d6) δ: 8.24 (d, J=7.5Hz, 1H), 7.85 (d,
139.73, 136.00, 133.77, 132.92, 130.10 (2C), 129.49, 129.12 J=7.5Hz, 1H), 7.58 (dd, J=7.5, 7.5Hz, 1H), 7.49 (d, J=8.6Hz,
(2C), 124.14, 123.93 (q, J=290.1Hz), 90.14 (q, J=32.9Hz), 2H), 6.95 (d, J=8.6Hz, 2H), 5.15 (s, 2H), 3.80 (s, 3H); 13C-NMR
90.10, 80.84; 19F-NMR (368MHz, CDCl3) δ: −72.02 (s, 3F); (125MHz, acetone-d6) δ: 163.02, 162.14, 161.40, 146.40, 136.18,
IR (KBr, cm−1) ν: 3462, 3065, 2930, 2878, 1752, 1454, 1173, 132.37 (2C), 132.15, 130.83, 127.23, 123.76, 114.62 (2C), 88.94,
1000, 915, 720; LR-MS (ESI): m/z 490 [M+Na]+; HR-MS 80.05, 55.54; IR (KBr, cm−1) ν: 3444, 3078, 2961, 2933, 2837,
(ESI): m/z Calcd for C16H10ClF3INO2Na [M+Na]+ 489.9289. 1789, 1739, 1611, 1515, 1390, 1252, 1144, 982, 876, 814, 717;
1
Found 489.9283. Ether 40b: Colorless oil; H-NMR (400MHz, LR-MS (ESI): m/z 432 [M+Na]+; HR-MS (ESI): m/z Calcd for
CDCl3) δ: 8.12 (dd, J=7.6, 0.9Hz, 1H), 7.88 (dd, J=7.6, 0.9Hz, C16H12INO4Na [N+Na]+ 431.9703. Found 431.9722.
1H), 7.53 (dd, J=7.2, 1.3Hz, 2H), 7.32–7.42 (m, 2H), 7.30 (dd,
J=7.6, 7.6Hz, 1H), 5.25 (d, J=10.3Hz, 1H), 5.19 (d, J=10.3Hz,
1H), 3.15 (s, 3H); 13C-NMR (100MHz, CDCl3) δ: 164.17,
145.94, 136.28, 134.73, 133.15, 132.84, 129.19 (2C), 128.87,
128.46 (2C), 124.12, 122.12 (q, J=289.4Hz), 93.80 (q,
J=32.9Hz), 89.95, 78.97, 51.54; 19F-NMR (368MHz, CDCl3) δ:
3-Hydroxy-7-iodo-2-(4-methoxybenzyloxy)-3-trifluoro-
−73.41 (s, 3F); IR (neat, cm−1) ν: 3433, 1748, 1640, 1457, 1186, methylisoindolin-1-one (24a) and 4-Iodo Isomer (24b)
1122, 1000, 733; LR-MS (ESI): m/z 486 [M+Na]+; HR-MS
According to the procedure described for the preparation of
(ESI): m/z Calcd for C17H13F3INO3Na [M+Na]+ 485.9784. the alcohol 14a and b from phthalimide 13, the phthalimide 23
Found 485.9791.
(6.60g, 16.1mmol) was converted into alcohol 24a (1.77g,
23%) and 24b (1.74g, 23%). Alcohol 24a: White powder;
1H-NMR (400MHz, acetone-d6) δ: 8.15 (dd, J=8.1, 0.9Hz,
1H), 7.80 (d, J=8.1Hz, 1H), 7.54 (dd, J=8.1, 8.1Hz, 1H), 7.50
(d, J=8.5Hz, 2H), 6.97 (d, J=8.5Hz, 2H), 5.24 (d, J=9.0Hz,
1H), 5.12 (d, J=9.0Hz, 1H), 3.81 (s, 3H); 13C-NMR (100MHz,
acetone-d6) δ: 163.87, 161.15, 143.81, 141.61, 135.49, 132.03
(2C), 130.30, 127.88, 124.94, 123.57 (q, J=286.6Hz), 114.53
2-Benzyloxy-3-methoxy-4-methyl-3-trifluoromethyl- (2C), 89.64, 86.25 (q, J=32.9Hz), 80.22, 55.53; 19F-NMR
isoindolin-1-one (41)
(368MHz, CDCl3) δ: −79.34 (s, 3F); IR (KBr, cm−1) ν: 3420,
The mixture of iodide 40b (330mg, 0.712mmol), trimethyl- 3186, 2956, 2836, 1717, 1697, 1613, 1517, 1254, 1194, 1092, 976,
boroxine (0.299mL, 2.14mmol), Pd(OAc)2 (16.0mg, 0.0712mmol), 827, 708; LR-MS (ESI): m/z 502 [M+Na]+; HR-MS (ESI): m/z
PPh3 (37.3mg, 0.142mmol), and K2CO3 (197mg, 1.42mmol) in Calcd for C17H13F3INO4Na [M+Na]+ 501.9734. Found 501.9740.
1
dioxane (7.1mL) and H2O (0.71mL) was heated to reflux for 18h. Alcohol 24b: White powder; H-NMR (400MHz, acetone-d6)
The mixture was diluted with H2O and extracted with EtOAc δ: 8.24 (dd, J=8.1, 0.9Hz, 1H), 7.84 (dd, J=7.6, 1.4Hz, 1H),
twice. The combined organic layer was washed with H2O and 7.41–7.88 (m 3H), 6.95 (d, J=9.0Hz, 2H), 5.21 (d, J=9.9Hz,

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Chem. Pharm. Bull.
Vol. 64, No. 7 (2016)
1H), 5.13 (d, J=9.9Hz, 1H), 3.81 (s, 3H); 13C-NMR (100MHz,
acetone-d6) δ: 162.87, 161.05, 146.72, 139.74, 133.74, 133.00,
131.93 (2C), 127.96, 124.11, 123.92 (q, J=290.4Hz), 114.46
(2C), 90.09, 90.07 (q, J=32.9Hz), 80.56, 55.48; 19F-NMR
(368MHz, acetone-d6) δ: −75.38 (s, 3F); IR (KBr, cm−1) ν:
3181, 2960, 2836, 1702, 1612, 1516, 1254, 1196, 1131, 983, 833,
756; LR-MS (ESI): m/z 502 [M+Na]+; HR-MS (ESI): m/z
2-(4-Methoxybenzyloxy)-3-(2-oxo-2-phenylethyl)-3,7-
Calcd for C17H13F3INO4Na [M+Na]+ 501.9734. Found 501.9732. bistrifluoromethylisoindolin-1-one (27)
According to the procedure described for the preparation of
the trifluoromethylated compound 18 from iodide 16, the io-
dide 26 (440mg, 0.757mmol) was converted into trifluorometh-
1
ylated compound 27 (141mg, 36%). White powder; H-NMR
(400MHz, acetone-d6) δ: 8.05 (d, J=7.2Hz, 1H), 8.01 (d,
J=7.6Hz, 1H), 7.86–7.95 (m, 3H), 7.57 (dd, J=7.4, 7.4Hz, 1H),
3-Chloro-7-iodo-2-(4-methoxybenzyloxy)-3-trifluoro- 7.38–7.61 (m, 4H), 6.86 (d, J=8.5Hz, 2H), 5.27 (d, J=9.4Hz,
methylisoindolin-1-one (25)
1H), 5.04 (d, J=9.4Hz, 1H), 3.74 (s, 3H); 13C-NMR (100MHz,
According to the procedure described for the preparation of acetone-d6) δ: 193.78, 165.85, 161.08, 141.87, 136.95, 134.40,
the chloride 15 from alcohol 14a, the alcohol 24a (1.72g, 134.20, 131.98 (2C), 129.40 (2C), 129.25, 128.74 (2C), 128.32
3.59mmol) was converted into chloride 25 (1.55g, 87%). (q, J=5.6Hz), 127.88, 127.66, 127.27, 125.51 (q, J=284.7Hz),
1
White powder; H-NMR (400MHz, acetone-d6) δ: 8.27 (dd, 123.11 (q, J=272.5Hz), 114.53 (2C), 79.52, 67.85 (q, J=29.1Hz),
J=8.1, 0.9Hz, 1H), 7.92 (d, J=7.6Hz), 7.66 (dd, J=7.6, 7.6Hz, 55.43, 34.97; 19F-NMR (368MHz, acetone-d6) δ: −60.90 (s,
1H), 7.43 (d, J=8.5Hz, 2H), 6.99 (d, J=8.5Hz, 2H), 5.34 (d, 3F), −76.96 (s, 3F); IR (KBr, cm−1) ν: 3442, 2957, 1742, 1693,
J=9.0Hz, 1H), 5.19 (d, J=9.0Hz, 1H), 3.83 (s, 3H); 13C-NMR 1612, 1518, 1323, 1255, 1193, 1140, 1006, 812, 867; LR-MS
(100MHz, acetone-d6) δ: 163.78, 161.36, 144.58, 140.68, (ESI): m/z 546 [M+Na]+; HR-MS (ESI): m/z Calcd for
136.38, 132.28, 128.40, 127.03, 125.11 (q, J=1.9Hz), 122.45 (q, C26H19F6NO4Na [M+Na]+ 546.1110. Found 546.1097.
J=283.8Hz), 114.65, 90.79, 80.18, 78.85 (q, J=35.7Hz), 55.54;
19F-NMR (368MHz, acetone-d6) δ: −76.31 (s, 3F); IR (KBr,
cm−1) ν: 3422, 2959, 2834, 1742, 1515, 1459, 1249, 974, 706;
LR-MS (ESI): m/z 520 [M+Na]+; HR-MS (ESI): m/z Calcd for
C17H12ClF3INO3Na [M+Na]+ 520.9395. Found 519.9382.
2-Hydroxy-3-(2-oxo-2-phenylethyl)-3,7-bistrifluoromethyl-
isoindolin-1-one (28)
To a solution of PMBether 27 (52.3mg, 0.100mmol) and
pentamethyl benzene (44.4mg, 0.300mmol) in CH2Cl2
(2.0mL), TFA (1.0mL) was added at 0°C, and the mixture was
stirred for 0.5h at 0°C, then for 2h at rt. The mixture was neu-
tralized with sat. NaHCO3 aq. at 0°C, then the phases were
7-Iodo-2-(4-methoxybenzyloxy)-3-(2-oxo-2-phenylethyl)-3- separated. The organic layer was washed with H2O and brine,
trifluoromethylisoindolin-1-one (26)
dried over Na2SO4, filtered, and evaporated under reduced
According to the procedure described for the preparation of pressure. The residue was purified with flash column chroma-
the phenylketone 8 from chloride 2, the chloride 25 (498mg, tography (SiO2, n-hexane–EtOAc=4:1→2:1) to afford 28
1
1.00mmol) was converted into acetophenone 26 (464mg, 80%). (36.8mg, 91%). Pale yellow powder; H-NMR (400MHz, ace-
White powder; 1H-NMR (400MHz, acetone-d6) δ: 8.09 (d, tone-d6) δ: 7.81–8.09 (m, 5H), 7.39–7.66 (m, 3H), 4.20–4.39 (m,
J=7.6Hz, 1H), 7.86 (d, J=8.5Hz, 2H), 7.76 (d, J=7.6Hz, 1H), 2H); 13C-NMR (100MHz, acetone-d6) δ: 193.90, 164.41, 141.69,
7.56 (dd, J=7.6, 7.6Hz, 1H), 7.34–7.46 (m, 5H), 6.86 (d, 137.19, 134.40, 133.50, 129.94, 129.48 (2C), 128.79 (2C), 128.06
J=8.5Hz, 2H), 5.27 (d, J=9.4Hz, 1H), 5.03 (d, J=9.4Hz, 1H), (q, J=5.6Hz), 127.73, 127.43, 125.44 (q, J=284.7Hz), 123.74 (q,
4.24 (s, 1H), 4.23 (s, 1H), 3.73 (s, 3H); 13C-NMR (100MHz, ac- J=273.4Hz), 67.93 (q, J=28.2Hz), 34.68; 19F-NMR (368MHz,
etone-d6) δ: 193.71, 167.72, 161.04, 142.37, 142.15, 137.05, acetone-d6) δ: −60.74 (3F), −77.48 (3F); IR (KBr, cm−1) ν:
134.86, 134.33, 134.95, 131.95 (2C), 129.39 (2C), 128.73 (2C), 3422, 3187, 2926, 1720, 1691, 1598, 1327, 1279, 1172, 814, 688;
127.99 (q, J=217.1Hz), 127.80, 123.77, 114.51 (2C), 90.18, 79.49, LR-MS (ESI): m/z 426 [M+Na]+; HR-MS (ESI): m/z Calcd for
66.83 (q, J=29.1Hz), 55.44, 35.03; 19F-NMR (368MHz, ace- C18H11F6NO3Na [M+Na]+ 426.0535. Found 426.0531.
tone-d6) δ: −76.93 (s, 3F); IR (KBr, cm−1) ν: 3436, 3066, 2998,
2955, 2836, 1730, 1695, 1611, 1517, 1259, 1195, 1156, 1002, 822,
688; LR-MS (ESI): m/z 604 [M+Na]+; HR-MS (ESI): m/z Calcd
for C25H19F3INO4Na [M+Na]+ 604.0203. Found 604.0228.

Vol. 64, No. 7 (2016)
Chem. Pharm. Bull.
749
4,5,6,7-Tetrafluoro-2-(4-methoxybenzyloxy)isoindoline-1,3- CH2Cl2. The organic layer was washed with H2O and brine,
dione (30) dried over Na2SO4, filtered, and evaporated under reduced
To a solution of phthalimide 29 (1.51g, 6.42mmol), 4-me- pressure. The residue was purified with flash column chroma-
thoxylbenzylalcohol (1.06g, 7.70mmol) and PPh3 (2.02g, tography (SiO2, n-hexane–EtOAc=9:1) to afford ether 32
1
7.70mmol) in tetrahydrofuran (THF) (13mL), diisopropyl (100mg, 54%). White powder; H-NMR (400MHz, CDCl3) δ:
azodicarboxylate in toluene (4.05mL, 7.70mmol) was added at 7.43 (d, J=9.0Hz, 2H), 6.90 (d, J=9.0Hz, 2H), 5.18 (d,
0°C, and the reaction mixture was stirred for 1h at 0°C and J=9.9Hz, 1H), 5.05 (d, J=9.9Hz, 1H), 3.80 (s, 3H), 3.12 (s,
for 12h at rt. The reaction mixture was evaporated under re- 3H); 13C-NMR (100MHz, CDCl3) δ: 160.35, 159.91, 144.58
duced pressure. The residue was triturated with EtOAc to af- (dddd, J=264.0, 14.1, 14.1, 1.9Hz), 144.13 (ddd, J=266.9, 12.2,
ford benzylether 30 (1.40g, 61%). Pale yellow powder; 1.9Hz), 141.82–144.94 (m, 2C), 131.28 (2C), 126.18, 121.29 (q,
1H-NMR (400MHz, acetone-d6) δ: 7.47 (d, J=8.5Hz, 2H), J=286.6Hz), 115.81 (dd, J=13.2, 2.8Hz), 113.89 (2C), 113.48
6.95 (d, J=8.5Hz, 2H), 5.13 (s, 2H), 3.81 (s, 3H); 13C-NMR (q, J=12.2, 2.8Hz), 91.40 (q, J=35.7Hz), 79.21, 55.26, 52.16;
(125MHz, DMSO-d6) δ: 160.04, 158.19 (2C), 143.09–145.45 19F-NMR (368MHz, CDCl3) δ: −77.21 (3F), −136.30 (1F),
(m, 2C), 141.49–143.79 (m, 2C), 131.63 (2C), 125.80, 113.92 −137.66 (1F), −143.80 (1F), 146.03 (1F); IR (KBr, cm−1) ν:
(2C), 111.11 (d, J=8.4Hz, 2C), 79.33, 55.19; 19F-NMR 3503, 2959, 2846, 1766, 1613, 1505, 1391, 1206, 1029, 914, 733;
(368MHz, acetone-d6) δ: −139.54 (s, 2F), −146.37 (s, 2F); IR LR-MS (ESI): m/z 462 [M+Na]+; HR-MS (ESI): m/z Calcd for
(KBr, cm−1) ν: 3513, 3039, 2984, 2850, 1736, 1610, 1499, 1406, C18H12F7NO4Na [M+Na]+ 462.0547. Found 462.0558.
1254, 1154, 942, 860, 733; LR-MS (ESI): m/z 378 [M+Na]+;
HR-MS (ESI): m/z Calcd for C16H9F4NO4Na [M+Na]+
378.0360. Found 378.0345.
4,5,6,7-Tetrafluoro-2-hydroxy-3-methoxy-3-trifluoromethyl-
isoindolin-1-one (34)
According to the procedure described for the preparation of
N-oxyl 28 from PMBether 27, PMBether 32 (30.0mg,
4,5,6,7-Tetrafluoro-3-hydroxy-2-(4-methoxybenzyloxy)-3- 0.0591mmol) was converted into 34 (1.3mg, 6%). White pow-
1
trifluoromethylisoindolin-1-one (31)
der; H-NMR (400MHz, acetone-d6) δ: 3.31 (s, 3H); 13C-NMR
According to the procedure described for the preparation of (100MHz, acetone-d6) δ: 159.39, 142.83–146.66 (m, 4C),
alcohol 14a and b from phthalimide 13, the phthalimide 30 122.64 (q, J=287.5Hz), 116.57 (d, J=11.3Hz), 114.91 (d,
(1.29g, 3.63mmol) was converted into alcohol 31 (1.43g, J=10.3Hz), 91.71 (q, J=32.0Hz), 52.52; 19F-NMR (368MHz,
1
93%). White powder; H-NMR (400MHz, acetone-d6) δ: 7.46 acetone-d6) δ: −78.04 (s, 3F), −139.84 (s, 1F), −142.44 (s, 1F),
(d, J=8.5Hz, 2H), 6.96 (d, J=8.5Hz, 2H), 5.22 (d, J=9.4Hz, −148.50 (s, 1F), −150.57 (s, 1F); IR (KBr, cm−1) ν: 3434,
1H), 5.12 (d, J=9.4Hz, 1H), 3.81 (s, 3H); 13C-NMR (125MHz, 2935, 1735, 1508, 1198, 1109, 918, 803, 731; LR-MS (ESI): m/z
acetone-d6) δ: 161.32, 159.48, 145.46 (ddd, J=259.1, 15.6, 318 [M−H]−; HR-MS (ESI): m/z Calcd for C10H3F7NO3
15.6Hz), 144.65 (dd, J=260.3, 12.0Hz), 144.62 (dd, J=260.3, [M−H]− 318.0007. Found 318.0021.
12.0Hz), 143.97 (ddd, J=257.9, 13.2, 13.2Hz), 132.17 (2C),
127.47, 123.13 (q, J=286.7Hz), 120.29 (d, J=13.2Hz), 114.60
(2C), 113.67 (d, J=12.0Hz), 87.65 (q, J=34.8Hz), 80.75, 55.54;
19F-NMR (368MHz, acetone-d6) δ: −79.03 (s, 3F), −139.73 (s,
1F), −142.66 (s, 1F), −148.13 (s, 1F), −150.75 (s, 1F); IR
(KBr, cm−1) ν: 3255, 3010, 2970, 2943, 2843, 1560, 1613, 1519,
1254, 1181, 978, 904, 823, 730; LR-MS (ESI): m/z 448
[M+Na]+; HR-MS (ESI): m/z Calcd for C17H10F7NO4Na
[M+Na]+ 448.0390. Found 448.0368.
4,5,6,7-Tetrafluoro-2-(4-methoxybenzyloxy)-3-(2,2,2-
trifluoroethoxy)-3-trifluoromethylisoindolin-1-one (33)
According to the procedure described for the preparation
of ether 32 from alcohol 31 in which 2,2,2-trifluoroenthanol
was used as the alcohol instead, alcohol 31 (1.00g, 2.35mmol)
was converted into ether 33 (0.593g, 50%). White powder;
1H-NMR (400MHz, acetone-d6) δ: 7.47 (d, J=8.5Hz, 2H), 6.98
(d, J=8.5Hz, 2H), 5.20 (s, 2H), 4.17–4.30 (m, 1H), 4.05–4.17
(m, 1H), 3.82 (s, 3H); 13C-NMR (100MHz, DMSO-d6) δ:
4,5,6,7-Tetrafluoro-3-methoxy-2-(4-methoxybenzyloxy)-3- 160.04, 159.39, 141.90–146.29 (m, 4C), 131.16 (2C), 128.59
trifluoromethylisoindolin-1-one (32) (d, J=195.4Hz), 125.93, 123.38 (q, J=279.2Hz), 120.93 (q,
To a solution of Ms2O (110mg, 0.635mmol) in CH2Cl2 J=286.6Hz), 114.04 (2C), 113.20 (ddd, J=78.0, 12.2, 2.8Hz),
(1.0mL), a solution of alcohol 31 (180mg, 0.423mmol) and 90.24 (q, J=34.8Hz), 79.36, 61.87 (q, J=35.7Hz), 55.18;
Et3N (94µL, 0.677mmol) in CH2Cl2 (1.0mL) was added at 19F-NMR (368MHz, acetone-d6) δ: −74.48 (s, 3F), −77.29
−78°C, and the mixture was stirred for 0.5h at the same tem- (s, 3F), −137.71 (s, 1F), −140.71 (s, 1F), −145.83 (s, 1F),
perature. To the mixture, MeOH (2.0mL) was added, and the −149.04 (s, 1F); IR (KBr, cm−1) ν: 3435, 2967, 2851, 1750,
mixture was stirred for 0.5h at −78°C, then for 18h at rt. H2O 1615, 1516, 1290, 1175, 1032, 997, 917, 731; LR-MS (ESI): m/z
was added to the mixture and the whole was extracted with 530 [M+Na]+; HR-MS (ESI): m/z Calcd for C19H11F10NO4Na

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Chem. Pharm. Bull.
Vol. 64, No. 7 (2016)
[M+Na]+ 530.0421. Found 530.0434.
3-(4-Fluorophenyl)propyl Benzoate (36d)
According to the procedure C, 3-(4-fluorophenyl)-1-propa-
nol 42d (1.34g, 8.89mmol) was converted into benzoate 36d
(1.97g, 86%). Colorless oil; 1H-NMR (500MHz, CDCl3) δ:
8.01 (dd, J=7.5. 1.2Hz, 2H), 7.55 (dd, J=7.5, 7.5Hz, 1H), 7.43
(dd, J=7.5, 7.5Hz, 2H), 7.15 (dd, J=8.6, 5.3Hz, 2H), 6.96 (dd,
J=10.9, 10.9Hz, 2H), 4.32 (t, J=6.9Hz, 2H), 2.75 (t, J=8.1Hz,
2H), 2.06 (tt, J=7.5, 6.9Hz, 2H); 13C-NMR (100MHz, CDCl3)
4,5,6,7-Tetrafluoro-2-hydroxy-3-(2,2,2-trifluoroethoxy)-3- δ: 166.33, 161.19 (d, J=243.4Hz), 136.63 (d, J=14.3Hz),
trifluoromethylisoindolin-1-one (35)
132.76, 129.86 (d, J=55.4Hz), 129.51 (d, J=28.2Hz), 128.20,
According to the procedure with that described for the 115.12, 114.91, 63.90, 31.31, 30.21; 19F-NMR (368MHz, CDCl3)
preparation of 28 from PMBether 27, PMBether 33 (53.0mg, δ: −117.79 (s, 1F); IR (neat, cm−1) ν: 3421, 1717, 1644, 1509,
0.104mmol) was converted into 35 (26.8mg, 67%). White 1274, 1221, 1116, 711; LR-MS (ESI): m/z 281 [M+Na]+;
powder; 1H-NMR (400MHz, acetone-d6) δ: 4.17–4.29 (m, HR-MS (ESI): m/z Calcd for C16H15FO2Na [M+Na]+ 281.0948.
1H), 4.00–4.11 (m, 1H); 13C-NMR (100MHz, acetone-d6) δ: Found 281.0960.
159.46, 145.78 (ddd, J=259.3, 13.9, 13.9Hz), 143.23–146.48 (m,
3C), 124.29 (q, J=275.3Hz), 122.29 (q, J=284.8Hz), 115.64
(d, J=11.2Hz), 114.82 (q, J=12.2Hz), 91.09 (q, J=34.8Hz),
62.76 (q, J=36.6Hz); 19F-NMR (368MHz, acetone-d6) δ:
−74.77 (s, 3F), −77.64 (s, 3F), −138.55 (s, 1F), −141.89 (s,
1F), −147.54 (s, 1F), −149.86 (s, 1F); IR (KBr, cm−1) ν: 3425,
3-(4-Trifluoromethylphenyl)propyl Benzoate (36e)
According to the procedure C, 3-(4-trifluoromethylphenyl)-
3126, 2926, 1722, 1519, 1502, 1410, 1297, 1173, 927, 807, 733;
LR-MS (ESI): m/z 386 [M−H]−; HR-MS (ESI): m/z Calcd for 1-propanol 42e (1.59g, 7.79mmol) was converted into ben-
C11H2F10NO3 [M−H]– 385.9880. Found 385.9882.
zoate 36e (1.99g, 83%). Colorless oil; 1H-NMR (500MHz,
Preparation of Substrates for Aerobic Benzylic C–H CDCl3) δ: 7.98 (d, J=8.1Hz, 2H), 7.51–7.58 (m, 3H), 7.43 (dd,
Oxidation Full spectroscopic data were described for new J=7.5, 7.5Hz, 2H), 7.31 (d, J=8.0Hz, 2H), 4.33 (t, J=6.3Hz,
compounds. Compound 36a,35) b,36) g,37) h,38) j,39) and k40) 2H), 2.84 (t, J=7.5Hz, 2H), 2.11 (tt, J=6.9, 6.9Hz, 2H);
were prepared following the reported procedures.
13C-NMR (100MHz, CDCl3) δ: 166.28, 145.26, 132.78, 130.04,
General Procedure for Benzoate from Alcohol 129.32 (2C), 128.58 (2C), 128.18, 128.17 (q, J=32.0Hz, 2C),
(Procedure C)
125.17 (q, J=3.8Hz, 2C), 124.21 (q, J=271.6Hz), 63.83, 32.05,
29.75; 19F-NMR (368MHz, CDCl3) δ: −62.69 (s, 3F); IR (neat,
cm−1) ν: 3431, 1643, 1327, 1274, 1118, 1067, 708; LR-MS (ESI):
m/z 331 [M+Na]+; HR-MS (ESI): m/z Calcd for C17H15F3O2Na
[M+Na]+ 331.0916. Found 331.0908.
Aerobic Benzylic C–H Oxidation, Etherification, and
Acetamidation Full spectroscopic data were described for
3-(4-Methoxyphenyl)propyl Benzoate (36c)
To
a
solution of 3-(4-methoxyphenyl)-1-propanol 42c new compounds. Compound 37b,41) f,42) g,43) h,44) i,45) j,46) l,47)
(1.66g, 10.0mmol) in CH2Cl2 (20mL), BzCl (1.39mL, m,48) and n49) are known compounds.
12.0mol) and pyridine (1.93mL, 24.0 mmmol) were added at
0°C. The reaction mixture was stirred for 1h at the same tem- (Procedure D)
perature, and for 2h at rt. The mixture was cooled to 0°C, and
sat. NaHCO3 aq. was added. The phases were separated. The
organic layer was washed with H2O, 1N HCl aq., H2O, and
brine, dried over Na2SO4, filtered, and evaporated under re-
duced pressure. The residue was purified with flash column
chromatography (SiO2, n-hexane–EtOAc=19:1→9:1) to afford
General Procedure for the Oxidation of Benzylic C–H
1
benzoate 36c (1.69g, 63%). Colorless oil ; H-NMR (500MHz,
CDCl3) δ: 8.02 (d, J=7.5Hz, 2H), 7.55 (dd, J=7.5, 7.5Hz, 1H),
7.43 (dd, J=7.5, 7.5Hz, 2H), 7.12 (d, J=8.6Hz, 2H), 6.82 (d,
J=8.6Hz, 2H), 4.31 (t, J=7.5Hz, 2H), 3.77 (s, 3H), 2.72 (t,
3-Oxo-3-phenylpropyl 4-trifluoromethylbenzoate (37a)
To a solution of benzoate 36a (72.1mg, 0.300mmol) in 35
J=7.5Hz, 2H), 2.05 (tt, J=7.5, 7.5Hz, 2H); 13C-NMR (5.8mg, 0.015mmol), TFE (0.15mL), Co(OAc)2 (0.53mg,
(100MHz, CDCl3) δ: 166.36, 157.74, 132.99, 132.69, 130.21, 0.00300mmol) and Mn(OAc)3·H2O (0.80mg, 0.00300mmol)
129.36 (2C), 129.15 (2C), 128.16 (2C), 113.69 (2C), 64.06, were added. The reaction mixture was stirred for 48h at 60°C
54.99, 31.18, 30.32; IR (neat, cm−1) ν: 3434, 1716, 1637, 1513, under O2 atmosphere. The mixture was evaporated under re-
1274, 1116, 711; LR-MS (ESI): m/z 293 [M+Na]+; HR-MS duced pressure, and the residue was purified with flash column
(ESI): m/z Calcd for C17H18O3Na [M+Na]+ 293.1148. Found chromatography (SiO2, n-hexane–EtOAc=9:1) to afford ketone
293.1147.
37a (59.8mg, 75%). White powder; 1H-NMR (500MHz,
CDCl3) δ: 8.08 (d, J=8.6Hz, 2H), 7.98 (d, J=8.6Hz, 2H), 7.66
(d, J=8.6Hz, 2H), 7.58 (dd, J=7.4, 7.4Hz, 1H), 7.48 (dd,
J=8.0Hz, 2H), 4.80 (t, J=6.3Hz, 2H), 3.46 (t, J=6.3Hz, 2H);
13C-NMR (125MHz, CDCl3) δ: 196.80, 165.31, 136.49, 134.47

Vol. 64, No. 7 (2016)
Chem. Pharm. Bull.
751
(q, J=32.4Hz, 2C), 133.55, 133.20, 130.01 (2C), 128.76, 128.10
(2C), 125.37 (q, J=4.8Hz, 2C), 123.58 (q, J=273.5Hz), 60.77,
3-(4-Fluorophenyl)-3-oxopropyl Benzoate (37e)
According to the procedure D, benzoate 36e (77.5mg,
37.33; 19F-NMR (368MHz, CDCl3) δ: −63.46 (s, 3F); IR (KBr, 0.300mmol) was converted into ketone 37e (56.7mg, 69%).
cm−1) ν: 3431, 3072, 2979, 1719, 1683, 1324, 1269, 1169, 1100, White powder; H-NMR (400MHz, CDCl3) δ: 7.95–8.04 (m,
1
1064, 958, 866, 741; LR-MS (ESI): m/z 345 [M+Na]+; HR-MS 4H), 7.53 (dd, J=7.2, 7.2Hz, 1H), 7.40 (dd, J=7.6, 7.6Hz, 2H),
(ESI): m/z Calcd for C17H13F3O3Na [M+Na]+ 345.0709. Found 7.13 (dd, J=8.5Hz, 2H), 4.75 (t, J=6.7Hz, 2H), 3.41 (t,
345.0707.
J=6.7Hz, 2H); 13C-NMR (100MHz, CDCl3) δ: 195.43, 166.45,
165.87 (d, J=254.7Hz), 132.99, 130.73 (d, J=9.4Hz, 2C),
129.89, 129.53 (2C), 128.29 (2C), 115.78 (d, J=21.6Hz, 2C),
60.17, 37.39; 19F-NMR (368MHz, CDCl3) δ: −104.88 (s, 1F);
IR (neat, cm−1) ν: 3415, 3072, 2955, 1717, 1677, 1598, 1507,
1332, 1274, 1215, 1120, 976, 850, 713; LR-MS (ESI): m/z 295
[M+Na]+; HR-MS (ESI): m/z Calcd for C16H13FO3Na [M+Na]+
295.0741. Found 295.0731.
3-(4-Methoxyphenyl)-3-oxopropyl Benzoate (37c)
According to the procedure D, benzoate 36c (81.1mg,
0.300mmol) was converted into ketone 37c (36.0mg, 42%).
Colorless oil; 1H-NMR (500MHz, CDCl3) δ: 7.93–7.99 (m,
4H), 7.52 (dd, J=7.5, 7.5Hz, 1H), 7.39 (dd, J=7.4, 7.4Hz, 2H),
6.93 (d, J=9.2Hz, 2H), 4.74 (t, J=6.3Hz, 2H), 3.85 (s, 3H),
3.38 (t, J=6.3Hz, 2H); 13C-NMR (100MHz, CDCl3) δ: 195.60,
166.55, 163.71, 132.94 (2C), 130.41, 130.02, 129.74, 129.58
(2C), 128.29 (2C), 113.81 (2C), 60.51, 55.47, 37.16; IR (neat,
Methyl 5-Oxo-5-phenylpentanimidate (37k)
According to the procedure D, benzoate 36k (17.1mg,
cm−1) ν: 3433, 1637, 1508, 1458, 1275, 1174, 1110, 669; LR-MS 0.0894mmol) was converted into ketone 37k (14.3mg, 78%).
(ESI): m/z 307 [M+Na]+; HR-MS (ESI): m/z Calcd for White powder; H-NMR (400MHz, CDCl3) δ: 7.94 (dd, J=9.9,
1
C17H16O4Na [M+Na]+ 307.0941. Found 307.0929.
1.8Hz, 2H), 7.53 (dd, J=9.0, 9.0Hz, 1H), 7.44 (dd, J=7.6Hz,
2H), 3.66 (s, 3H), 3.03 (t, J=7.2Hz, 2H), 2.43 (t, J=7.2Hz,
2H), 2.05 (tt, J=7.2, 7.2Hz, 2H); 13C-NMR (100MHz, CDCl3)
δ: 199.39, 173.72, 136.76, 133.07, 128.58 (2C), 128.00 (2C),
51.57, 37.41, 33.09, 19.29; IR (KBr, cm−1) ν: 3433, 1636, 1563,
1507, 1265, 1101, 664; LR-MS (ESI): m/z 228 [M+Na]+;
HR-MS (ESI): m/z Calcd for C12H15NO2Na [M+Na]+ 228.0995.
Found 228.1002.
3-Oxo-3-(4-trifluoromethylphenyl)propyl Benzoate (37d)
According to the procedure D, benzoate 36d (92.5mg,
0.300mmol) was converted into ketone 37d (42.6mg, 44%).
White powder; 1H-NMR (500MHz, CDCl3) δ: 8.08 (d,
J=8.0Hz, 2H), 7.96 (d, J=6.9Hz, 2H), 7.73 (d, J=8.0Hz, 2H),
7.53 (dd, J=7.5Hz, 1H), 7.39 (dd, J=7.5, 7.5Hz, 2H), 4.77 (t,
J=6.3Hz, 2H), 3.47 (t, J=6.3Hz, 2H); 13C-NMR (125MHz,
CDCl3) δ: 196.16, 166.49, 139.16, 134.71 (q, J=32.4Hz, 2C),
133.11, 129.82, 129.58, 128.46 (2C), 128.36 (2C), 125.81 (q,
J=3.6Hz, 2C), 123.49 (q, J=272.3Hz), 59.96, 37.85; 19F-NMR
3-Phenyl-3-(2,2,2-trifluoroethoxy)propyl Benzoate (38)
To a solution of benzoate 36b (72.1mg, 0.300mmol) in 35
(368MHz, CDCl3) δ: −63.49 (s, 3F); IR (neat, cm−1) ν: 3412, (5.8mg, 0.015mmol), TFE (3.0mL), NBS (106.8mg, 2.0eq)
3078, 2957, 1716, 1685, 1414, 1322, 1273, 1123, 1065, 857, 710; was added. The reaction mixture was stirred for 20h at rt. To
LR-MS (ESI): m/z 345 [M+Na]+; HR-MS (ESI): m/z Calcd for the mixture, 10% Na2S2O3 aq. was added, and the whole was
C17H13F3O3Na [M+Na]+ 345.0709. Found 345.0705.
extracted with EtOAc. The organic layer was washed with
H2O and brine, dried over Na2SO4, filtered, and evaporated
under reduced pressure. The residue was purified with flash
column chromatography (SiO2, n-hexane–EtOAc=97:3→4:1)
to afford ether 38 (37.3mg, 37%). Colorless oil; 1H-NMR
(400MHz, CDCl3) δ: 7.94 (d, J=7.2Hz, 2H), 7.49 (dd, J=7.6,
7.6Hz, 1H), 7.22–7.40 (m, 7H), 4.55 (dd, J=8.5, 5.4Hz, 1H),
4.36–4.45 (m, 1H), 4.24–4.34 (m, 1H), 3.50–3.71 (m, 2H),
2.20–2.31 (m, 1H), 2.01–2.12 (m, 1H); 13C-NMR (100MHz,
CDCl3) δ: 166.41, 139.74, 132.95, 130.17, 129.52 (2C), 128.88

752
Chem. Pharm. Bull.
(2012).
Vol. 64, No. 7 (2016)
(2C), 128.51, 128.35 (2C), 126.61 (2C), 123.99 (q, J=278.1Hz),
80.49, 65.88 (q, J=33.8Hz), 61.45, 37.19; 19F-NMR (368MHz,
CDCl3) δ: −74.33 (s, 3F); IR (neat, cm−1) ν: 3427, 1723, 1634,
1446, 1274, 1117, 1071, 798; LR-MS (ESI): m/z 361 [M+Na]+;
HR-MS (ESI): m/z Calcd for C18H17F3O3Na [M+Na]+ 361.1022.
Found 361.1019.
14) Zhang Q., Chen C., Ma H., Miao H., Zhang W., Sun Z., Xu J., J.
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1747–1754 (2003).
16) Ozawa J., Tashiro M., Ni J., Oisaki K., Kanai M., Chem. Sci., 7,
1904–1909 (2016).
17) Prakash G. K. S., Yudin A. K., Chem. Rev., 97, 757–786 (1997).
18) Regioisomers 14a and b, obtained after the trifluoromethylation of
13, were characterized by the conversion of 14b into 41, whose
structure was determined by nuclear Overhauser effect (NOE) anal-
ysis. The structure of 14a was subsequently deduced from the struc-
ture of 14b.
3-Acetamido-3-phenylpropyl Benzoate (39)
To a solution of benzoate 36b (72.1mg, 0.300mmol) 35
(5.8mg, 0.015mmol) in CH3CN (3.0mL), NBS (106.8mg,
2.0eq) was added. The reaction mixture was stirred for 24h
at rt. To the mixture, 10% Na2S2O3 aq. was added, and the 19) Tomashenko O. A., Escudero-Adán E. C., Martínez Belmonte M.,
Grushin V. V., Angew. Chem. Int. Ed., 50, 7655–7659 (2011).
20) Jacq J., Berthiol F., Einhorn C., Einhorn J., Synlett, 15, 2263–2266
whole was extracted with EtOAc. The organic layer was
washed with H2O and brine, dried over Na2SO4, filtered, and
evaporated under reduced pressure. The residue was purified
(2010).
21) Yoshino H., Tsuchiya Y., Saito I., Tsujii M., Chem. Pharm. Bull., 35,
with preparative TLC (SiO2, n-hexane–EtOAc=4:1) to afford
3438–3441 (1987).
1
ether 39 (38.9mg, 44%). White powder; H-NMR (500MHz,
22) Coe P. L., Croll B. T., Patrick C. R., Tetrahedron, 23, 505–508
(1967).
23) Sonobe T., Oisaki T., Kanai M., Chem. Sci., 3, 3249–3255 (2012).
24) Seki Y., Tanabe K., Sasaki D., Sohma Y., Oisaki K., Kanai M.,
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2193–2198 (2015).
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CDCl3) δ: 7.96 (d, J=8.6Hz, 2H), 7.54 (dd, J=8.1, 8.1Hz, 1H),
7.38–7.44 (m, 2H), 7.22–7.35 (m, 5H), 5.97 (brs, 1H), 5.19 (td,
J=8.0, 8.0Hz, 1H), 4.29 (t, J=6.3Hz, 2H), 2.18–2.36 (m, 2H),
1.96 (s, 3H); 13C-NMR (100MHz, CDCl3) δ: 169.29, 166.45,
141.13, 133.02, 129.53 (2C), 128.88 (2C), 128.37 (2C), 128.25,
127.70, 126.51 (2C), 61.99, 51.05, 34.86, 23.41; IR (KBr, cm−1)
ν: 3277, 3075, 1718, 1653, 1558, 1271, 1115, 714; LR-MS (ESI):
m/z 320 [M+Na]+; HR-MS (ESI): m/z Calcd for C18H19NO3Na
[M+Na]+ 320.1257. Found 320.1254.
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Conflict of Interest The authors declare no conflict of
interest.
29) When 1 was used as the catalyst instead of 35, 82% (1
H-NMR
yield) and 54% (1H-NMR yield) were observed for the trifluoro-
etherification and the acetoamidation, respectively.
30) Michaudel Q., Thevenet D., Baran P. S., J. Am. Chem. Soc., 134,
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