Expeditious synthesis of carboxylic esters and high-yielding macrolactones using trifluoromethyl-substituted benzoic anhydrides with 4-(dimethylamino)pyridine: An evaluation of the reactivities of aromatic acid anhydrides as dehydration reagents compared with 2-methyl-6-nitrobenzoic anhydride

Article abstract of DOI:10.3987/COM-16-13583

Trifluoromethyl-substituted benzoic anhydrides as structural congeners of 2-methyl-6-nitrobenzoic anhydride (MNBA) were prepared and investigated for comparative reactivity in the synthesis of carboxylic esters and macrolactones. 2-Fluoro-6-(trifluoromethyl)benzoic anhydride (FTFBA) was found to be a promising dehydrating agent in the presence of 4-(dimethylamino)pyridine (DMAP), and was successfully employed in the synthesis of threo-aleuritic acid lactone in good yield with high chemoselectivity.

Full text of DOI:10.3987/COM-16-13583

HETEROCYCLES, Vol. 94, No. 2, 2017
255
HETEROCYCLES, Vol. 94, No. 2, 2017, pp. 255 - 275. © The Japan Institute of Heterocyclic Chemistry
Received, 22nd September, 2016, Accepted, 11th January, 2017, Published online, 30th January, 2017
DOI: 10.3987/COM-16-13583
EXPEDITIOUS SYNTHESIS OF CARBOXYLIC ESTERS AND
HIGH-YIELDING
TRIFLUOROMETHYL-SUBSTITUTED BENZOIC ANHYDRIDES WITH
-(DIMETHYLAMINO)PYRIDINE: AN EVALUATION OF THE
MACROLACTONES
USING
4
REACTIVITIES
DEHYDRATION
OF
AROMATIC
REAGENTS
ACID
ANHYDRIDES
AS
COMPARED
WITH
2
-METHYL-6-NITROBENZOIC ANHYDRIDE
Isamu Shiina* and Takayuki Tonoi
Department of Applied Chemistry, Faculty of Science, Tokyo University of
Science, 1-3 Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan
Abstract – Trifluoromethyl-substituted benzoic anhydrides as structural
congeners of 2-methyl-6-nitrobenzoic anhydride (MNBA) were prepared and
investigated for comparative reactivity in the synthesis of carboxylic esters and
macrolactones. 2-Fluoro-6-(trifluoromethyl)benzoic anhydride (FTFBA) was
found to be
-(dimethylamino)pyridine (DMAP), and was successfully employed in the
synthesis of threo-aleuritic acid lactone in good yield with high chemoselectivity.
a
promising dehydrating agent in the presence of
4
INTRODUCTION
Synthesis of carboxylic esters and lactones is a fundamental and important process for obtaining natural
1
products or useful artificial compounds in organic chemistry. Coupling reactions between activated
derivatives of carboxylic acids and alcohols were employed to perform high yielding esterification
2
reactions with equimolar amounts of carboxylic acids and alcohols under mild conditions. In 2002, we
first developed a highly useful condensation reaction for the synthesis of carboxylic esters from nearly
equimolar amounts of carboxylic acids and alcohols using 2-methyl-6-nitrobenzoic anhydride (MNBA)
as the dehydrating reagent and by adding a catalytic amount of 4-(dimethylamino)pyridine (DMAP) or
3
4
-(dimethylamino)pyridine N-oxide (DMAPO) in the presence of triethylamine (Scheme 1).

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HETEROCYCLES, Vol. 94, No. 2, 2017
Scheme 1. Efficient dehydration condensation reaction using MNBA, as developed by Shiina (2002)
This highly efficient condensation reaction proceeds smoothly at room temperature; therefore, it has been
adapted into a convenient and powerful method for the synthesis of a variety of macrolactones with high
product selectivities via the mixed anhydride formation generated from the corresponding
ω-hydroxycarboxylic acids (seco acids) using MNBA with nucleophilic catalysts. A variety of lactones
and related compounds were successfully prepared in high yields by this method using MNBA in the
4
presence of DMAP or DMAPO (Scheme 2).
O2 O2
N
N
O
O
Me
O
O
Me
BnO
OH
OBn O
O
(1.3 eq.)
TBDPSO
OH
OTBDPS
catalyst (10 mol%)
H
Et N (6.0 eq.)
3
CH Cl (2 mM)
catalyst = DMAP; 89%
DMAPO; 90%
2
2
rt, 13 h
O
HO
O
H
O
OH
O
octalactin A
Scheme 2. High-yielding lactonization using MNBA, as developed by Shiina (2002)

HETEROCYCLES, Vol. 94, No. 2, 2017
257
One advantage of this procedure is its simplicity; the addition of seco acids to the mixture of MNBA and
promoters at a suitable temperature affords the desired macrolactones in excellent yields with high purity.
After the establishment of this novel strategy, various efficient lactonizations of structurally complicated
5
seco acids using MNBA with DMAP were reported in the total synthesis of natural products (Scheme 3).
O2 O2
N
N
O
Me
O
O
Me
OTBS
(1.2 eq.)
OH
O
OTBS
DMAP (2.4 eq.)
OH
O
O
CH Cl (1 mM), rt
2
2
slow addition (16 h)
4%
8
HF Py
O
THF, 0 °C
OH
O
patulolide C
99%
Scheme 3. Total synthesis of patulolide C using MNBA, as reported by Shibasaki (2003)
In this study, we report a complementary method using trifluoromethyl-substituted benzoic anhydrides
for the MNBA-mediated dehydration condensation reactions in order to expand our mixed anhydride
formation technology, wherein we prove that 2-fluoro-6-(trifluoromethyl)benzoic anhydride (FTFBA)
accelerates reactions effectively to afford the desired esters or lactones in high yields and with high
product selectivities from the corresponding carboxylic acids with alcohols or seco acids.
RESULTS AND DISCUSSION
4
i
The esterification of 3-phenylpropanoic acid with 3-phenylpropanol was performed as a probe reaction
for comparing the reactivity of different substitution patterns of trifluoromethyl-group-bearing benzoic
anhydrides. First, the patterns of non-ortho-substituted (i.e., 3,4- or 3,5-disubstituted) benzoic anhydrides
were examined in the presence of a catalytic amount of DMAP (10 mol%) and an excess amount of
triethylamine (Et
3
N) (2.2 equiv.) as an auxiliary base in dichloromethane at room temperature, and the
results are shown in Table 1. When a combination of the trifluoromethyl group and halogens was used as
2
b,6
the substituent, a corresponding ester 3-phenylpropyl 3-phenylpropanoate (A)
was obtained in good
yield (entries 1–3) but with a substantially lower chemoselectivity than that obtained with MNBA (cf.
entry 9). When a nitro group was used instead of the halogens, the reactions stalled at ca. 60% yield
(entries 6–8). The chemoselectivities were not improved when non-ortho-substituted benzoic anhydrides
were used.

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HETEROCYCLES, Vol. 94, No. 2, 2017
Table 1. Esterification using 3,4- or 3,5-disubstituted benzoic anhydrides
X
X
Y
Z
Y
Z
O
X
Y
O
O
R1 OH
O
(1.2 eq.)
R1 OR2
OR2
2
+
R OH
+ Z
DMAP
(10 mol%)
Et N (2.2 eq.)
CH Cl , rt, 4 h
2 2
O
A
O
(1.2 eq.)
(1.0 eq.)
B
3
1
R = Ph(CH )
2
2
3
2
R = Ph(CH )
2
Yield of A / %a
A/Bb
63/1
32/1
16/1
−
Entry
X,Y,Z
1
2
3
4
5
6
7
8
9
4-F-3-CF
4-Cl-3-CF
3-F-4-CF
3-F-5-CF
3-Br-5-CF
3
3
3
3
3
3
(2)
81
(3)
(4)
(5)
(6)
(7)
(8)
(9)
88
80
Not availablec
Not availablec
−
4-NO
5-NO
3-NO
2-Me-6-NO
-3-CF
-3-CF
60
61
62
98
67/1
69/1
37/1
>500/1
2
2
3
3
-4-CF
2
(MNBA) (1)
2
a
c
Isolated yield b Determined by 1H NMR using a crude mixture.
These benzoic anhydrides, which were not obtained in pure form, were unavailable for the reaction.
Next, disubstituted benzoic anhydrides with a fluorine atom at the ortho-position on each aromatic ring
were investigated (Table 2). When a trifluoromethyl group as an additional substituent was present at the
meta- or para-position on the aromatic rings, the chemoselectivities were found to be insufficient but
moderate-to-good yields were obtained (entries 1−4).
Table 2. Esterification using ortho-substituted (2-F) benzoic anhydrides

HETEROCYCLES, Vol. 94, No. 2, 2017
259
The following two structural modifications of the substituted benzoic anhydrides are assumed to have
3
a,c
positive effects on dehydration condensation : (i) an electron-withdrawing group, such as a nitro group,
on the aromatic ring increases the electrophilicity of the carboxyl group, and (ii) a bulky substituent, such
as a methyl group, at the ortho-position on the aromatic ring providing a hindrance near the carboxyl
group improves the chemoselectivity toward the desired ester. However, when a nitro or a methyl group,
which is one of the components of ortho-substituted groups of MNBA, was introduced at the
ortho-position instead of a fluorine atom, it was not sufficient to afford the desired ester with a high
chemoselectivity equivalent to that achieved with MNBA (Table 3, entries 2 and 3 vs. entry 4).
Table 3. Esterification using mono-ortho-substituted (2-Cl, 2-NO , and 2-Me) benzoic anhydrides
2
We further screened disubstituted benzoic anhydrides bearing a trifluoromethyl group at the
ortho-position on each aromatic ring in order to improve both yield and chemoselectivity toward the
desired ester (Table 4). When an additional substituent such as a fluorine or chlorine atom or a nitro
group was introduced at the meta- or para-positions on the aromatic ring, a reduction in the
chemoselectivities was observed (entries 2−5). We then introduced the substituents at the ortho-,
ortho’-positions on the aromatic rings; it was found that the combination of a fluorine atom and a
trifluoromethyl group or a methyl and trifluoromethyl group afforded the desired products in high yields
with high chemoselectivities (entries 6 and 7), whereas ortho-disubstituted benzoic anhydrides with two
trifluoromethyl groups exhibited a lower reactivity than that achieved by the above two combinations
because of the overcharged steric hindrance around the carboxyl group of the aromatic acid anhydride
(entry 8).

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HETEROCYCLES, Vol. 94, No. 2, 2017
Table 4. Esterification using ortho-substituted (2-CF ) benzoic anhydrides
3
Thus, three trifluoromethyl-substituted benzoic anhydrides, FTFBA, 2-methyl-6-(trifluoromethyl)benzoic
anhydride (MTFBA), and 2,6-bis(trifluoromethyl)benzoic anhydride (2,6-BTFBA), were found to be
promising dehydrating agents in the presence of DMAP.
We further examined in detail the product yields and chemoselectivities in the esterification reaction of
3
-phenylpropanoic acid with 3-phenylpropanol using these three dehydrating agents for a prolonged
reaction time in order to compare their reactivities with time. The results obtained are shown in Table 5.
When FTFBA was employed with a catalytic amount of DMAP (10 mol%), the reaction proceeded
rapidly for 1 h to afford the desired ester A in high yield (entry 1, 86%) and with high chemoselectivity
(A/B = 302/1). In contrast, in the case of MTFBA and 2,6-BTFBA, the reaction proceeded sluggishly in
the initial stage (for 1−4 h, entries 5–6 and 9–10) and the product yields gradually increased (for 24 h,
entries 7–8 and 11–12) to the same level as that achieved with MNBA (entries 13−16) while maintaining
high chemoselectivities. We then focused on the reactivity of the corresponding aromatic acid chlorides
as dehydrating agents in the esterification reaction using the same method as that employed for
substituted benzoic anhydrides. The reaction was performed using 2-fluoro-6-(trifluoromethyl)benzoyl
chloride
,6-bis(trifluoromethyl)benzoyl chloride (2,6-BTFBC) under identical conditions as those used for the
reactions reported in Table 5; the results are shown in Table 6. FTFBC exhibited excellent reactivity in
(FTFBC),
2-methyl-6-(trifluoromethyl)benzoyl
chloride
(MTFBC),
and
2

HETEROCYCLES, Vol. 94, No. 2, 2017
261
the esterification to give the desired coupling product in high yields with high chemoselectivities within 1
h (entry 1), and these results were maintained for prolonged reaction times (entries 2−4). MTFBC showed
the same level of reactivity and chemoselectivity as that shown by FTFBC (entries 6−8); however, a
certain level of reduction in the product yield was observed as compared to that obtained using FTFBC in
the initial stage of the reaction (entry 5). On employing 2,6-BTFBC, the reactivity in the initial reaction
stage was observed to be significantly suppressed (entry 9, 64%), but the product yields gradually
increased up to 90% (entries 10−12). In addition, 2-methyl-6-nitrobenzoyl chloride (MNBC) exhibited
high reactivity in the intermolecular coupling reaction to provide the desired ester A with high
chemoselectivity (entries 13−16).
Table 5. Reactivity of aromatic acid anhydrides with DMAP

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HETEROCYCLES, Vol. 94, No. 2, 2017
Table 6. Reactivity of aromatic acid chlorides with DMAP
The results obtained using aromatic acid anhydrides or aromatic acid chlorides in the presence of DMAP
are plotted on graphs, as shown in Figure 1. FTFBA is observed to have the same level of reactivity as
that of MNBA, whereas MTFBA and 2,6-BTFBA exhibit lower reactivities in the initial reaction stage,
probably because of the steric hindrance near the carbonyl group imparted by the additional substituent,
such as a methyl or trifluoromethyl group, at the ortho-position on the aromatic ring of the acid
anhydrides. Aromatic acid chlorides, such as MNBC, are found effective for the synthesis of carboxylic
esters because of rapid formation of the reactive mixed anhydride intermediate obtained by the extraction
of hydrogen chloride from acid chlorides with carboxylic acid in the presence of DMAP and Et N.
3
Figure 1. Time courses of product yields in the esterification using substituted benzoic anhydrides (left)
or substituted benzoyl chlorides (right) with DMAP.

HETEROCYCLES, Vol. 94, No. 2, 2017
263
7
The proposed mechanism for esterification is depicted in Figure 2. The formation of a pyridinium salt
(INT-1) of the substituted benzoic acid with DMAP proceeds first (STEP 1), followed by the formation of
mixed anhydride (MA) through the reaction of carboxylic acid with INT-1 (STEP 2). Next, the
chemoselective nucleophilic substitution of DMAP with MA takes place to afford the pyridinium salt
(STEP 3, INT-2), followed by the generation of the desired ester by a nucleophilic attack of the substrate
alcohol with INT-2 via the transition state shown (STEP 4, TS). Finally, regeneration of DMAP as a free
nucleophile occurs to complete its catalytic cycle (STEP 5). All the steps in this procedure are reversible
except that of the ester formation via the TS. When substituted benzoyl chlorides are used instead of
substituted benzoic anhydrides, the formation of INT-1 proceeds faster because of the higher
electrophilicity of acid chlorides; therefore, it is postulated that product yields in the initial stage of
intermolecular coupling reactions are generally higher when substituted benzoyl chlorides are used.
Et NH
3
F3C
F
Et
3
N
2-F-6-CF C H CO
F3 F3
3
6
3
2
C
C
Ralkyl
O
Raliphatic
O
H
O
H
O
DMAP
O
N
F
O
O
F
CF3
Cl
or
NMe2
STEP 5
STEP 1
F
O
X
NMe2
F3C
F
F3
C
O
H
O
N
H
O
F
O
Me N
2
Ralkyl
INT-1
N
Raliphatic
X = 2-F-6-CF C H CO or Cl
3
6
3
2
O
TS
STEP 4
STEP 3
STEP 2
F3C
F
HO
Raliphatic
O
N
O
O
Me N
CF3
O
2
Raliphatic
Raliphatic
Ralkyl
OH
DMAP
+ 2-F-6-CF C H CO H or HCl
3 6 3 2
O
F
O
O
DMAP
INT-2
MA
Figure 2. Proposed reaction mechanism for esterification using substituted benzoic anhydrides or
substituted benzoyl chlorides.

264
HETEROCYCLES, Vol. 94, No. 2, 2017
To further compare the reactivities and chemoselectivities of the selected aromatic acid anhydrides and
4
d
corresponding aromatic acid chlorides, macrolactonization of seco acid 25 prepared from threo-aleuritic
acid by treatment with PhCH(OMe) and 10-camphorsulfonic acid was performed, and the results
2
obtained are summarized in Table 7. FTFBA exhibited high reactivity comparable with that of MNBA in
the macrolactonization to give the desired monomeric lactone 26 in high yield with excellent
chemoselectivity, accompanied with a small amount of a dimerized product 27 (entry 1 cf. entry 7). The
yield and chemoselectivity of the product decreased as the size of the substituent at the ortho-position on
8
each aromatic ring of the substituted benzoic anhydride became larger (entries 3 and 5 cf. entry 1). It is
experimentally determined that a combination of the substituents of FTFBA is suitable for the present
9
lactone synthesis as well as that of the substituents of MNBA. The yields and chemoselectivities
decreased rapidly on employing corresponding substituted benzoyl chlorides (entries 2, 4, 6, and 8),
whereas the use of the substituted benzoic anhydrides afforded higher yields and chemoselectivities
(entries 1, 3, 5, and 7).
Table 7. Synthesis of the protected threo-aleuritic acid lactone 26
Transformation of seco acid into a monomeric lactone requires high strain energy via the TS in an
intramolecular reaction as compared to that required in facilitating an intermolecular ester formation.
When 1.4 mmol of aromatic acid chloride is used as the dehydrating agent in 1 L solvent for lactone

HETEROCYCLES, Vol. 94, No. 2, 2017
265
−
synthesis, the concentration of the substituted benzoic acid anion (ArCO ) must be 1.4 mM; however, the
2
−
concentration of ArCO must be increased to 2.8 mM when using 1.4 mmol of aromatic acid anhydride
2
−
as the dehydrating agent. The lactone formation rate is proportional to the concentration of ArCO
2
, as
shown by the TS in Figure 2. Therefore, higher yields of the desired monomeric lactone 26 are obtained
in the reactions using substituted benzoic anhydrides (entries 1, 3, 5, and 7) compared to those obtained in
the reactions using substituted benzoyl chlorides (entries 2, 4, 6, and 8). Moreover, an enhancement in the
rate of INT-1 production using substituted benzoyl chlorides causes an increase in the concentration of
MA in the reaction system, as depicted in Figure 2. Thus, the chemoselectivity of the desired monomeric
lactone 26 [intramolecular coupling product] over that of the undesired dimer 27 [intermolecular coupling
product] (= 26/27) in the reactions using substituted benzoyl chlorides as the dehydrating agents (entries 2,
4
, 6, 8, and 10) decreases compared with those in the reactions using substituted benzoic anhydrides
(entries 1, 3, 5, 7, and 9).
In summary, we demonstrated the utility of trifluoromethyl-substituted benzoic anhydrides that are
structural congeners of MNBA, such as FTFBA, MTFBA, and 2,6-BTFBA, as promising dehydrating
agents in esterification reactions. The utility of FTFBA was also exhibited by the synthesis of
threo-aleuritic acid lactone in high yield with high product selectivity. The results suggest that this
method of using trifluoromethyl-substituted benzoic anhydrides, which is complementary to
MNBA-mediated dehydration condensation reaction, has enabled us to expand our mixed anhydride
technology. Furthermore, MNBC is found to show fairly high reactivity among the corresponding acid
chlorides in the intermolecular coupling reaction. We are now investigating other applications of these
dehydrating agents for the syntheses of various natural products and valuable complex molecules in our
laboratory.
EXPERIMENTAL
General
All reactions were performed under argon atmosphere in dried glassware unless otherwise noted. Infrared
(IR) spectra were obtained using a Jasco FT/IR-4600 Fourier transform infrared spectrometer. Proton and
1
13
carbon nuclear magnetic resonance ( H and C NMR) spectra were recorded with chloroform (in CDCl )
3
1
13
on the following instruments: JEOL JNM-ECA500 ( H at 500 MHz and C at 125 MHz). Mass spectra
were determined by a Bruker Daltonics micrOTOF focus (ESI-TOF) mass spectrometer. Thin layer
chromatography was performed on Wakogel B5F.

266
HETEROCYCLES, Vol. 94, No. 2, 2017
Starting materials
All reagents were purchased from Tokyo Kasei Kogyo Co., Ltd., Kanto Chemical Co., Inc., Wako Pure
Chemical Industries, Ltd. or Aldrich Chemical Co., Inc. and used without further purification unless
otherwise noted. Dichloromethane was distilled from diphosphorus pentoxide, then calcium hydride, and
dried over MS 4 Å. Triethylamine was also distilled prior to use. Meanwhile, the raw materials for the
synthesis of substituted benzoic anhydrides were purchased as follows. 4-Fluoro-3-
(trifluoromethyl)benzoic acid, 3-fluoro-4-(trifluoromethyl)benzoic acid, 3-fluoro-5-(trifluoromethyl)-
benzoic acid, 5-nitro-3-(trifluoromethyl)benzoic acid, 2-fluoro-3-(trifluoromethyl)benzoic acid, 2-fluoro-
5-(trifluoromethyl)benzoic acid, 2-nitro-4-(trifluoromethyl)benzoic acid, 2- (trifluoromethyl)benzoic acid,
4-fluoro-2-(trifluoromethyl)benzoic acid, 5-fluoro-2-(trifluorzzomethyl)benzoic acid, and 2-fluoro-
6-(trifluoromethyl)benzoic acid were purchased from Tokyo Kasei Kogyo Co., Ltd (TCI). 4-
Nitro-3-(trifluoromethyl)benzoic
acid,
2-fluoro-4-(trifluoromethyl)benzoic
acid,
2-chloro-5-
(trifluoromethyl)benzoic acid, and 4-nitro-2-(trifluoromethyl)benzoic acid were purchased from Aldrich
Chemical Co., Inc. 2,4,5-Trifluoro-3-(trifluoromethyl)benzoic acid, 2-chloro-3-(trifluoromethyl)benzoic
acid, 4-chloro-2-(trifluoromethyl)benzoic acid, and 2,6-bis(trifluoromethyl)benzoic acid were purchased
from Wako Pure Chemical Industries, Ltd. 4-Chloro-3-tri(fluoromethyl)benzoic acid,
3-bromo-5-(trifluoromethyl)benzoic acid, 3-nitro-4-t(rifluoromethyl)benzoic acid, and 3-fluoro-
2-(trifluoromethyl)benzoic acid were purchased from CombiBlocks, Inc. 2-Methyl-
4-(trifluoromethyl)benzoic acid was purchased from Frontier Scientific, Inc., and 2-methyl-
6-(trifluoromethyl)benzoic acid was purchased from CGeneTech, Inc. 2-Fluoro-6-
(trifluoromethyl)benzoyl chloride (FTFBC) (22’) was purchased from Aldrich, and 2,6-
bis(trifluoromethyl)benzoyl chloride (2,6-BTFBC) (24’) was purchased from APOLLO Scientific Ltd.
All benzoic anhydrides were prepared from the corresponding substituted benzoic acids according to the
2
b
3c
reported procedure, whereas MNBA was purchased from TCI (M1439). TCBA was prepared from the
1
1
2b
12
corresponding substituted benzoic acid and TCBC according to the reported procedure. MNBC was
purchased from TCI (M1438). threo-Aleuritic acid was purchased from Fluka Chemical Co., Ltd.
Typical experimental procedure for the esterification reaction
A typical experimental procedure is described for the reaction of 3-phenylpropanoic acid with
3
-phenylpropanol (Table 4, entry 6): To a solution of triethylamine (31 µL, 0.22 mmol) in CH
mL) at rt were added DMAP (1.2 mg, 0.010 mmol), FTFBA (47.8 mg, 0.120 mmol) and
-phenylpropanoic acid (18.0 mg, 0.120 mmol). After stirring for 10 min, a solution of 3-phenylpropanol
13.5 mg, 0.10 mmol) in CH Cl (0.6 mL) was added. After the reaction mixture was stirred for 4 h at rt,
2 2
Cl (0.9
3
(
2
2

HETEROCYCLES, Vol. 94, No. 2, 2017
267
saturated aqueous NH
4
Cl was added at 0 °C. The mixture was extracted with CH
2
Cl
2
, and the organic
layer was washed with water and birne, and dried over Na
evaporation of the solvent, the crude product was purified by thin layer chromatography (hexane/EtOAc
2/1) to afford 3-phenylpropyl 3-phenylpropanoate (23.9 mg, 89.1%).
-Fluoro-3-(trifluoromethyl)benzoic anhydride (2): Mp 89.5−91.0 °C; H NMR (500 MHz, CDCl
2 4
SO . After filtration of the mixture and
=
1
4
3
): δ
1
3
8
.41 (dd, J = 2.3, 6.5 Hz, 2H), 8.37 (ddd, J = 2.3, 4.5, 9.0 Hz, 2H), 7.41 (dd, J = 9.0, 9.0 Hz, 2H); C
): δ 163.6 (d, J = 267.6 Hz), 159.8, 136.6 (d, J = 9.6 Hz), 130.6 (dq, J = 3.8, 3.8
Hz), 124.9 (d, J = 2.4 Hz), 121.7 (q = 273.5 Hz), 119.8 (dq, J = 13.2, 34.4 Hz), 118.2 (d, J = 21.6 Hz);
NMR (125 MHz, CDCl
3
+
－1
HRMS (ESI-TOF): [M+Na ] calcd for C16
H
6
F
8
O
3
Na 421.0087, found 421.0081; IR (cm ): 1792, 1729.
1
4
-Chloro-3-(trifluoromethyl)benzoic anhydride (3): Mp 127.5−129.0 °C; H NMR (500 MHz, CDCl
3
):
1
3
δ 8.44 (d, J = 2.3 Hz, 2H), 8.23 (dd, J = 2.3, 8.3 Hz, 2H), 7.73 (d, J = 8.3 Hz, 2H); C NMR (125 MHz,
CDCl ): δ 159.9, 139.6, 134.4, 132.6, 129.7 (q, J = 32.3 Hz), 129.6, 127.2, 122.1 (q, J = 273.5 Hz);
HRMS (ESI-TOF): [M+Na ] calcd for C16
3
+
－1
H
6
Cl
2
F
6
O
3
Na 452.9496, found 452.9494; IR (cm ): 1791,
1
733, 1319.
1
3
-Fluoro-4-(trifluoromethyl)benzoic anhydride (4): Mp 98.0−100.0 °C; H NMR (500 MHz, CDCl
3
): δ
1
3
8
.04 (d, J = 7.5 Hz, 2H), 7.95 (d, J = 9.5 Hz, 2H), 7.83 (dd, J = 7.5, 7.5 Hz, 2H),; C NMR (125 MHz,
): δ 163.8 (d, J = 261.5 Hz), 159.3, 133.7 (d, J = 7.1 Hz), 128.2 (q, J = 3.5 Hz), 126.1 (d, J = 4.8
Hz), 124.2 (dq, J = 13.2, 32.7 Hz), 121.8 (q, J = 273.4 Hz), 118.9 (d, J = 22.6 Hz); HRMS (ESI-TOF):
CDCl
3
+
－1
[
M+Na ] calcd for C16
H
6
F
8
O
3
Na 421.0087, found 421.0086; IR (cm ): 1793, 1733, 1422.
1
4
-Nitro-3-(trifluoromethyl)benzoic anhydride (7): Mp 161.0−162.0 °C; H NMR (500 MHz, CDCl
3
): δ
1
3
8
.60 (d, J = 1.3 Hz, 2H), 8.50 (dd, J = 1.3, 8.5 Hz, 2H), 8.05 (d, J = 8.5 Hz, 2H); C NMR (125 MHz,
CDCl
3
): δ 158.5, 151.5, 135.2, 131.7, 130.2 (q, J =5.9), 125.8, 124.9 (q, J = 23.9), 121.2 (q, J = 274.7
+
－1
Hz); HRMS (ESI-TOF): [M+Na ] calcd for C16
H
6
F
6
N
2
O
7
Na 474.9977, found 474.9960; IR (cm ): 1798,
1
734, 1553.
1
5
-Nitro-3-(trifluoromethyl)benzoic anhydride (8): Mp 165.0−166.0 °C; H NMR (500 MHz, CDCl
3
): δ
1
3
9
3
.14 (s, 2H), 8.85 (s, 2H), 8.72 (s, 2H); C NMR (125 MHz, CDCl ): δ 158.4, 148.9, 133.9 (q, J = 35.9
Hz), 132.6 (q, J = 3.6 Hz), 131.0, 128.3, 126.4 (q, J = 3.6 Hz), 122.1 (q, J = 273.4 Hz); HRMS
+
－1
(
ESI-TOF): [M+Na ] calcd for C16
H
6
F
6
N
2
O
7
Na 474.9977, found 474.9994; IR (cm ): 1795, 1736, 1545,
1
329.
1
3
-Nitro-4-(trifluoromethyl)benzoic anhydride (9): Mp 137.0−139.0 °C; H NMR (500 MHz, CDCl
3
): δ
1
3
8
.58 (s, 2H), 8.48 (d, J = 8.0 Hz, 2H), 8.09 (d, J = 8.0 Hz, 2H); C NMR (125 MHz, CDCl
3
): δ 158.2,

268
HETEROCYCLES, Vol. 94, No. 2, 2017
1
48.7, 134.0, 132.8, 129.3 (q, J = 6.0 Hz), 128.9 (q, J = 34.7 Hz), 126.6, 121.2 (q, J = 274.7 Hz); HRMS
+
－1
(
6 6 2 7
ESI-TOF): [M+Na ] calcd for C16H F N O Na 474.9977, found 474.9962; IR (cm ): 1802, 1740.
1
2
-Fluoro-3-(trifluoromethyl)benzoic anhydride (10): Mp 87.0−89.0 °C; H NMR (500 MHz, CDCl
3
):
1
3
δ 8.29 (dd, J = 6.5, 7.5 Hz, 2H), 7.94 (dd, J = 6.5, 7.5 Hz, 2H), 7.45 (dd, J = 7.5, 7.5 Hz, 2H); C NMR
(125 MHz, CDCl
3
): δ 159.8 (d, J = 272.4 Hz), 157.8, 136.6, 133.3, 124.5 (d, J = 4.8 Hz), 121.9 (q, J =
+
2
73.5 Hz), 120.5 (dq, J = 13.2, 33.6 Hz), 118.5 (d, J = 8.3 Hz); HRMS (ESI-TOF): [M+Na ] calcd for
－
1
16 6 8 3
C H F O Na 421.0087, found 421.0075; IR (cm ): 1798, 1736.
1
2
-Fluoro-4-(trifluoromethyl)benzoic anhydride (11): Mp 65.0−68.0 °C; H NMR (500 MHz, CDCl
3
):
1
3
δ 8.22 (dd, J = 7.3, 7.8 Hz, 2H), 7.59 (d, J = 7.8 Hz, 2H), 7.51 (d, J = 9.5 Hz, 2H); C NMR (125 MHz,
CDCl
3
): δ 162.0 (d, J = 265.2 Hz), 157.9, 137.9 (dq, J = 8.8, 34.0 Hz), 133.8, 122.4 (q, J = 273.6 Hz),
+
1
21.4, 120.1 (d, J = 9.6 Hz), 115.0 (qd, J = 1.1, 57.9 Hz); HRMS (ESI-TOF): [M+Na ] calcd for
－
1
C
16
H
6
F
8
O
3
Na 421.0087, found 421.0081; IR (cm ): 1798, 1729, 1429.
1
2
-Fluoro-5-(trifluoromethyl)benzoic anhydride (12): Mp 97.0−98.0 °C; H NMR (500 MHz, CDCl ):
3
1
3
δ 8.38 (dd, J = 2.0, 6.3 Hz, 2H), 7.94 (ddd, J =2.0, 3.5, 9.0 Hz, 2H), 7.38 (dd, J = 9.0, 9.0 Hz, 2H); C
NMR (125 MHz, CDCl ): δ 164.1 (d, J = 268.8 Hz), 157.7, 133.4 (q, J = 3.6 Hz), 130.6 (d, J = 3.6 Hz),
27.6 (q, J = 36.0 Hz), 122.9 (q, J = 272.3 Hz), 118.5 (d, J = 24.0 Hz), 117.6 (d, J = 9.6 Hz); HRMS
3
1
+
－1
(
ESI-TOF): [M+Na ] calcd for C16
H
6
F
8
O
3
Na 421.0087, found 421.0073; IR (cm ): 1798, 1731.
1
2
,4,5-Trifluoro-3-(trifluoromethyl)benzoic anhydride (13): Mp 69.0−71.0 °C; H NMR (500 MHz,
1
3
3 3
CDCl ): δ 8.06−8.14 (m, 2H); C NMR (125 MHz, CDCl ): δ 156.0, 155.9 (d, J =273.5 Hz), 152.5 (ddd,
J = 4.7, 18.2, 275.5 Hz), 147.1 (ddd, J = 3.5, 12.8, 252.9 Hz), 123.5 (d, J = 20.4 Hz), 120.5 (q, J = 276.0
+
Hz), 114.1 (ddd, J = 4.8, 10.2, 12.0 Hz), 111.0−112.0 (m); HRMS (ESI-TOF): [M+Na ] calcd for
－
1
C
16
H
2
F
12
O
3
Na 492.9710, found 492.9714; IR (cm ): 1799, 1739, 1505, 1174, 1132.
1
2
-Chloro-3-(trifluoromethyl)benzoic anhydride (14): Mp 107.5−108.5 °C; H NMR (500 MHz,
3
CDCl ): δ 8.09 (dd, J = 1.5, 7.5 Hz, 2H), 7.95 (dd, J = 1.5, 7.5 Hz, 2H), 7.54 (dd, J = 7.5, 7.5 Hz, 2H);
1
3
C NMR (125 MHz, CDCl
3
): δ 159.5, 134.8, 132.9, 131.7 (q, J = 5.9 Hz), 131.1, 130.7 (q, J = 31.2 Hz),
+
1
27.0, 122.3 (q, J = 274.7 Hz); HRMS (ESI-TOF): [M+Na ] calcd for C16
H
6
Cl
2
F
6
O
3
Na 452.9496, found
－
1
4
52.9491; IR (cm ): 1794, 1738, 1132.
1
2
-Nitro-4-(trifluoromethyl)benzoic anhydride (15): Mp 120.5−121.5 °C; H NMR (500 MHz, CDCl
3
):
): δ 158.4, 146.8,
35.1 (q, J = 35.4 Hz), 130.9, 130.9, 129.3, 122.7 (q, J = 274.0 Hz), 121.9 (q, J = 3.6 Hz); HRMS
1
3
δ 8.38, 8.08 (d, J = 8.0 Hz, 2H), 7.97 (d, J = 8.0 Hz, 2H); C NMR (125 MHz, CDCl
3
1

HETEROCYCLES, Vol. 94, No. 2, 2017
269
+
－1
(
6 6 2 7
ESI-TOF): [M+Na ] calcd for C16H F N O Na 474.9977, found 474.9979; IR (cm ): 1818, 1758, 1545,
1
323, 1135.
1
2
-Methyl-4-(trifluoromethyl)benzoic anhydride (16): Mp 93.5−94.5 °C; H NMR (500 MHz, CDCl
3
):
1
3
δ 8.12 (d, J = 8.0 Hz, 2H), 7.59 (d, J = 8.0 Hz, 4H), 2.76 (s, 6H); C NMR (125 MHz, CDCl
3
): δ 161.5,
1
43.3, 135.0 (q, J = 32.4 Hz), 131.6, 130.7, 129.0 (q, J = 3.7 Hz), 123.3 (q, J = 273.4 Hz), 123.0 (q, J =
+
－
3
.7 Hz), 21.9; HRMS (ESI-TOF): [M+Na ] calcd for C18
H
12
F
6
O
3
Na 413.0588, found 413.0577; IR (cm
1
): 1795, 1733, 1334, 1163, 1126.
1
2
-(Trifluoromethyl)benzoic anhydride (17): Mp 59.5−61.5 °C; H NMR (500 MHz, CDCl
3
): δ 7.98 (d,
J = 7.5 Hz, 2H), 7.83 (d, J = 7.5 Hz, 2H), 7.72 (dd, J = 7.5, 7.5 Hz, 2H), 7.70 (dd, J = 7.5, 7.5 Hz, 2H);
1
3
C NMR (125 MHz, CDCl
3
): δ 160.6, 132.8, 132.0, 131.2, 129.6 (q, J = 32.8 Hz), 128.7, 127.2 (q, J =
+
5
3
.2 Hz), 123.0 (q, J = 273.5 Hz) ; HRMS (ESI-TOF): [M+Na ] calcd for C16
H
8
F
6
O
3
Na 385.0275, found
－
1
85.0265; IR (cm ): 1805, 1740, 1169, 1314.
1
4
-Chloro-2-(trifluoromethyl)benzoic anhydride (18): Mp 73.0−74.0 °C; H NMR (500 MHz, CDCl ):
3
1
3
δ 7.94 (d, J = 8.0 Hz, 2H), 7.82 (d, J = 2.0 Hz, 2H), 7.68 (dd, J = 2.0, 8.0 Hz, 2H); C NMR (125 MHz,
CDCl ): δ 159.5, 139.8, 133.0, 132.2, 131.4 (q, J = 33.6 Hz), 126.7, 122.9 (q, J = 6.0 Hz), 122.2 (q, J =
3
+
－
2
74.7 Hz); HRMS (ESI-TOF): [M+Na ] calcd for C16
H
6
Cl
2
F
6
O
3
Na 452.9496, found 452.9510; IR (cm
1
): 1791, 1729, 1302.
1
4
-Nitro-2-(trifluoromethyl)benzoic anhydride (19): Mp 122.0−123.0 °C; H NMR (500 MHz, CDCl
3
):
1
3
δ 8.69 (d, J = 2.2 Hz, 2H), 8.57 (dd, J = 2.2, 8.8 Hz, 2H), 8.14 (d, J = 8.8 Hz, 2H); C NMR (125 MHz,
CDCl ): δ 158.5, 149.8, 133.4, 132.5, 131.2 (q, J = 34.8 Hz), 127.1, 124.0 (q, J = 273.6 Hz), 122.8 (q, J =
3
+
－1
5
.0 Hz); HRMS (ESI-TOF): [M+Na ] calcd for C16
H
6
F
6
N
2
O
7
Na 474.9977, found 474.9971; IR (cm ):
1
812, 1752, 1541, 1287, 1156.
1
3
-Fluoro-2-(trifluoromethyl)benzoic anhydride (20): Mp 70.5−71.5 °C; H NMR (500 MHz, CDCl
3
):
1
3
δ 7.67 (ddd, J = 4.5, 7.5, 8.5 Hz, 2H), 7.52 (d, J = 7.5 Hz, 2H), 7.41 (dd, J = 8.5, 10.0 Hz, 2H); C NMR
125 MHz, CDCl ): δ 160.2 (d, J = 3.5 Hz), 160.0 (d, J = 259.1 Hz), 134.1 (d, J = 9.7 Hz), 131.4, 124.9 (d,
J = 3.5 Hz), 121.9 (q, J = 274.7 Hz), 120.6 (d, J = 21.6 Hz), 116.3 (dq, J = 13.2, 33.6 Hz); HRMS
(
3
+
－1
(
ESI-TOF): [M+Na ] calcd for C16
H
6
F
8
O
3
Na 421.0087, found 421.0102; IR (cm ): 1809, 1749, 1297,
1
135.
1
4
-Fluoro-2-(trifluoromethyl)benzoic anhydride (21): Mp 64.0−65.0 °C; H NMR (500 MHz, CDCl
3
):
1
3
δ 8.06 (dd, J = 5.3, 9.0 Hz, 2H), 7.55 (dd, J = 2.0, 8.5 Hz, 2H), 7.39 (ddd, J = 2.0, 7.5, 9.0 Hz, 2H); C
3
NMR (125 MHz, CDCl ): δ 164.7 (d, J = 258.0 Hz), 159.4, 134.6 (d, J = 8.4 Hz), 132.8 (dd, J = 8.4, 33.6

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HETEROCYCLES, Vol. 94, No. 2, 2017
Hz), 124.5, 122.1 (q, J = 273.5 Hz), 119.0 (d, J = 21.6 Hz), 115.7 (dq, J = 6.0, 25.0 Hz); HRMS
+
－1
(
ESI-TOF): [M+Na ] calcd for C16
H
6
F
8
O
3
Na 421.0087, found 421.0065; IR (cm ): 1801, 1735, 1304,
1
145.
1
2
-Fluoro-6-(trifluoromethyl)benzoic anhydride (FTFBA) (22): Mp 74.0−76.0 °C; H NMR (500 MHz,
1
3
3
CDCl ): δ 7.62−7.66 (m, 2H), 7.56 (d, J = 8.0 Hz, 2H), 7.40 (dd, J = 4.0, 8.0 Hz, 2H); C NMR (125
MHz, CDCl
3
): δ 159.6 (d, J = 254.5 Hz), 156.7, 133.0 (d, J = 8.4 Hz), 129.9 (q, J = 33.0 Hz), 122.3 (q, J
+
=
274.7 Hz), 122.3, 120.0 (d, J = 20.3 Hz), 118.6 (d, J = 18.0 Hz); HRMS (ESI-TOF): [M+Na ] calcd for
－
1
C
16 6 8 3
H F O Na 421.0087, found 421.0065; IR (cm ): 1814, 1750, 1318, 1153.
1
2
-Methyl-6-(trifluoromethyl)benzoic anhydride (MTFBA) (23): Mp 105.0−106.0 °C; H NMR (500
1
3
3 3
MHz, CDCl ): δ 7.54 (d, J = 7.0 Hz, 2H), 7.45−7.50 (m, 4H), 2.50 (s, 6H); C NMR (125 MHz, CDCl ):
δ 161.6, 136.8, 134.1, 130.4, 129.6, 127.5 (q, J = 32.3 Hz), 123.8 (q, J = 3.6 Hz), 123.4 (q, J = 273.4 Hz),
+
－1
1
9.2; HRMS (ESI-TOF): [M+Na ] calcd for C18
H
12
F
6
O
3
Na 413.0588, found 413.0569; IR (cm ): 1809,
1
754.
1
2
7
1
-Methyl-6-(trifluoromethyl)benzoyl chlroride (MTFBC) (23’): H NMR (500 MHz, CDCl
3
): δ
): δ 168.3, 135.9, 134.4,
34.1, 130.4, 125.5 (q, J = 33.6 Hz), 123.9 (q, J = 3.6 Hz), 123.2 (q, J = 273.4 Hz), 19.1; LRMS
1
3
.53−7.56 (m, 1H), 7.45−7.51 (m, 2H), 2.48 (s, 3H); C NMR (125 MHz, CDCl
3
+
－1
(
ESI-TOF): m/z 187 (M −Cl); IR (cm ): 1797, 1324, 1177, 1138.
1
2
,6-Bis(trifluoromethyl)benzoic anhydride (2,6-BTFBA) (24): Mp 163.5−164.5 °C; H NMR (500
1
3
3 3
MHz, CDCl ): δ 7.96 (d, J = 8.0 Hz, 4H), 7.78 (t, J = 8.0 Hz, 2H); C NMR (125 MHz, CDCl ): δ 157.8,
+
1
31.2, 130.1, 129.3 (q, J = 33.6 Hz), 127.7, 125.5 (q, J = 23.3 Hz); HRMS (ESI-TOF): [M+Na ] calcd for
－
1
C
18 6 12 3
H F O Na 521.0023, found 521.0006; IR (cm ): 1828, 1767, 1343, 1299, 1137.
Typical experimental procedure for the synthesis of threo-aleuritic acid lactone 26
An experimental procedure is described for the preparation of lactone 26 using FTFBA with DMAP
Table 7, Entry 1): To a solution of FTFBA (23.9 mg, 0.060 mmol) and DMAP (14.7 mg, 0.120 mmol) in
CH Cl (21.0 mL) at rt was slowly added a solution of threo-aleuritic acid (25) (19.6 mg, 0.050 mmol) in
(
2
2
CH Cl (14.0 mL) with a mechanically driven syringe for 16.5 h. After the reaction mixture had been
2
2
stirred for 1 h at rt, saturated aqueous NaHCO was added at 0 °C. The mixture was extracted with
3
CH Cl , and the organic layer was washed with water and birne, and dried over Na SO . After filtration of
2
2
2
4
the mixture and evaporation of the solvent, the crude product was purified by thin layer chromatography
hexane/EtOAc = 3/1) to afford the desired lactone 26 (a mixture of stereoisomeric benzylidene acetals,
ca. 1:1, 16.5 mg, 88.1%) as a white solid and its dimer 27 (0.9 mg, 4.8%) as a pale yellow oil.
(

HETEROCYCLES, Vol. 94, No. 2, 2017
271
1
threo-Aleuritic acid lactone 26: Mp 53.5−54.5 °C; H NMR (500 MHz, CDCl
3
): δ 7.50–7.46 (m, 2H),
7
1
1
.38–7.34 (m, 3H), [5.86, 5.84] (s, 1H), 4.15 (t, J = 5.5 Hz, 2H), 3.84 (m, 2H), 2.40–2.30 (m, 2H), 1.91–
1
3
.29 (m, 22H); C NMR (125 MHz, CDCl
3
): δ 174.0, [138.2, 138.1], 129.2, 128.3, 126.7, [102.5,
02.4], [82.1, 82.0], [80.8, 80.5], 64.2, 34.6, [32.9, 32.8], [32.1, 32.0], 28.8, 28.6, [28.5, 28.4], 28.1, 27.6,
[25.7, 25.6], 25.3, 24.9, 24.7,24.1. The values in square brackets indicate the chemical shifts of the
+
identical carbons of two benzylidene diastereomers; HRMS (ESI-TOF): [M+H ] calcd for
－
1
C
23
H
35
O
4
375.2535, found 375.2526; IR (cm ): 1732.
1
threo-Aleuritic acid lactone dimer 27: H NMR (500 MHz, CDCl
3
): δ 7.50–7.45 (m, 4H), 7.39–7.34 (m,
1
3
6
H), 5.86 (s, 2H), 4.08 (t, J = 6.5 Hz, 4H), 3.84 (m, 4H), 2.31 (t, J = 7.5 Hz, 4H), 1.73–1.26 (m, 44H); C
3
NMR (125 MHz, CDCl ): δ 174.0, 138.2, 129.2, 128.3, 126.7, 102.6, [82.7, 82.6], [81.4, 81.3], 64.2, 34.4,
[33.1, 33.0], [32.9, 32.8], [29.4, 29.3], [29.1, 29.0], 29.0, 28.9, 28.9, 28.5, 25.8, 25.7, 24.9; HRMS
+
－1
(
68 8
ESI-TOF): [M+Na ] calcd for C46H O Na 771.4812, found 771.4827; IR (cm ): 1733.
ACKNOWLEDGEMENTS
This study was partly supported by a Research Grant from the Center for Chirality and Grants-in-Aid for
Scientific Research from the Ministry of Education, Sports and Culture, Japan.
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3
b
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9
2
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b,c,10
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