Divergent pathways for reactions of CF3-containing Isobenzofuran-1-ones and amines

Article abstract of DOI:10.1016/j.jfluchem.2018.11.012

Unprecedented isobenzofuran-1-ones (phthalides) with CF₃ and ethoxy groups both at the 3-position were readily synthesized from the corresponding aromatic 1,2-diesters and reacted with a variety of primary amines to find out convenient conversion to the corresponding γ-lactams, while secondary amines behaved in a totally different manner to affect the net substitution reactions for the EtO moiety, where characteristics of the strongly electron-withdrawing CF₃ group was considered to play a significantly important role.

Full text of DOI:10.1016/j.jfluchem.2018.11.012

Accepted Manuscript
Title: Divergent Pathways for Reactions of CF3-containing
Isobenzofuran-1-ones and Amines
Authors: Kana Mitobe, Tomoko Kawasaki-Takasuka,
Tomohiro Agou, Toshio Kubota, Takashi Yamazaki
PII:
S0022-1139(18)30388-9
DOI:
Reference:
https://doi.org/10.1016/j.jfluchem.2018.11.012
FLUOR 9255
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Received date:
Revised date:
Accepted date:
28 September 2018
22 November 2018
22 November 2018
Please cite this article as: Mitobe K, Kawasaki-Takasuka T, Agou T,
Kubota T, Yamazaki T, Divergent Pathways for Reactions of CF3-containing
Isobenzofuran-1-ones and Amines, Journal of Fluorine Chemistry (2018),
https://doi.org/10.1016/j.jfluchem.2018.11.012
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Divergent Pathways for Reactions of CF3-containing Isobenzofuran-1-ones and Amines
Kana Mitobe,a Tomoko Kawasaki-Takasuka,a Tomohiro Agou,b Toshio Kubotab and Takashi
Yamazakia,*
a Division of Applied Chemistry, Institute of Engineering, Tokyo University of Agriculture and
Technology, 2-24-16 Nakamachi, Koganei 184-8588, Japan
b Department of Biomolecular Functional Engineering, Ibaraki University, Nakanarusawa 4-
12-1, Hitachi 316-8511, Japan
Graphical abstract
RNH2: 12 examples including bifunctional reagents
R2NH: only cyclic sec-amines, and no reactions for the corresponding acyclic counterpart
Highlights
 Facile construction of CF3-containing -lactams starting from primary amines
 Further cyclization from the product using 2-aminoethanol
 Net substitution reactions from cyclic secondary amines
Abstract: Unprecedented isobenzofuran-1-ones (phthalides) with CF3 and ethoxy groups both at the
3-position were readily synthesized from the corresponding aromatic 1,2-diesters and reacted with a
variety of primary amines to find out convenient conversion to the corresponding -lactams, while
secondary amines behaved in a totally different manner to affect the net substitution reactions for the
EtO moiety, where characteristics of the strongly electron-withdrawing CF3 group was considered to
play a significantly important role.
Keywords: Trifluoromethyl • Phthalide • Lactams • Lactones • Amines

1. Introduction
We have recently reported [1] the facile entry of a trifluoromethyl moiety to aromatic 1,2-
diesters by using the well-known Ruppert-Prakash reagent [2] (TMSCF3), leading to ready as well as
successful construction of the corresponding unprecedented isobenzofuranones like 1 in good to high
chemical yields, contrary to our initial expectation of the formation of 1,2-bis(trifluoroacetyl)benzene
(Scheme 1) [3,4]. Convenient syntheses of the corresponding lactols were readily realized by
subjection of a variety of nucleophiles to 1. As one of the typical examples, the reductive
transformation of 1 to 2 by LiAlH4 was demonstrated in Scheme 1 whose further reaction with ethyl
diethylphosphonoacetate in the presence of lithium bromide and triethylamine [5] furnished the
corresponding indanone 3 by way of the multiple steps successively occurring in a one-pot manner
[6]. Another representative result was indicated by the action of MeLi whose first equivalent acted
as a nucleophile to 1 and the rest as a base, affording the hydroxylated indanone 4. In both cases,
the characteristic point was the in situ generation of the highly electrophilic carbonyl function with
the CF3 group by elimination of an ethanol molecule from the lactol tautomers, and this moiety readily
and substantially accepted the intramolecular nucleophilic attack.
During the study on the synthetic utility of the phthalide 1 as the representative model, its facile
conversion to the corresponding -lactams 5 [7] was observed in excellent yields by such a simple
protocol as addition of primary amines in THF at room temperature without an inert atmosphere.
This method is in quite sharp contrast to the previous report by Pohmakotr et al. [8] to the similar
compound 7, requiring toluene reflux temperature in the presence of a catalytic amount of p-TsOH.
The products 5g (R: CH2CH2OH) and 5k (R: NH2) from 1 were found to be further transformed to
the corresponding tricyclic system 15 and the phthalazinone 11, respectively, in a facile manner.
Moreover, different from the cases of primary amines, the net substitution of the ethoxy group in 1
[9]was interestingly occurred by reactions with cyclic secondary amines to furnish 6. In this article
was demonstrated these intriguing behavior of 1 to a variety of amines.
2. Results and Discussion
In Table 1 were summarized results of the reactions of 3-ethoxy-3-(trifluoromethyl)isobenzo-
furan-1-one 1, as the typical phthalide model, with a variety of primary amines. First of all,
subjection of 1 to a solution containing benzylamine under the previously reported conditions as
shown in Scheme 1 [Error! Bookmark not defined.] afforded the corresponding 3-hydroxylated -
lactam 5a in 96% isolated yield
(Entry 1). However, this transformation was found to proceed even at room temperature in the
absence of an acid catalyst and this system recorded the same level of the product yield just by mixing
with 1.2 equiv of benzylamine in THF (Entry 2). Encouraged by this result, 1 was treated with a
variety of amines and we successfully clarified that amines including the ones as an aqueous solution
(Entries 5 and 7) or a hydrochloride salt (Entry 8) [10] were among the potent reactants to afford the
desired -lactam products 5 in high to excellent yields. Nice participation of aniline was also noticed
(Entry 9) under this synthetic protocol in spite of slower progress possibly because of its lower

nucleophilicity [11]. Ethanes with vicinal two functionalities like 2-hydroxyamine (Entry 10) and
to produce 1:2 product 9. Selective construction of 9 was accomplished in high yield by the addition
of an excess amount of 1 to ethylenediamine (Entry 12). Apparent from the results of Entries 5 and
7, we have no need to care about the presence of water in the reaction medium, and thus, the present
protocol is readily performed in a simple sample vial under air without utilization of dehydrated
solvents, which clearly showed the significant convenience of the present protocol.
For the convenience of the reaction, We also tried the one-pot process starting from diethyl
phthalate under the identical conditions described in our previous report [Error! Bookmark not
defined.], and after the reaction with TMSCF3 and hydrolysis of the resultant silyl ether, 1.3 equiv of
4-MeO-C6H4CH2NH2 was added and stirring was further continued for 4 h at room temperature.
This combined route furnished the same product 5b in 57% yield which was well compared with the
yields of the separate two steps of 78% for the first trifluoromethylation step and 95% for the second
when considered about the convenient omission of the one isolation process containing extraction
and chromatographic separation.
The reaction mechanism was explained as shown in Scheme 2. Thus, nucleophilic attack of
amines should be occurred at the carbonyl group in 1 to afford Int-1 which should be in an
equilibrating relationship with Int-2. Conversion to the CF3C=O group formed after elimination of
EtOH would affect the intramolecular attack by the amide nitrogen atom at the last step to furnish the
products 5. In this process, the strongly electron-withdrawing nature of the CF3 group seemed to
effectively accelerate the reaction by increase of the carbonyl electrophilicity as well as stabilization
of the N,O-hemiacetal forms in 5. In the case of the non-fluorinated substrate [12] (H and 7-Cl
instead of CF3 and 7-H in our instance, respectively), the fact that the reaction with methylamine in
MeCN required 3 h reflux to give the similar lactam in 50% yield would be a clear proof of the
activation ability of the CF3 group.
As demonstrated in Table 1, because the selection of the reaction conditions led to possible as
well as selective formation of different products like 5j and 9 when 1,2-bifunctional H2NCH2CH2NH2
was employed as a nucleophile, hydrazines were employed at the next stage (Scheme 3). Subjection
of 1 to a THF solution containing NH2NH2·H2O proved to afford the same type of -lactam 5k in
94% yield after 3 h stirring at room temperature, while construction of the corresponding six-
membered phthalazinone 11a was accomplished in 91% yield just by conducting the reaction under
the reflux temperature. On the other hand, behavior of methyl hydrazine was totally different and
the room temperature condition led to direct production of 11b in excellent yield without observation
of the isomeric -lactam product like 5k. Formation of 11a was considered to be initiated by the
conversion of 1 to 5k, followed by the condensation of the free NH2 group with the CF3C=O moiety
in the ring-opened tautomer of 5k (seef Int-3 in Scheme 2). For obtaining further mechanistic
insight, ab initio calculation was performed for the comparison of the regioisomeric 5k and 10a [13].

Our result anticipated that the -lactam 5k was energetically more stable in THF by 3.64 kcal/mol
than the corresponding isomer 10a whose difference increased as high as 5.06 kcal/mol when we paid
attention to their free energy at 25 °C. As a consequence, the irreversible dehydration of 10a at the
elevated temperature would be the key factor for the ready promotion of this intriguing isomerization
to the actual product 11a by way of the energetically less preferable intermediate 10a.
Employment of secondary amines was attempted at the next stage with aiming at the
construction of the tertiary amide either with the trifluoroacetyl or the corresponding hemiacetal (or
hydrate) moieties because the absence of a hydrogen atom on the amide nitrogen should refuse the
resultant cyclization to the -lactam form. In spite of more than 90% recovery of 1 when mixed
with dimethyl- or dibutylamines, the cyclic counterparts like pyrrolidine, piperidine, and morpholine
unexpectedly furnished the corresponding -lactones 6 in high to excellent yields (Scheme 4). The
structure of 6 was unambiguously confirmed by the X-ray crystallographic analysis of 6c [14], and
the possible reaction mechanism to 6 was described in Scheme 4. Thus, 1 would be converted to
Int-4 and -5 in a similar manner to the case when primary amines were employed (see Scheme 2).
In the case if Int-5, the CF3C=O group would accept the intramolecular nucleophilic attack to give
Int-6, possibly due to its high electrophilicity. The important point in this instance is the absence of
a hydrogen atom on nitrogen, and the consecutive disposition of Int-6 should eventually afford the
final products 11. In the rare cases of non-fluorinated compounds, the closely related 12 was
reported to provide the product 14 [15] by the mechanism of the secondary amine addition at the
carbonyl group in 13, followed by the intramolecular cyclization with exclusion of the amide amine
part. However, we proposed the different mechanism because it was extraordinary rare case for the
CF3C=O group generated from 1 which captured any reactants by intermolecular processess. The
fact that acyclic secondary amines resulted in total recovery of the substrate 1 would stem from the
severer sterically repulsive interaction in crowded intermediates Int-4 to -6 caused by freely rotating
two alkyl moieties which should be more or less alleviated by the corresponding cyclic secondary
amines with the limited movement.
The methanesulfonic acid-mediated intramolecular Friedel-Crafts type reactions of compounds
5 was already reported by the Anbarasan’s group [Error! Bookmark not defined.d], and we also
found out that the pendant group on the lactam nitrogen in 5 was nicely participated in cyclization to
afford the tricyclic ring system 15 [16] in excellent yield just by heating 5i in DCE (Scheme 5).
3. Conclusions
As described above, we have successfully demonstrated that reactions of the isobenzofuran-1-
one 1 with a variety of primary amines including ones with the additional functionalities like OH and
NH2 afforded the corresponding -lactams 5 in high to excellent yields usually in 2-4 h stirring at
room temperature. Hydrazines afforded products depending on the reaction temperature, and in
spite of the formation of -lactams 5 at room temperature, six-membered phthalazinones 11 were
constructed at the elevated temperature. On the other hand, on the contrary to our expectation,
cyclic secondary amines were proved to follow the net substitution for the ethoxy group in 1 again at

room temperature. In addition to the characteristic point of the present reactions usually occurring
at room temperature, another special features to be mentioned are the possible employment of an
aqueous amine solution without requirement of inert atmosphere, which allows scale-up of the present
process in an extremely facile manner. Moreover, when compared with the non-fluorinated
substances, presence of the CF3 group is believed to play a crucial role for acceleration of the present
transformation both by increase of the electrophilicity of the carbonyl group and stabilization of N,O-
hemiacetal as well as -acetal structures. Further extension of the present protocol and utilization of
synthesized products are in progress in this laboratory.
4. Experimental Section
4.1 General
1H (300.40 MHz), 13C (75.45 Hz), and 19F (282.65 Hz) NMR spectra were recorded in CDCl3
unless otherwise noted and chemical shifts were recorded in parts per million (ppm), downfield from
internal tetramethylsilane (Me4Si:  0.00, for 1H and 13C) or hexafluorobenzene (C6F6:  –163.00 for
19F). Data were tabulated in the following order: number of protons, multiplicity (s, singlet; d,
doublet; t, triplet; q, quartet; quint, quintet; sext, sextet; m, multiplet; b, broad peak), coupling
constants in Hertz. Infrared (IR) spectra were reported in wave numbers (cm–1). Some melting
point data were obtained from the differential scanning calorimetry (DSC) analysis. High resolution
mass spectra (HRMS) experiments were performed with a quadrupole mass spectrometer equipped
with a FAB ion source. Only identifiable peaks are shown for the minor stereoisomers.
Most of reactions were performed with magnetic stirring using flame-dried glassware.
Anhydrous THF, Et2O, and CH2Cl2 were purchased and used without further purification. Unless
otherwise noted, materials were obtained from commercial suppliers and were used without further
purification. Spherical neutral silica gel (63-210 m) was employed for column chromatography.
4.2 Typical procedure for the preparation of 3-hydroxy-3-(trifluoro-methyl)isoindolin-1-ones (5)
4.2.1 2-Benzyl-3-hydroxy-3-(trifluoromethyl)isoindolin-1-ones (5a)
To a sample vial were added 3-ethoxy-3-(trifluoromethyl)isobenzofuran-1(3H)-one 1 (0.123 g,
0.501 mmol), benzylamine (0.11 g, 1.0 mmol), and THF and the whole mixture was stirred at room
temperature for 2 h. After addition of water, the mixture was extracted with AcOEt three times and
the combined organic layer was dried over anhydrous Na2SO4. The crude materials obtained after
concentration under reduced pressure was chromatographed on silica gel (hexane: AcOEt=2:1) to
give 5a (0.153 g, 0.498 mmol) in quantitative yield. Rf=0.19 (hexane:AcOEt= 2:1). 1H NMR 
3.45 (1H, s), 4.54 (1H, d, J=15.3 Hz), 4.98 (1H, d, J=15.3 Hz), 7.22-7.38 (3H, m), 7.36-7.38 (2H, m),
7.59-7.72 (3H, m), 7.82-7.85 (1H, m). 13C NMR  43.1, 88.0 (q, J=33.3 Hz), 122.8 (q, J=286.2 Hz),
123.6, 123.8, 127.2, 127.7, 128.3, 130.8, 131.1, 133.0, 136.8, 140.6, 169.1. 19F NMR  –79.50 (s).
IR (KBr)  3146, 2963, 2920, 2853, 1685, 1671, 1433, 1399, 1360, 1297, 1272, 1187, 1170, 1140,

961, 944, 770, 739, 711, 697 cm–1. HRMS (FAB–, m/z): [M-H]– calcd for C16H11F3NO2, 306.0742;
Found, 306.0766.
4.2.2 3-Hydroxy-2-(4-methoxybenzyl)-3-(trifluoromethyl)isoindolin-1-one (5b)
1 (0.124 g, 0.502 mmol) and 4-methoxybemzylamine (0.13 mL, 1.00 mmol) was employed to
give 0.145 g of 5b (0.430 mmol, 86% yield) as a white solid. Rf=0.14 (hexane:AcOEt=1:1), mp
145.7 °C. 1H NMR  3.74 (3H, s), 3.83(1H, br), 4.46 (1H, d, J=15.3 Hz), 4.94 (1H, d, J=15.3 Hz),
6.74-6.78 (2H, m), 7.29-7.32 (2H, m), 7.56-7.71 (3H, m), 7.77-7.80 (1H, m). 13C NMR (Acetone-
d6)  43.0, 55.4, 88.4 (q, J=32.9 Hz), 114.2, 124.0, 124.4 (q, J=285.7 Hz), 124.7, 130.0, 130.8, 132.1,
132.6, 133.7, 141.9, 159.6, 168.6. 19F NMR  –79.40 (s). IR (KBr)  3102, 2964, 2919, 2841,
1669, 1613, 1514, 1397, 1360, 1292, 1269, 1247, 1199, 1171, 1138, 1109, 1083, 963, 943, 811
cm–1. HRMS (FAB–, m/z): [M]– calcd for C17H14F3NO3, 337.0926 ; Found, 337.0913.
4.2.3 3-Hydroxy-2-(2-phenethyl)-3-(trifluoromethyl)isoindolin-1-one (5c)
1 (0.739 g, 3.00 mmol) and 2-phenylethylamine (0.48 mL, 3.81 mmol) was employed to give
0.877 g of 5c (2.728 mmol, 91% yield) as a white solid. Rf=0.34 (hexane:AcOEt=2:1), mp 118.0 °C.
1H NMR  2.73 (1H, dt, J=4.6, 12.0 Hz), 2.97 (1H, dt, J=5.8, 11.9 Hz), 3.23 (1H, dt, J=5.7, 11.0 Hz),
3.59 (1H, dt, J=5.0, 12.5 Hz), 5.53 (1H, brs), 7.12 (2H, d, J=6.9 Hz), 7.19-7.28 (3H, m), 7.36-7.46
(2H, m), 7.46-7.54 (1H, m), 7.68 (1H, d, J=7.5 Hz). 13C NMR (Acetone-d6)  35.4, 42.3, 88.3 (q,
J=32.5 Hz), 123.9, 124.6 (q, J=285.7 Hz), 124.7, 127.2, 129.4, 129.5, 132.1, 132.7, 133.6, 139.9,
141.7, 168.2. 19F NMR  –80.10 (s). IR (KBr)  3272, 3062, 3028, 2986, 2955, 2940, 1693, 1409,
1367, 1281, 1245, 1184, 1136, 1079, 1005, 978, 943, 855, 763, 699 cm–1. HRMS (FAB–, m/z): [M-
H]– calcd for C17H13F3NO2, 320.0898 ; Found, 320.0856.
4.2.4 3-Hydroxy-2-methyl-3-(trifluoromethyl)isoindolin-1-one (5d)
1 (0.123 g, 0.500 mmol) and 40% NH3 aq. (0.07 mL, 0.65 mmol) was employed to give 0.109
g of 5d (0.470 mmol, 94% yield) as a white solid. Rf=0.19 (hexane:AcOEt=2:1), mp 129.5 °C. 1H
NMR  2.78 (3H, s), 5.64 (1H, br), 7.44-7.52 (2H, m), 7.59-7.64 (1H, m), 7.71-7.74 (1H, s). 13C
NMR  24.3, 87.2 (q, J=32.9 Hz), 122.86 (q, J=283.9 Hz), 122.91, 123.3, 130.7, 131.3, 132.2, 140.4,
167.5. 19F NMR  –80.07 (s). IR (KBr)  3207, 2988, 2951, 1683, 1476, 1437, 1410, 1374, 1270,
1250, 1174, 1155, 1123, 1077, 1039, 978, 935, 764, 736, 699 cm–1. HRMS (FAB–, m/z): [M-H]–
calcd for C10H7F3NO2, 230.0428 ; Found, 230.0431.
4.2.5 2-Butyl-3-hydroxy-3-(trifluoromethyl)isoindolin-1-one (5e)
1 (0.124 g, 0.502 mmol) and BuNH2 (0.06 mL, 0.61 mmol) was employed to give 0.0912 g of
5e (0.334 mmol, 66% yield) as a white solid. Rf=0.34 (n-hexane:AcOEt=2:1), mp 66.4 °C. 1H
NMR  0.88 (3H, t, J=7.4 Hz), 1.25 (2H, sext, J=7.3 Hz), 1.44 (1H, m), 1.59 (1H, m), 2.99 (1H, ddd,
J=4.9, 10.5, 13.8 Hz), 3.33 (1H, ddd, J=5.1, 11.1, 14.1 Hz), 7.41-7.49 (2H, m), 7.54-7.89 (1H, m),
7.67-7.70 (1H, m). 13C NMR  13.5, 20.3, 29.9, 39.8, 87.8 (q, J=33.1 Hz), 123.0 (q, J=284.9 Hz),
123.2, 123.8, 130.9, 131.1, 132.7, 140.8, 168.7. 19F NMR  –79.97 (s). IR (KBr)  3173, 2965,

2936, 2877, 1695, 1678, 1473, 1399, 1373, 1326, 1267, 1195, 1164, 1127, 1084, 945, 858, 764, 738,
710 cm–1. HRMS (FAB–, m/z): [M-H]– calcd for C13H13F3NO2, 272.0898 ; Found, 272.0882.
4.2.6 3-Hydroxy-3-(trifluoromethyl)isoindolin-1-one (5f)
1 (0.123 g, 0.500 mmol) and 25% NH3 aq. (0.50 mL, 7.34 mmol) was employed to give 0.0845
g of 5f (0.389 mmol, 78% yield) as a white solid after recrystallization from AcOEt. Rf= 0.09
(hexane:AcOEt=2:1), mp 164.0 °C. 1H NMR (Acetone-d6)  6.80 (1H, s), 7.64-7.76 (4H, m), 8.59
(1H, br). 13C NMR (Acetone-d6)  86.4 (q, J=33.3 Hz), 124.2, 124.4, 124.5 (q, J=283.9 Hz), 132.0,
132.8, 133.9, 142.8, 169.5. 19F NMR  –80.54 (s). IR (KBr)  3335, 3276, 3104, 1709, 1671,
1475, 1432, 1394, 1283, 1267, 1184, 1167, 1132, 1079, 966, 948, 808, 772, 725, 702 cm–1. HRMS
(FAB–, m/z): [M-H]– calcd for C9H5F3NO2, 216.0272 ; Found, 216.0316.
4.2.7 2,3-Dihydroxy-3-(trifluoromethyl)isoindolin-1-one (5g)
1 (0.246 g, 1.000 mmol), hydroxyl- amine hydrochloride (0.0702 mL, 1.010 mmol), and Et3N
(0.15 mL, 1.1 mmol) in H2O (1.0 mL) were reacted to give 0.1668 g of 5g (0.712 mmol, 71% yield)
as a white powder. Rf=0.06 (hexane:AcOEt=2:1), mp 122.9-125.5 °C. 1H NMR (DMSO-d6) 
7.70-7.77 (4H, m), 8.37 (1H, brs), 10.31 (1H, brs). 13C NMR (Acetone-d6)  87.4 (q, J=32.9 Hz),
123.89, 123.90 (q, J=286.4 Hz), 124.7, 130.5, 132.1, 133.9, 139.1, 164.8. 19F NMR (Acetone-d6) 
–77.76 (s). IR (KBr)  3155, 1741, 1698, 1618, 1494, 1471, 1445, 1293, 1270, 1251, 1187, 1153,
1128, 1080, 976, 962, 945, 873, 765, 739 cm–1. HRMS (FAB–, m/z): [M-H]– calcd for C9H5F3NO3,
232.0222 ; Found, 232.0199.
4.2.8 3-Hydroxy-2-phenyl-3-(trifluoromethyl)isoindolin-1-one (5h) [Error! Bookmark not
defined.d]
1 (0.123 g, 0.500 mmol) and aniline (0.07 mL, 0.77 mmol) was reacted for 24 h under reflux to
give 0.111 g of 5h (0.378 mmol, 76% yield) as an orange solid. Rf=0.14. (hexane:AcOEt=2:1).
1H NMR  4.21 (1H, brs), 7.37-7.47 (5H, m), 7.62-7.74 (2H, m), 7.78-7.85 (2H, m). 13C NMR
(Acetone-d6)  89.9 (q, J=32.2 Hz), 124.2 (q, J=286.2 Hz), 124.4, 124.9, 128.8, 129.5, 129.7, 132.3,
134.1, 136.1, 141.5, 167.2.
4.2.9 3-Hydroxy-2-(2-hydroxyethyl)-3-(trifluoromethyl)isoindolin-1-one (5i)
1 (0.123 g, 0.500 mmol) and 2-aminoethanol (0.06 mL, 1.0 mmol) was employed to give 0.1188
g of 5i (0.455 mmol, 91% yield) as a clear solid. Rf=0.23 (hexane:AcOEt=1:1), mp 80.5 °C. 1H
NMR  3.01 (1H, br), 3.53-3.62 (1H, m), 3.87 (2H, s), 4.23 (1H, d, J=15.0 Hz), 6.48 (1H, br), 7.57-
7.77 (4H, m). 13C NMR  42.2, 60.4, 87.2 (q, J=32.9 Hz), 123.1 (q, J=287.2 Hz), 123.4, 123.7,
130.5, 131.0, 133.2, 140.9, 169.2. 19F NMR  –79.69 (s). IR (KBr)  3280, 3164, 2971, 2952,
2906, 1712, 1699, 1471, 1396, 1319, 1260, 1195, 1164, 1084, 1052, 943, 867, 768, 740, 712 cm–1.
HRMS (FAB–, m/z): [M]– calcd for C11H10F3NO3, 261.0613 ; Found, 261.0589.
4.2.10 2-(2-Aminoethyl)-3-hydroxy-3-(trifluoromethyl)isoindolin-1-one (5j)

1 (0.123 g, 0.500 mmol) and ethylenediamine (0.06 mL, 2.4 mmol) was employed to give
0.0674 g of 5j (0.259 mmol, 52% yield) as a white solid by silica gel column chromatography
19
(CHCl3:MeOH=4:1). From the reaction mixture, 9 was obtained in 38% yield determined by F
NMR. Rf=0.22 (CHCl3:MeOH=4:1), mp 138.5 °C. 1H NMR  2.74 (1H, dt, J=1.8, 12.6 Hz), 3.11
(1H, td, J=2.2, 13.1 Hz), 3.30 (1H, t, J=13.4 Hz), 4.41 (1H, td, J=2.3, 15.3 Hz), 4.85 (3H, brs), 7.52-
7.65 (2H, m), 7.72 (1H, d, J=7.2 Hz), 7.79 (1H, d, J=7.5 Hz). 13C NMR  39.8, 41.9, 86.3 (q, J=32.0
Hz), 123.4, 123.6 (q, J=1.3 Hz), 123.9 (q, J=288.8 Hz), 130.4, 130.8, 132.8, 141.9, 168.0. 19F NMR
 –79.25 (s). IR (KBr)  3204, 2998, 2960, 1691, 1469, 1391, 1364, 1290, 1279, 1177, 1153, 1086,
1063, 973, 937, 885, 860, 768, 735, 711 cm–1. HRMS (FAB–, m/z): [M-H]– calcd for C11H10F3N2O2,
259.0694 ; Found, 259.0697.
4.2.11 1,2-Bis{3-hydroxy-3-(trifluoromethyl)isoindolin-1-on-2-yl}ethylene (9)
1 (0.616 g, 2.503 mmol) and ethylenediamine (0.03 mL, 0.04 mmol) was reacted for 0.5 h to
give 0.168 g of 9 (0.365 mmol, 73% yield) as a white solid. Rf=0.40 (hexane:AcOEt=2:1), mp
185.2 °C. 1H NMR  3.71 (1H, d, J=12.6 Hz), 3.79 (1H, d, J=12.3 Hz), 4.49 (1H, d, J=12.6 Hz),
4.56 (1H, d, J=12.3 Hz), 7.16 (2H, brs), 7.30-7.32 (2H, m), 7.44-7.49 (2H, m), 7.63-7.68 (2H, m),
7.75-7.77 (2H, m). 13C NMR  39.70, 39.72, 89.6 (q, J=32.9 Hz), 122.9 (q, J=286.3 Hz), 123.2,
123.9, 130.1, 131.0, 133.7, 141.5, 170.2. 19F NMR  –80.22 (s). IR (KBr)  3180, 2964, 2804,
1685, 1472, 1444, 1421, 1389, 1320, 1264, 1184, 1155, 1131, 1097, 1079, 946, 904, 762, 737, 697
cm–1. HRMS (FAB–, m/z): [M-H]– calcd for C20H13F6N2O4, 459.0780 ; Found, 459.0856.
4.2.12 2-Amino-3-hydroxy-3-(trifluoromethyl)isoindolin-1-one (5k)
1 (0.123 g, 0.501 mmol) and H2NNH2·H2O (0.05 mL, 1.0 mmol) was reacted to give 0.109 g
of 5k (0.470 mmol, 94% yield) as a white solid. Rf=0.15 (hexane:AcOEt=1:1), mp 90.9 °C. 1H
NMR  4.15 (2H, s), 4.53 (1H, brs), 7.60-7.71 (2H, m), 7.74-7.76 (1H, m), 7.84-7.86 (1H, m). 13C
NMR  86.5 (q, J=32.7 Hz), 122.7 (q, J=286.4 Hz), 123.5, 123.8, 129.7, 131.0, 133.0, 138.8, 167.7.
19F NMR  –81.15 (s). IR (KBr)  3450, 3370, 3293, 3043, 2828, 2723, 1720, 1619, 1491, 1402,
1283, 1243, 1199, 1178, 1157, 1119, 1087, 972, 920, 767 cm–1. HRMS (FAB–, m/z): [M]– calcd
for C9H7F3N2O2, 232.0460 ; Found, 232.0453.
4.2.13 4-(Trifluoromethyl)phthalazin-1(2H)-one (11a)
1 (0.123 g, 0.501 mmol) and H2NNH2·H2O (0.05 mL, 1.0 mmol) was reacted to give 0.0971 g
of 11a (0.453 mmol, 91% yield) as a white solid. Rf=0.36 (hexane:AcOEt=2:1), mp 222.0 °C.1H
NMR  7.86-8.02 (3H, m), 8.51-8.54 (1H, m), 10.58 (1H, brs). 13C NMR (DMSO-d6)  121.3 (q,
J=273.5 Hz), 123.7 (q, J=2.5 Hz), 125.1, 126.6, 127.8, 132.6 (q, J=33.9 Hz), 132.8, 134.5, 159.3.
19F NMR  –65.79 (s). IR (KBr)  3178, 3114, 3027, 2966, 2914, 1690, 1612, 1382, 1334, 1294,
1249, 1194, 1173, 1149, 1129, 997, 877, 795, 783, 772 cm–1. HRMS (FAB+, m/z): [M+H]+ calcd
for C9H6F3N2O, 215.0432 ; Found, 215.0475.
4.2.14 2-Methyl-4-(trifluoromethyl)phthalazin-1(2H)-one (11b)

1 (0.124 g, 0.502 mmol) and methylhydrazine (0.05 mL, 0.96 mmol) was reacted to give 0.0885
g of 11b (0.388 mmol, 84% yield) as a white solid. Rf=0.54 (hexane:AcOEt=2:1), mp 105.2 °C.
1H NMR  3.91 (3H, s), 7.82-7.97 (3H, m), 8.51 (1H, dd, J=2.4, 6.9 Hz). 13C NMR (Acetone-d6) 
39.9, 122.2 (q, J=274.2 Hz), 124.6 (q, J=2.7 Hz), 126.2, 127.8, 128.6, 132.1 (q, J= 34.5 Hz), 133.3,
134.7, 159.4. 19F NMR  –65.43 (s). IR (KBr)  3115, 3091, 3037, 2992, 2953, 2912, 1672, 1608,
1595, 1388, 1335, 1279, 1214, 1192, 1167, 1131, 1048, 998, 788, 745 cm–1. HRMS (FAB+, m/z):
[M+H]+ calcd for C10H8F3N2O, 229.0589 ; Found, 229.0587.
4.2.15 3-(Pyrrolidin-1-yl)-3-(trifluoromethyl)isobenzofuran-1(3H)-one (6a)
1 (0.123 g, 0.500 mmol) and pyrrolidine (0.05 mL, 0.61 mmol) was reacted to give 0.118 g of
6a (0.434 mmol, 87% yield) as a pail oil. Rf=0.66 (hexane:AcOEt=2:1). 1H NMR  1.78-1.82
(4H, m), 2.78-2.92 (4H, m), 7.63-7.77 (3H, m), 7.93 (1H, d, J=7.5 Hz). 13C NMR  24.3, 47.27,
47.30, 98.8 (q, J=32.2 Hz), 122.1 (q, J=284.7 Hz), 123.9, 125.9, 127.4, 131.4, 134.6, 143.4, 168.3.
19F NMR  –76.16 (s). IR (KBr)  3027, 2978, 2879, 1773, 1605, 1468, 1381, 1336, 1321,1284,
1235, 1184, 1161, 1134, 1107, 1085, 878, 804, 761, 717 cm–1. HRMS (FAB+, m/z): [M]+ calcd for
C13H12F3NO2, 271.0820 ; Found, 271.0817.
4.2.16 3-(Piperidin-1-yl)-3-(trifluoromethyl)isobenzofuran-1(3H)-one (6b)
1 (0.123 g, 0.500 mmol) and piperidine (0.10 mL, 1.01 mmol) was reacted to give 0.103 g of
6b (0.362 mmol, 72% yield) as a pail oil. Rf=0.28 (hexane:AcOEt=2:1). 1H NMR  1.45-1.62
(6H, m), 2.53-2.60 (2H, m), 2.83-2.91 (2H, m), 7.59-7.68 (2H, m), 7.73-7.78 (1H, m), 7.92 (1H, d,
J=9.2 Hz). 13C NMR  23.8, 25.7, 47.41, 47.43, 100.7 (q, J=31.2 Hz), 122.3 (q, J=285.7 Hz), 123.4,
125.8, 127.5, 131.3, 134.8, 143.7, 168.1. 19F NMR  –72.53 (s). IR (CHCl3)  3020, 2946, 1771,
1379, 1274, 1259, 1216, 1189, 1167, 1119, 1015, 942, 929, 854, 760, 670, 492 cm–1. HRMS (FAB+,
m/z): [M+H]+ calcd for C14H15F3NO2, 286.1055 ; Found, 286.1079.
4.2.17 3-Morpholino-3-(trifluoromethyl)isobenzofuran-1(3H)-one (6c)
1 (0.123 g, 0.501 mmol) and morpholine (0.05 mL, 0.57 mmol) was reacted to give 0.140 g of
6c (0.488 mmol, 98% yield) as a white solid. Rf=0.34 (hexane:AcOEt=2:1). mp 83.2 °C. 1H
NMR  2.57-2.64 (2H, m), 2.86-2.93 (2H, m), 3.64-3.77 (4H, m), 7.61-7.81 (3H, m), 7.94-7.97 (1H,
m). 13C NMR  46.69, 46.72, 66.35, 66.36, 99.1 (q, J=31.2 Hz), 122.1 (q, J=286.0 Hz), 123.6, 126.1,
127.4, 131.7, 135.0, 142.5, 167.5. 19F NMR  –73.09 (s). IR (KBr)  3006, 2966, 2919, 2898,
2861, 1779, 1305, 1464, 1455, 1340, 1309, 1268, 1217, 1160, 1119, 1103, 1086, 1036, 986, 888
cm–1. HRMS (FAB+, m/z): [M+2H]+ calcd for C13H14F3NO3, 289.0926 ; Found, 289.0952.
4.3.1 9b-(Trifluoromethyl)-2,3-dihydrooxazolo[2,3-a]isoindol-5(9bH)-one (15)
A 1,2-dichloroethane (0.5 mL) solution containing 0.117 g of 3-hydroxy-2-(2-hydroxyethyl)-
3-(trifluoromethyl)isoindolin-1-one (5i, 0.450 mmol) and 0.171 g of p-TsOH·H2O (0.900 mmol) was
heated to 80 ºC and the stirring was continued for 6 h. The usual work-up, followed by purification
by silica gel column chromatography (hexane:AcOEt=2:1) afforded 0.096 g of the title compound 15

(0.395 mmol, 88% yield). Rf=0.43 (hexane:AcOEt=2:1). 1H NMR  3.52-3.63 (1H, m), 4.15-4.29
(2H, m), 4.42-4.47 (1H, m), 7.61-7.82 (3H, m), 7.82-7.85 (1H, m). 13C NMR  43.3, 71.6, 96.5 (q,
J=33.1 Hz), 123.5 (q, J=285.9 Hz), 123.9, 124.7, 131.7, 132.3, 133.8, 139.9, 172.8. 19F NMR  –
80.69 (s). IR (CHCl3)  3083, 3059, 2983, 2913, 1739, 1613, 1469, 1350, 1327, 1308, 1246, 1177,
1082, 1062, 1004, 962, 955, 763, 731, 702 cm–1. HRMS (FAB+, m/z): [M+2H]+ calcd for
C11H10F3NO2, 245.0664 ; Found, 245.0712.
References and notes
[1] K. Mitobe, K. Terashima, T. Kawasaki-Takasuka, T. Agou, T. Kubota, T. Yamazaki,
Preparation and reactions of CF3‐ containing phthalides, Eur. J. Org. Chem. in press.
https://doi.org/10.1002/ejoc.201801384.
[2] (a) G.K. Surya Prakash, A.K. Yudin, Perfluoroalkylation with organosilicon reagents, Chem.
Rev. 97 (1997) 757–786;
(b) J.-A. Ma, D. Cahard, Asymmetric fluorination, trifluoromethylation, and
perfluoroalkylation reactions, Chem. Rev. 108 (2008) 1–43.
[3] (a) For the reaction of the Ruppert-Prakash reagent with esters, see, J. Wiedemann, T. Heiner,
G. Mloston, G.K. Surya Prakash, G.A. Olah, Direct preparation of trifluoromethyl ketones from
carboxylic esters: trifluoromethylation with (trifluoromethyl)trimethylsilane, Angew. Chem.
Int. Ed. Engl. 37 (1998) 820–821;
(b) R.P. Singh, G.-F. Cao, R.L. Kirchmeier, J.M. Shreeve, Cesium fluoride catalyzed
trifluoromethylation of esters, aldehydes, and ketones with (trifluoromethyl)trimethylsilane, J.
Org. Chem. 64 (1999) 2873–2876.
[4] This compound was previously synthesized in 45% yield starting from 1,2-dibromobenzene.
See, U.D.G. Prabhu, K.C. Eapen, C. Tamborski, Regiospecific synthesis of aromatic
compounds via organometallic intermediates. 4. Synthesis of ortho-disubstituted benzenes, J.
Org. Chem. 49 (1984) 2792–2795.
[5] (a) M.W. Rathke, M. Nowak, The Horner-Wadsworth-Emmons modification of the Wittig
reaction using triethylamine and lithium or magnesium salts, J. Org. Chem. 50 (1985) 2624–
2626;
(b) M.A. Blanchette, W. Choy, J.T. Davis, A.P. Essenfeld, S. Masamune, W.R. Roush, T. Sakai,
Horner-Wadsworth-Emmons reaction: Use of lithium chloride and an amine for base-sensitive
compounds, Tetrahedron Lett. 27 (1986) 2183–2186.
[6] (a) This process contains an interesting proton shift which was already reported by us as well
as others. Y. Hamada, T. Kawasaki-Takasuka, T. Yamazaki, Base-promoted isomerization of
CF3-containing allylic alcohols to the corresponding saturated ketones under metal-free

conditions, Beilstein J. Org. Chem. 13 (2017) 1507–1512;
(b) A. Ikeda, M. Omote, S. Nomura, M. Tanaka, A. Tarui, K. Sato, A. Ando, Oxidative 3,3,3-
trifluoropropylation of arylaldehydes, Beilstein J. Org. Chem. 9 (2013) 2417–2421;
(c) S. Martinez-Erro, A. Sanz-Marco, A.B. Gómez, A. Vázquez-Romero, M.S.G. Ahlquist, B.
Martín-Matute, Base-catalyzed stereospecific isomerization of electron-deficient allylic
alcohols and ethers through ion-pairing, J. Am. Chem. Soc. 138 (2016) 13408–13414.
[7] A similar type of fluorinated -lactams have already been reported in the literature. For
example, (a) A.G. Griesbeck, N. Nazarov, J.M. Neudörfl, M. Heffen, Intermolecular
photodecarboxylation of electron-deficient substrates by phthalimides in water: efficiency,
selectivity and online monitoring, Green Chem. 14 (2012) 3004–3006.
(b)
Bis(difluoromethyl)trimethylsilicate anion: key intermediate in nucleophilic
A
difluoromethylation of enolizable ketones with Me3SiCF2H, D.-B. Chen, C.-F. Ni, Y.-C. Zhao,
X. Cai, X.-J. Li, P. Xiao, J.-B. Hu, Angew. Chem. Int. Ed. 55 (2016) 12632–12636. (c) C.
Masusai, D. Soorukram, C. Kuhakarn, V. Reutrakul, M. Pohmakotr, Stereoselective synthesis
of gem-difluoromethylenated linear azatriquinanes, Eur. J. Org. Chem. (2018) 160–169. (d)
S.B. Munoz, V. Krishnamurti, P. Barrio, T. Mathew, G.K. Surya Prakash, Direct
difluorination− hydroxylation, trifluorination, and C(sp2)−H fluorination of enamides, Org. Lett.
20 (2018) 1042–1045.
[8] V. Pharikronburee, T. Punirun, D. Soorukram, C. Kuhakarn, P. Tuchinda, V. Reutrakul, M.
Pohmakotr, Fluoride-catalyzed nucleophilic addition of PhSCF2SiMe3 to anhydrides: synthesis
of γ-difluoromethylated γ-lactams, Org. Biomol. Chem. 11 (2013) 2022–2033.
[9] This type of substitution seemed to be extremely rare even in the case of non-fluorinated
compounds, and only 1 example was found under photolysis conditions for the isobenzofuran-
1-one with an alkoxy group at the 3-position where the reaction should be actually occurred.
See, S.V. Kessar, A.K.S. Mankotia, K.R. Agnihotri, Intramolecular photoreactions of 2-
formylbenzamides and 2-formylbenzylamines, J. Chem. Soc., Chem. Commun. (1993) 598–
599.
[10] (a) Similar compounds were reported by using different processes. T. Billard, B.R. Langlois,
G. Blond, Trifluoromethylation of nonenolizable carbonyl compounds with a stable piperazino
hemiaminal of trifluoroacetaldehyde, Eur. J. Org. Chem. (2001) 1467–1471;
(b) A. Hoffmann-Roeder, P. Seiler, F. Diederich, Nucleophilic trifluoromethylation of cyclic
imides using (trifluoromethyl)trimethylsilane CF3SiMe3, Org. Biomol. Chem. 2 (2004) 2267–
2269;
(c) S. Mizuta, N. Shibata, M. Hibino, S. Nagano, S. Nakamura, T. Toru, Ammonium
bromides/KF
catalyzed
trifluoromethylation
of
carbonyl
compounds
with
(trifluoromethyl)trimethylsilane and its application in the enantioselective trifluoromethylation
reaction, Tetrahedron 63 (2007) 8521–8528;
(d) V.K. Pandey, P. Anbarasan, One-pot cascade trifluoromethylation/cyclization of imides:
Synthesis of ‑ trifluoromethylated amine derivatives, J. Org. Chem. 79 (2014) 4154–4160;
(e) J. Ozawa, M. Tashiro, J.-Z. Ni, K. Oisaki, M. Kanai, Chemo- and regioselective oxygenation

of C(sp3)–H bonds in aliphatic alcohols using a covalently bound directing activator and
atmospheric oxygen, Chem. Sci. 7 (2016) 1904–1909;
(f) Y. Kadoh, K. Oisaki, M. Kanai, Enhanced structural variety of nonplanar N-oxyl radical
catalysts and their application to the aerobic oxidation of benzylic C–H bonds, Chem. Pharm.
Bull. 64 (2016) 737–753.
[11] For example, the pKa value of the protonated aniline is reported to be 4.60 which is lower than
the one benzylamine of 9.35. Lange’s Handbook of Chemistry, 15th Ed. (Ed.; J.A. Dean):
McGraw-Hill, New York, 1999.
[12] K. Aksjonova, S. Belyakov, E. Liepinsh, A. Boman, T. Lundstedt, P. Lek, P. Trapencieris,
Functionalization of 3-chlorobenzaldehyde, Synthesis 44 (2012) 2200-2208.
[13] Full optimization of each species was carried out by Gaussian 09W (rev. D01) using the
B3LYP/ 6-31+G* level of theory, followed by the single point calculation using the CPCM
method for consideration of the solvent effect by THF. Gaussian 09W (Rev. D.01), M.J.
Frisch, G.W. Trucks, H.B. Schlegel, G.E. Scuseria, M.A. Robb, J.R. Cheeseman, G. Scalmani,
V. Barone, B. Mennucci, G.A. Petersson, H. Nakatsuji, M. Caricato, X. Li, H.P. Hratchian,
A.F. Izmaylov, J. Bloino, G. Zheng, J.L. Sonnenberg, M. Hada, M. Ehara, K. Toyota, R.
Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai, T. Vreven, J.A.
Montgomery, Jr., J.E. Peralta, F. Ogliaro, M. Bearpark, J.J. Heyd, E. Brothers, K.N. Kudin,
V.N. Staroverov, R. Kobayashi, J. Normand, K. Raghavachari, A. Rendell, J.C. Burant, S.S.
Iyengar, J. Tomasi, M. Cossi, N. Rega, N.J. Millam, M. Klene, J.E. Knox, J.B. Cross, V.
Bakken, C. Adamo, J. Jaramillo, R. Gomperts, R.E. Stratmann, O. Yazyev, A.J. Austin, R.
Cammi, C. Pomelli, J.W. Ochterski, R.L. Martin, K. Morokuma, V.G. Zakrzewski, G.A. Voth,
P. Salvador, J.J. Dannenberg, S. Dapprich, A.D. Daniels, Ö. Farkas, J.B. Foresman, J.V. Ortiz,
J. Cioslowski, D.J. Fox, Gaussian: Wallingford, CT, 2009.
[14] CCDC 1817610 contains the supplementary crystallographic data for the -lactone compound
6c.
[15] K. B. Sloan, S. A. M. Koch, Effect of nucleophilicity and leaving group ability on the SN2
reactions of amines with (acyloxy)alkyl -halides: A product distribution study, J. Org. Chem.
48 (1983) 635–640.
[16] (a) Some compounds possessing this 2,3-dihydrooxazoloisoindolinone structure were reported
to possess biological activities. See, N.A.L. Pereira, F.X. Sureda, M. Turch, M. Amat, J.
Bosch, M.M.M. Santos, Synthesis of phenylalaninol-derived oxazolopyrrolidone lactams and
evaluation as NMDA receptor antagonists, Monatsh. Chem. 144 (2013) 473–477;
(b) J. Soares, N.A.L. Pereira, A. Monteiro, M. Leao, C. Bessa, D.J.V.A. dos Santos, L. Raimundo, G.
Queiroz, A. Bisio, A. Inga, C. Pereira, M.M.M. Santos, L. Saraiva, Oxazoloisoindolinones with
in vitro antitumor activity selectively activate a p53-pathway through potential inhibition of the
p53–MDM2 interaction, Eur. J. Pharm. Sci. 66 (2015) 138–147.
Figures

Scheme 1. Representative transformation of the phthalide 1.
Scheme 2. The plausible mechanism for the reaction of 1 with primary amines.
Scheme 3. Reactions of 1 with hydrazines
Scheme 4. Reactions of 1 with cyclic secondary amines.
Scheme 5. Intramolecular cyclization of 5i
OH
O
(EtO)2P(O)CH2CO2Et
LiBr, Et3N
O
CO2Et
CF3
CF3
EtO
3
50% yield
2
88% yield
LiAlH4
O
O
O
MeLi (2.2 equiv)
CF3
CF3
EtO
HO
1
4
74% yield
RNH2,
rt, 2-4 h
R2NH,
rt, 6 h
O
O
N-R
CF3
O
CF3
R2N
HO
5
6
PhCH2NH2,
cat. TsOH,
toluene
O
O
O
NCH2Ph
OH
reflux, 24 h
OMe
PhSCF2
PhSCF2
95% yield
7
8

Table 1. Reaction of the phthalide 1 with a variety of primary amines.
Entry
1a,b PhCH2–
R
Time (h)
Isolated yield (%)
96 (5a)
2
2
3
2
3
3
2
4
2
PhCH2–
95 (5a)
3b
4
4-MeO-C6H4CH2–
PhCH2CH2–
Me–
86 (5b)
91 (5c)
5c
6
94 (5d)
Bu–
96 (5e)
7b,c H–
8d
OH–
78 (5f)
71 (5g)

9e
10
Ph–
24
2
76 (5h)
HOCH2CH2–
H2NCH2CH2–
H2NCH2CH2–
91 (5i)
11b
12f
2
52 (5j) 38 (9)
73 (9)
2
a This reaction was performed in the presence of a catalytic amount
b
of TsOH in toluene under 2 h reflux.
2 equiv of an amine was
c
used.
40% (Entry 5) and 25% (Entry 7) aqueous solutions were
e
employed. d NH2OH·HCl and Et3N (2.0 equiv each) were used.
The reaction was carried out under reflux. f 5 equiv of 1 was used
to 1,2-ethylenediamine.