Fluoride-catalyzed nucleophilic addition of PhSCF2SiMe 3 to anhydrides: Synthesis of γ-difluoromethylated γ-lactams

Article abstract of DOI:10.1039/c3ob27193e

PhSCF₂SiMe₃ (1) underwent fluoride-catalyzed nucleophilic addition to the carbonyl group of anhydrides to provide the corresponding γ-difluoro(phenylsulfanyl)methyl γ-lactols, which were employed for the synthesis of γ-difluoromethyl

Full text of DOI:10.1039/c3ob27193e

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Fluoride-catalyzed nucleophilic addition of
PhSCF2SiMe3 to anhydrides: synthesis of
Cite this: Org. Biomol. Chem., 2013, 11,
2022
γ-difluoromethylated γ-lactams†
Vannapha Pharikronburee, Teerachai Punirun, Darunee Soorukram,
Chutima Kuhakarn, Patoomratana Tuchinda, Vichai Reutrakul and
Manat Pohmakotr*
Received 8th November 2012,
Accepted 7th January 2013
PhSCF2SiMe3 (1) underwent fluoride-catalyzed nucleophilic addition to the carbonyl group of anhydrides
to provide the corresponding γ-difluoro(phenylsulfanyl)methyl γ-lactols, which were employed for the
synthesis of γ-difluoromethylated γ-lactams.
DOI: 10.1039/c3ob27193e
www.rsc.org/obc
difluoromethylenated products. However, to the best of our
knowledge, there are no reports on the fluoride-catalyzed
Introduction
Organofluorines are important in pharmaceuticals, agrochem- nucleophilic addition of 1 to succinic anhydrides. As part of
icals and materials, as they often enhance their chemical and our efforts to demonstrate the synthetic utility of 1, we report
metabolic stability, lipophilicity and binding selectivity.1 As a here for the first time fluoride-catalyzed nucleophilic addition
consequence, the development of efficient methodology for of 1 to succinic anhydrides. It was anticipated that the result-
the synthesis of organofluorine compounds has attracted ing adducts 3 and/or 4 could be utilized for the synthesis of
considerable attention in organic synthesis.2 Mostly, syntheses γ-difluoromethylated γ-lactams 8 by sequential esterification,
of organofluorines have involved the use of sulfur tetra- lactamization, reductive cleavage of the hydroxyl group fol-
fluoride,3 diethylaminosulfur trifluoride (DAST),4 Selectfluor,5 lowed by reductive removal of the phenylsulfanyl group as
N-fluoro-bis[(trifluoromethyl)sulfonyl]imide (NFSI),6 and zinc summarized in Scheme 1. It should be emphasized that the
difluoromethylsulfinate7 as fluorinating agents. More recently, γ-lactam moiety is an important subunit found in a number of
electrochemical fluorination,8 electrophilic perfluoroalkyla- biologically active natural products.16 Additionally, a number
tion9 of organic compounds as well as palladium- and copper- of synthetic approaches toward the synthesis of the γ-lactam
catalyzed coupling reactions of nucleophilic fluorinated units and their synthons are still of great interest.17
reagents10 with aryl halides, vinyl halides, alkynes and term-
inal alkenes have been continuously reported.
First introduced by Prakash and co-workers as a nucleophi-
lic (phenylsulfanyl)difluoromethylating agent,11a–c difluoro-
(phenylsulfanyl)trimethylsilane
(PhSCF2SiMe3,
1)
was
employed as a useful difluoromethyl and gem-difluoromethy-
lene building block and its synthetic utilities were reported by
several research groups. Fluoride-catalyzed nucleophilic
addition of
1
with carbonyl compounds,11 ketoesters,12
imines,13 alkyl iodides14 and cyclic imides15 has been demon-
strated and the resulting adducts have been transformed into
the
corresponding
difluoromethylated
and
gem-
Department of Chemistry and Center of Excellence for Innovation in Chemistry,
Faculty of Science, Mahidol University, Rama VI Road, Bangkok 10400, Thailand.
E-mail: manat.poh@mahidol.ac.th; Fax: +66 2 644 5126; Tel: +66 2 201 5158
†Electronic supplementary information (ESI) available: Copies of 1H, 13C, and
19F NMR of all compounds, and COSY-45, HMBC and HMQC of 3fA and 3fB. See
DOI: 10.1039/c3ob27193e
Scheme 1
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inseparable 4 : 1 mixture of diastereomers after aqueous work-
up. The reaction, however, afforded a mixture of 3b and the
Results and discussion
At first, we examined the reaction conditions of the fluoride- corresponding ketoacid 4b in 43% and 18% yields, respect-
catalyzed nucleophilic addition of 1 with phthalic anhydride ively, after work-up with 1 M HCl. The formation of 4b resulted
(2a) as a model reaction. It was found that treatment of 1 from acid-catalyzed ring-opening of the lactol adduct 3b. To
(2 equiv.) with 2a (1 equiv.) in THF in the presence of 10 mol% get more insight into the generality of the fluoride-catalyzed
of TBAF (tetrabutylammonium fluoride) at −78 °C to room nucleophilic addition of 1 to the carbonyl group of anhydrides,
temperature overnight followed by quenching with H2O gave anhydrides 2c–f were chosen as substrates. Under the standard
the expected adduct 3a in 56% yield. The best yield (91%) of conditions as for 2a, 1 reacted smoothly with anhydride 2c to
3a was obtained when 10 mol% of TBAT (tetrabutylammonium give the desired adduct 3c in 88% yield as an inseparable
triphenyldifluorosilicate) in THF was employed and the reac- 12.6 : 3.4 : 1 mixture of three diastereomers as revealed by 19F
tion was carried out at −10 °C to room temperature overnight NMR. We proposed that the major isomers of compounds 3b
(Table 1, entry 1). The reaction of 1 with 2b using 10 mol% of and 3c arose from the fluoride-catalyzed nucleophilic attack on
TBAT provided good yields of the expected adduct 3b as an the carbonyl group of the anhydride from the less hindered
Table 1 Preparation of compounds 3, 4 and 5
Entry
1
Anhydrides 2
3a (yield)
5a (yield)
2
3
4
5
6
f
—
a Isolated yield. b The ratio was determined by 1H NMR. c The ratio was determined by 19F NMR. d Combined yield of the mixture of cis- and trans-
isomers. e Combined yield of the mixture of products 3d and 4d. f The reaction was not performed.
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exo-face. Low chemoselectivities for the addition of 1 to cyclization to take place. It is worth mentioning that the 1H
unsymmetrical anhydrides 2e and 2f were observed. As shown NMR patterns of the recovered 5Bb are in good agreement
in Table 1 (entries 5–6), 1 : 1 ratios of isomers of the corres- with those of the starting trans-5Bb. This implied that the ther-
ponding adducts 3e and 3f were obtained. The regioisomers modynamically less stable cis-5Bb readily underwent isomeri-
3fA and 3fB were separated by chromatography and their struc- zation to the more stable trans-5Bb under the reaction
tures were established by COSY-45, HMQC and HMBC. Having conditions (p-TsOH in refluxing PhCH3). The trans-5Bb can
established a general access to γ-(difluoro(phenylsulfanyl)- react with benzylamine to yield the corresponding hemiaminal
methyl)-γ-lactols 3, we demonstrated that these compounds but it was unable to undergo cyclization. Upon aqueous work-
can be used as precursors for preparation of γ-difluoromethy- up, the hemiaminal derived from the trans-5Bb underwent
lated γ-lactams 8. Thus, treatment of lactol 3a with thionyl hydrolysis, leading to the recovery of trans-5Bb. Due to the low
chloride in methanol at −78 °C to room temperature for 5 h solubility of 5Bc in toluene, the reaction of 5Bc (5.6 : 1 mixture
afforded a good yield of the corresponding lactol ether 5Aa in of cis- and trans-isomers) with benzylamine and a catalytic
94% yield.
amount of p-TsOH was carried out in refluxing CH2Cl2 to give
A similar result was obtained when a diastereomeric 6c as a mixture of two separable isomers in 45% and 36%
mixture of 3e was employed leading to lactol ether 5Ae as a yields. Similarly to the case of 6b, the two isomers of 6c should
1 : 1 diastereomeric mixture (Table 1, entries 1and 5). The for- have cis-stereochemistry at the fused ring junction. The differ-
mation of lactol ether 5A from 3a and 3e could be rationalized ence should be derived from the stereochemistry at the carbi-
as the initial generation of the corresponding benzylic cation, nol carbon. Unfortunately, we were unable to precisely
followed by trapping by methanol. However, under similar correlate each of the NMR spectra with the exact structures. In
reaction conditions, 3b, 3c and a mixture of 3d and 4d gave the case of 5Ae, a 1 : 1 mixture of isomers of 6e was obtained,
high yields (91–97%) of the corresponding ketoesters 5Bb, 5Bc, as the reaction started from a 1 : 1 mixture of isomers of the
and 5Bd, respectively (Table 1, entries 2–4). The formation of ketoester 5Ae. Compounds 6a and 6e resulted presumably
the ketoester 5B resulted from acid-catalyzed ring-opening of from acid-catalyzed nucleophilic attack of benzylamine at the
3b–d to the corresponding ketoacid 4 followed by esterifica- carboxyl group of 5Aa and 5Ae followed by intramolecular
tion. As shown in Table 1, the 8 : 1 and 5.6 : 1 mixtures of 5Bb nucleophilic addition of the resulting ketoamides (Scheme 2,
and 5Bc, respectively, were obtained. The results could be eqn (1)). The formation of 5Bb–5Bd was explained by acid-cata-
explained by isomerization of the α-carbon next to the keto lyzed nucleophilic attack of benzylamine at the keto group of
group of the expected cis-isomer of the ketoesters 5Bb and 5Bc 5Bb–5Bd followed by lactamization of the initially formed
partly occurring during work-up conditions to lead to their aminol adduct (Scheme 2, eqn (2)).
trans-isomers.
Our next task was to accomplish the preparation of
Next, we investigated a synthetic conversion of the lactol γ-difluoromethylated γ-lactams
8
from γ-diflurorinated
ethers 5A and ketoesters 5B to N-benzyl-γ-hydroxy-γ-lactams 6, γ-hydroxy γ-lactams 6 by consecutive acid-catalyzed reduction
which was expected to be a precursor to for further transfor- reaction of compound 6 to 7 followed by reductive cleavage of
mation to the required γ-difluoromethylated γ-lactams 8 as the PhS–C bond of compound 7.12 Thus, compounds 6a–e
shown in Scheme 2. Thus, the reaction of 5Aa with benzyl- were transformed into the corresponding γ-(difluoro(phenyl-
amine and a catalytic amount of p-toluenesulfonic acid sulfanyl)methyl)-γ-lactams 7a–e in good yields (83–96%) by
(p-TsOH) in toluene under reflux overnight (15 h) led to the reacting with Et3SiH (10 equiv.) and BF3·OEt2 (3 equiv.) in dry
formation of 6a in good yield (96%). Under similar reaction CH2Cl2 at −78 °C to room temperature overnight. The mechan-
conditions, the 8 : 1 mixture of cis- and trans-isomers of 5Bb ism for the reduction of 6 to 7 could be rationalized by inital
afforded the corresponding lactam 6b as a single isomer in formation of an iminium ion intermediate 6A, followed by
48% yield, together with the recovered starting material 5Bb hydride addition from the same side of the hydrogen atom at
(52% yield). Unfortunately, the stereochemistry of 6b could not the ring-junction in order to avoid the steric interaction with
be established by means of any spectroscopic methods. the cyclohexane or cyclohexene ring to provide 7b or 7c as the
However, we thought that 6b should possess cis-stereo- sole stereoisomer (Scheme 3). Our proposed mechanism was
chemistry at the fused ring junction in order to allow the further confirmed when a mixture of two diastereomers
(1.3 : 1) of 6c was subjected to the acid-catalyzed reduction
reaction. Compound 7c was isolated in 81% yield as a single
isomer. Its 1H NMR patterns are similar to those obtained
when a major isomer of 6c was employed as a starting material
Scheme 2 Proposed mechanism for the formation of 6.
2024 | Org. Biomol. Chem., 2013, 11, 2022–2033
Scheme 3 Proposed mechanism for the reduction of 6.
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Table 2 Preparation of compounds 6, 7 and 8
Entry
1
5
6a (yield)
7a (yield)
8a (yield)
5Aa
2
5Bb (cis : trans = 8 : 1)
3
4
5
5Bc (cis : trans = 5.6 : 1)
5Bd
5Ae
a Isolated yield. b The ratio was determined by 1H NMR. c The reaction was carried out in CH2Cl2. d The ratios were determined by 19F NMR.
e The major diastereomer of 6c was used.
Conclusions
In summary, we have successfully demonstrated for the
first time
a fluoride-catalyzed nucleophilic addition of
PhSCF2SiMe3 (1) to various anhydrides to afford γ-phenylsulfa-
nyldifluoromethyl-γ-lactol derivatives, which were employed as
the starting materials for the synthesis of γ-difluoromethylated
γ-lactams. Thus, the research results provided a general entry
to γ-difluoromethylated γ-lactams and described a synthetic
application of PhSCF2SiMe3 as a difluoromethyl synthon.
Fig. 1 Observed NOE of 7c.
(Table 2, entry 3). The relative stereochemistry of 7c as shown
in entry 3 (Table 2) was confirmed by NOE experiments as
depicted in Fig. 1. Similarly, we assumed therefore that the
relative stereochemistry of 7b is as shown in Table 2 (entry 2).
Finally, reductive cleavage of the phenylsulfanyl group of 7
to the required γ-difluoromethylated γ-lactams 8 was smoothly
Experimental
General
achieved by treatment of 7 with Bu3SnH and a catalytic The 1H NMR spectra were recorded on either a Bruker-300
amount of AIBN in refluxing toluene. The results of our inves- (300 MHz) or a Bruker-500 (500 MHz) spectrometer in CDCl3
tigation are summarized in Table 2. γ-Difluoromethylated using tetramethylsilane as an internal standard. The 13C NMR
γ-lactams 8a–e were obtained in 69–98% yields as listed in spectra were recorded on either a Bruker DPX-300 (75 MHz) or
Table 2.
a
Bruker-500 (125 MHz) spectrometer in CDCl3 using
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tetramethylsilane as an internal standard. The 19F NMR 1H, CHH), 2.65* (dt, J = 5.5, 12.1 Hz, 2H, CH2), 2.28–2.19* (m,
spectra were recorded on a Bruker-500 (470 MHz) spectrometer 2H, CH2), 2.19–2.10* (m, 2H, CH2), 2.03–1.93 (m, 1H, CHH),
and chemical shifts (δ) were measured with fluorotrichloro- 1.85–1.70 (m, 3H, 3 × CHH), 1.68–1.55 (m, 1H, CHH),
methane (δ = 0) as an internal standard. The IR spectra were 1.53–1.30 (m, 3H, 3 × CHH), 1.19–1.05* (m, 2H, CH2). 13C NMR
recorded on either a Jasco A-302 or Perkin Elmer 683 infrared (125 MHz, CDCl3, minor isomer marked*): δ 175.8* (C), 175.4
spectrometer. The mass spectra were recorded by using a (C), 136.9* (2 × CH), 136.8 (2 × CH), 136.7* (CH), 130.4 (CH),
Thermo Finnigan Polaris Q mass spectrometer. The high reso- 129.2 (2 × CH), 129.1* (2 × CH), 128.1 (t, J = 279.9 Hz, CF2),
lution mass spectra were recorded on either a HR-TOF-MS 124.4 (C), 104.4 (dd, J = 28.4, 28.5 Hz, C), 43.9* (CH), 39.9
Micromass model VQ-TOF2 or a Finnigan MAT 95 mass spec- (CH), 39.0* (CH), 37.6 (CH), 24.2* (CH2), 23.6 (CH2), 23.2*
trometer. Melting points were recorded on
a
Büchi (CH2), 22.7 (CH2), 22.5 (CH2), 22.4 (CH2), 22.3* (CH2), 22.1
501 melting point apparatus and are uncorrected. Tetrahydro- (CH2). Some peaks of the minor isomer could not be detected
furan was distilled from sodium-benzophenone ketyl. Dichloro- by 13C NMR due to their low intensity. 19F NMR (470 MHz,
methane and toluene were distilled over calcium hydride and CDCl3, minor isomer marked*): δ −87.2 (d, J = 212.7 Hz, 1F),
stored over activated molecular sieves (4 Å). Dry methanol was −86.5 (d, J = 212.7 Hz, 1F), −85.1* (d, J = 215.0 Hz, 1F), −83.2*
obtained by distilling over magnesium turnings. All glassware (d, J = 215.0 Hz, 1F). IR (KBr): νmax 3381s, 1780s, 1260m cm−1
.
and syringes were oven-dried and kept in a desiccator before MS: m/z (% relative intensity) 314 (M+, 2), 160 (43), 155 (75),
use. Preparative thin-layer chromatography (PLC) was per- 126 (21), 109 (74), 81 (100). HRMS (ESI-TOF) calcd
formed by using Merck silica gel 60 PF254 (Art 7747). Column C15H16F2O3SNa [M + Na]+: 337.0686; found: 337.0673.
and flash column chromatography were performed by using
Merck silica gel 60 (Art 7734 and 7736, respectively).
3-(Difluoro(phenylsulfanyl)methyl-3-hydroxy-3a,4,7,7a-tetra-
hydroisobenzofuran-1(3H)-one (3c). According to the general
procedure A, the reaction of 1 (0.93 g, 4.0 mmol) and cis-1,2,3,6-
tetrahydrophthalic anhydride (0.30 g, 2.0 mmol, 19 : 1 cis-
General procedure A for the preparation of compounds 3
3-(Difluoro(phenylsulfanyl)methyl)-3-hydroxyisobenzofuran- dominant) provided a 12.6 : 3.4 : 1 mixture of isomers of 3c
1(3H)-one (3a). To a solution of 1 (0.93 g, 4.0 mmol) in THF (0.55 g, 88% yield) as a white solid after flash column chrom-
(3 mL) and phthalic anhydride (0.30 g, 2.0 mmol) at −10 °C atography (SiO2, 20% AcOEt in hexanes): m.p. 80–87 °C
was added a solution of 10 mol% TBAT (0.22 g, 0.4 mmol) in (AcOEt/hexanes). 1H NMR (500 MHz, CDCl3): δ 7.60–7.50 (m,
THF (2 mL). The reaction mixture was stirred at −10 °C (6 h) 4H, ArH of major and minor isomers), 7.42–7.28 (m, 6H, ArH
then quenched with water (3 mL) and extracted with AcOEt (3 of major and minor isomers), 6.00–5.38 (m, 2H, 2 × CH of
× 15 mL). The combined organic phase was washed with water major and minor isomers), 4.75–3.75 (br, 2H, OH of major and
(10 mL), brine (10 mL) and dried (anh. Na2SO4). Purification minor isomers), 3.50–2.80 (m, 4H, 2 × CH of major and minor
of the crude product by flash column chromatography (SiO2, isomers), 2.75–2.20 (m, 8H, 2 × CH2 of major and minor
20% AcOEt in hexanes) gave 3a as a white solid (0.56 g, 91% isomer). 13C NMR (125 MHz, CDCl3,): δ 176.3 (C), 136.8 (2 ×
yield): m.p. 79–80 °C (CH2Cl2/hexanes). 1H NMR (500 MHz, CH), 135.1 (C), 130.4 (CH), 129.2 (2 × CH), 127.9 (CH), 126.9
CDCl3): δ 7.96–7.92 (m, 1H, ArH), 7.80–7.74 (m, 2H, ArH), (CH), 125.4 (t, J = 314.6 Hz, CF2), 124.4 (CH), 104.8 (C), 38.2
7.74–7.68 (m, 1H, ArH), 7.63–7.58 (m, 2H, ArH), 7.50–7.45 (m, (CH), 36.3 (CH), 23.5 (CH2), 20.7 (CH2). Due to low intensity,
1H, ArH), 7.43–7.36 (m, 2H, ArH), 4.75–4.50 (br, 1H, OH). 13C the minor isomer could not be detected by 13C NMR. 19F NMR
NMR (125 MHz, CDCl3): δ 166.8 (C), 143.0 (2 × C), 136.8 (CH), (470 MHz, CDCl3): δ −88.1 (d, J = 212.7 Hz, 1F), −87.2 (d, J =
134.9 (CH), 131.9 (CH), 130.3 (CH), 129.2 (2 × CH), 127.4 (C), 212.7 Hz, 1F), −84.4 (d, J = 214.8 Hz, 1F), −83.1 (d, J = 214.8 Hz,
126.3 (t, J = 287.3 Hz, CF2), 125.7 (2 × CH), 124.5 (CH), 102.9 (t, 1F), −82.0 (d, J = 222.1 Hz, 1F), −80.9 (d, J = 222.1 Hz, 1F).
J = 30.4 Hz, C). 19F NMR (470 MHz, CDCl3): δ −87.1 (d, J = IR (KBr): νmax 3447br, 1734s, 1698s, 1442m, 1385m, 1119m,
213.4 Hz, 1F), −84.5 (d, J = 213.4 Hz, 1F). IR (KBr): νmax 3120br, 1036w, 943w, 751w, 691w cm−1. MS: m/z (% relative intensity)
1757s, 1276m, 945s cm−1. MS: m/z (% relative intensity) 309 312 (M+, 6), 293 (19), 273 (11), 160 (15), 153 (34), 126 (13), 97
(M+ + 1, 11), 308 (M+, 7), 160 (38), 149 (100), 121 (22), 65 (17). (14), 79 (100), 76 (44), 51 (9). HRMS (ESI-TOF) calcd
HRMS (ESI-TOF) calcd C15H10F2O3SNa [M + Na]+: 331.0216; C15H14F2O3SNa [M + Na]+: 335.0529; found: 335.0545.
found: 331.0231.
A mixture of 5-(difluoro(phenylsulfanyl)methyl)-5-hydroxydi-
3-(Difluoro(phenylsulfanyl)methyl)-3-hydroxy-hexahydroiso- hydrofuran-2(3H)-one (3d) and 5,5-difluoro-4-oxo-5-(phenylsul-
benzofuran-1(3H)-one (3b). According to the general procedure fanyl)pentanoic acid (4d). According to the general procedure
A, the reaction of 1 (0.93 g, 4.0 mmol) and hexahydrophthalic A, the reaction of 1 (0.93 g, 4.0 mmol) and succinic anhydride
anhydride (0.31 g, 2.0 mmol) provided a white solid of 3b (0.20 g, 2.0 mmol) gave a 1 : 7 mixture of 3d and 4d (0.44 g,
(0.55 g, 88% yield) as a 4 : 1 mixture of isomers after flash 85% yield) as colorless oil after flash column chromatography
1
column chromatrography (SiO2, 20% AcOEt in hexanes): (SiO2, 20% AcOEt in hexanes). H NMR (300 MHz, CDCl3, 3d
m.p. 90–97 °C (AcOEt/hexanes). 1H NMR (500 MHz, CDCl3, marked*): δ 8.39 (br, 1H, OH), 7.75–7.65 (m, 4H, ArH of 3d and
minor isomer marked*): δ 7.66–7.58 (m, 4H, ArH of major and 4d), 7.65–7.32 (m, 6H, ArH of 3d and 4d), 3.03 (t, J = 6.3 Hz,
minor isomers), 7.50–7.46 (m, 6H, ArH of major and minor 2H, CH2), 2.95–2.75* (m, 2H, CH2), 2.68 (t, J = 6.3 Hz, 2H,
isomers), 4.11 (br, 1H, OH), 3.40* (br, 1H, OH), 3.25* (t, J = CH2), 2.41–2.30* (m, 2H, CH2).13C NMR (75 MHz, CDCl3, 3d
6.2 Hz, 1H, CHH), 2.98–2.88 (m, 2H, 2 × CH), 2.88–2.78* (m, marked*): δ 194.5 (t, J = 29.5 Hz, C), 177.4 (C), 174.8* (C),
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136.7* (2 × CH), 136.4 (2 × CH), 130.5 (CH), 130.2* (CH), 129.3 3fB: m.p. 170–171 °C (CH2Cl2/hexanes). 1H NMR (500 MHz,
(2 × CH), 129.1* (2 × CH), 124.4* (t, J = 266.1 Hz, CF2), 124.3 CD3OD): δ 8.29 (dd, J = 0.8, 8.0 Hz, 1H, ArH), 8.24 (dd, J = 0.9,
(C), 124.2* (C), 122.2 (t, J = 287.5 Hz, CF2), 105.0* (dt, J = 7.3, 7.6 Hz, 1H, ArH), 7.97 (t, J = 7.9 Hz, 1H, ArH), 7.53–7.48 (m,
29.1 Hz, C), 31.1 (CH2), 29.0* (CH2), 28.0* (CH2), 26.8 (CH2). 2H, ArH), 7.47–7.42 (m, 1H, ArH), 7.39–7.33 (m, 2H, ArH).
19F NMR (470 MHz, CDCl3, 3d marked*): δ −85.4 (s, 2F), 13C NMR (125 MHz, CD3OD): δ 166.3 (C), 148.6 (C), 137.9 (2 ×
−88.4* (s, 2F). IR (neat): νmax 3205br, 3064br, 2928br, 1739s, CH), 136.1 (C), 135.0 (CH), 132.4 (C), 131.5 (CH), 131.4 (CH),
1714s, 1442m, 1232m, 1176m, 1089m, 1066m cm−1. MS: m/z 131.1 (CH), 130.2 (2 × CH), 128.3 (t, J = 285.6 Hz, CF2), 126.0
(% relative intensity) 260 (M+, 14), 241 (6), 196 (4), 162 (5), 161 (C), 100.0 (C). 19F NMR (470 MHz, CD3OD): δ −84.2 (d, J =
(11), 160 (100), 159 (23), 139 (6), 111 (5), 110 (23), 101 (60), 78 211.3 Hz, 1F), −85.1 (d, J = 211.3 Hz, 1F). IR (KBr): νmax 3427br,
(5), 73 (21), 65 (13), 55 (40). HRMS (ESI-TOF) calcd 1796s, 1535s, 1471m, 1441m, 1361s, 765m, 777m cm−1. MS:
C11H10F2O3SNa [M + Na]+: 283.0216; found: 283.0211.
m/z (% relative intensity) 353 (M+, 3), 196 (15), 194 (100), 178
A mixture of 3-(difluoro(phenylsulfanyl)methyl)-3-hydroxy-6- (60), 177 (8), 159 (99), 150 (28), 148 (19), 125 (8), 110 (38), 104
methylisobenzofuran-1(3H)-one and 3-(difluoro(phenylsulfa- (59), 78 (12), 77 (51), 76 (30), 75 (21), 63 (17). HRMS (ESI-TOF)
nyl)methyl)-3-hydroxy-5-methylisobenzofuran-1(3H)-one (3e). calcd C15H9F2O5NSNa [M + Na]+: 376.0067; found: 376.0020.
According to the general procedure A, the reaction of 1 (0.93 g,
General procedure B for the preparation of compounds 5
4.0 mmol) and 4-methylpthalic anhydride (0.33 g, 2.0 mmol)
provided a 1 : 1 mixture of regioisomers of 3e (0.52 g, 77%) as
3-(Difluoro(phenylsulfanyl)methyl)-3-methoxyisobenzofuran-
a white solid after flash column chromatography (SiO2, 20% 1(3H)-one (5Aa). To a solution of 3a (32 mg, 0.1 mmol) in dry
1
AcOEt in hexanes): m.p. 110–117 °C (AcOEt/hexanes). H NMR MeOH (2 mL) was slowly added SOCl2 (0.02 mL, 0.3 mmol)
(500 MHz, CDCl3): δ 7.76–7.72 (m, 1H, ArH), 7.66–7.16 (m, 2H, under an argon atmosphere. The reaction mixture was stirred
ArH), 7.60 (m, 4H, ArH), 7.55–7.50 (m, 2H, ArH), 7.46–7.41 (m, at −78 °C followed by slowly warming up to room temperature
3H, ArH), 7.39–7.33 (m, 4H, ArH), 2.48 (s, 3H, CH3), 2.47 (s, for 5 h. The reaction was quenched with sat. Na2CO3 (1 mL) at
3H, CH3). 13C NMR (125 MHz, CDCl3): δ 167.7 (C), 167.6 (C), 0 °C and then methanol was removed under vacuo. The
146.6 (C), 143.7 (C), 142.5 (C), 140.6 (C), 136.7 (2 × CH), 136.7 aqueous layer was extracted with AcOEt (3 × 3 mL). The com-
(2 × CH), 135.9 (CH), 132.8 (CH), 130.1 (3 × CH), 129.0 (3 × bined organic phase was washed with water, brine and dried
CH), 127.3 (2 × C), 126.3 (t, J = 286.9 Hz, CF2), 126.3 (t, J = (anh. Na2SO4). The crude was purified by column chromato-
287.0 Hz, CF2), 125.7 (CH), 125.4 (CH), 124.8 (CH), 124.7 (C), graphy (SiO2, 10% AcOEt in hexanes) to afford a colorless oil of
1
124.5 (C), 124.1 (CH), 103.8 (t, J = 30.9 Hz, C), 103.4 (t, J = 5Aa (30 mg, 94% yield). H NMR (500 MHz, CDCl3): δ 7.89 (d,
30.3 Hz, C). 22.0 (CH3), 21.3 (CH3). 19F NMR (470 MHz, J = 7.7 Hz, 1H, ArH), 7.73–7.57 (m, 3H, ArH), 7.56–7.51 (m, 2H,
CDCl3): δ −85.5 (s, 4F). IR (KBr): νmax 3379br, 3179br, 1758s, ArH), 7.37–7.33 (m, 1H, ArH), 7.31–7.25 (m, 2H, ArH), 3.16 (s,
1613m, 1475m, 1442m, 1281m, 1117m, 1094m, 1064s, 1041s, 3H, OCH3). 13C NMR (125 MHz, CDCl3): δ 166.5 (C), 140.8 (C),
948s, 780m, 758m cm−1. MS: m/z (% relative intensity) 322 137.0 (2 × C), 134.7 (CH), 132.0 (CH), 130.1 (CH), 129.0 (2 ×
(M+, 2), 255 (4), 165 (7), 164 (12), 163 (100), 160 (17), 135 (11), CH), 128.6 (C), 126.4 (t, J = 285.6 Hz, CF2), 125.9 (CH), 125.0
79 (5), 77 (18). HRMS (ESI-TOF) calcd
[M + Na]+: 345.03723; found: 345.0359.
C
16H12F2O3SNa (C), 124.9 (CH), 106.9 (t, J = 30.2 Hz, C), 52.0 (CH3). 19F NMR
(470 MHz, CDCl3): δ −84.7 (d, J = 213.1 Hz, 1F), −83.8 (d, J =
3-(Difluoro(phenylsulfanyl)methyl)-3-hydroxy-7-nitroisoben- 213.1 Hz, 1F). IR (neat): νmax 1782s, 1588m, 1563m, 1475m,
zofuran-1(3H)-one (3fA) and 3-(difluoro(phenylsulfanyl)- 1442m, 1387s, 1277m, 751s, 692s cm−1. MS: m/z (% relative
methyl)-3-hydroxy-4-nitroisobenzofuran-1(3H)-one
(3fB). intensity) 322 (M+, trace), 160 (30), 149 (100), 121 (13), 109 (6),
According to the general procedure A, the reaction of 1 (0.93 g, 93 (7), 77 (6), 65 (15), 51 (7). HRMS (ESI-TOF) calcd.
4.0 mmol) and 3-nitrophthalic anhydride (0.39 g, 2.0 mmol) C16H12F2O3SNa [M + Na]+: 345.0373; found: 345.0380.
provided a pale yellow solid of 3fA (0.26 g, 37% yield) and a
Methyl 2-(2,2-difluoro-2-(phenylsulfanyl)acetyl)cyclo hexane
yellow solid of 3fB (0.29 g, 41% yield) after flash column carboxylate (5Bb). According to the general procedure B, the
chromatography (SiO2, 40% AcOEt in hexanes). 3fA: reaction of a 4 : 1 mixture of 3b (0.19 g, 0.6 mmol) with SOCl2
1
m.p. 149–150 °C. H NMR (500 MHz, CDCl3 + CD3OD): δ 8.12 (0.14 mL, 1.8 mmol) provided a 8 : 1 mixture of cis- and trans-
(dd, J = 1.0, 7.7 Hz, 1H, ArH), 8.06 (dd, J = 0.6, 7.7 Hz, 1H, isomers of 5Bb (0.19 g, 97% yield) as a colorless oil after
ArH), 8.01 (t, J = 8.0 Hz, 1H, ArH), 7.56–7.52 (m, 2H, ArH), column chromatography (SiO2, 10% AcOEt in hexanes).
7.48–7.42 (m, 1H, ArH), 7.41–7.35 (m, 2H, ArH). 13C NMR 1H NMR (300 MHz, CDCl3, minor isomer marked*): δ 7.64 (d,
(125 MHz, CD3OD): δ 163.0 (C), 147.9 (C), 147.8 (C), 137.8 (2 × J = 7.1 Hz, 4H, ArH of major and minor isomers), 7.51–7.45
CH), 137.6 (CH), 131.4 (CH), 130.3 (2 × CH), 129.9 (CH), 127.7 (m, 2H, ArH of major and minor isomers), 7.44–7.38 (m, 4H,
(t, J = 285.8 Hz, CF2), 127.7 (CH), 126.1 (C), 120.7 (C), 104.5 (C). ArH of major and minor isomers), 3.68 (s, 6H, CH3 of major
19F NMR (470 MHz, CD3OD): δ −89.1 (s, 2F). IR (KBr): νmax and minor isomers), 3.68–3.63* (m, 1H, CH), 3.44–3.39 (m, 1H,
3429br, 1787s, 1617w, 1536s, 1474w, 1441w, 1360s, 1039s, CH), 3.00–2.90* (m, 1H, CH), 2.89–2.83 (m, 1H, CH), 2.25–2.03
762m, 754m cm−1. MS: m/z (% relative intensity) 354 (M+ + 1, (m, 4H, CH2 of major and minor isomers), 2.00–1.65 (m, 6H,
40), 194 (74), 178 (100), 159 (58), 148 (53), 139 (21), 120 (7), 110 3 × CHH of major and minor isomers), 1.58–1.30 (m, 6H, 3 ×
(24), 104 (74), 92 (13), 77 (33), 76 (39), 63 (19). HRMS (ESI-TOF) CHH of major and minor isomers). 13C NMR (75 MHz, CDCl3):
calcd C15H9F2NO5SNa [M + Na]+: 376.0067; found: 376.0041. δ 197.3 (t, J = 27.2 Hz, C), 173.5 (C), 136.7 (2 × CH), 130.3 (CH),
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129.1 (2 × CH), 125.0 (C), 123.1 (t, J = 291.5 Hz, CF2), 51.8 IR (neat): νmax 1741s, 1475w, 1441m, 1217m, 1172m, 1102m,
(CH3), 43.6 (CH), 43.0 (CH), 25.9 (CH2), 25.7 (CH2), 23.8 (CH2), 1069m, 752m, 691m cm−1. MS: m/z (% relative intensity) 275
22.6 (CH2). Due to low intensity, the minor isomer could not (M+ + 1, trace), 274 (M+, 6), 255 (16), 181 (7), 175 (13), 159 (15),
be detected by 13C NMR. 19F NMR (470 MHz, CDCl3, minor 147 (9), 116 (7), 115 (100), 109 (14), 87 (34), 77 (14), 65 (8), 59
isomer marked*): δ −81.8 (d, J = 217.6 Hz, 1F), −81.8* (d, J = (11), 55 (39). HRMS (ESI-TOF) calcd C12H12F2O3SNa [M + Na]+:
212.8 Hz, 1F), −81.2 (d, J = 217.6 Hz, 1F), −79.5* (d, J = 297.0372; found: 297.0418.
212.8 Hz, 1F). IR (neat): νmax 1798w, 1736s, 1475w, 1442m,
1199m, 1180m, 1040m, 1017m, 921m, 751m, 691m cm−1. MS: methylisobenzofuran-1(3H)-one and 3-(difluoro(phenylthio)-
m/z (% relative intensity) 328 (M+, 5), 310 (10), 309 (55), 297 methyl)-3-methoxy-6-methylisobenzofuran-1(3H)-one
(5Ae).
A mixture of 3-(difluoro(phenylthio)methyl)-3-methoxy-5-
(4), 277 (10), 170 (9), 169 (84), 141 (22), 110 (8), 109 (49), 81 According to the general procedure B, the reaction of a
(100), 80 (31), 77 (13). HRMS (ESI-TOF) calcd C16H18F2O3SNa 1 : 1 mixture of 3e (0.34 g, 1.0 mmol) with SOCl2 (0.20 mL,
[M + Na]+: 351.0842; found: 351.0840.
3.0 mmol) gave a colorless oil of 5Ae (0.33 g, 94% yield) as a
1
Methyl 6-(2,2-difluoro-2-(phenylsulfanyl)acetyl)cyclohex-3- 1 : 1 mixture of isomers. H NMR (300 MHz, CDCl3): δ 7.74 (d,
enecarboxylate (5Bc). According to the general procedure B, the J = 8.3 Hz, 1H, ArH), 7.66 (s, 1H, ArH), 7.58–7.44 (m, 6H, ArH),
reaction of a 12.6 : 3.4 : 1 mixture of 3c (0.31 g, 1.0 mmol) with 7.43–7.21 (m, 8H, ArH), 3.14 (s, 3H, OCH3), 3.13 (s, 3H, OCH3),
SOCl2 (0.20 mL, 3 mmol) provided 5.6 : 1 mixture of cis- and 2.43 (s, 3H, CH3), 2.42 (s, 3H, CH3).13C NMR (75 MHz, CDCl3):
trans-isomers of 5Bc (0.30 g, 92% yield) as a colorless oil after δ 166.7 (C), 166.6 (C), 146.4 (2 × C), 142.8 (2 × C), 141.2 (C),
column chromatography (SiO2, 10% AcOEt in hexanes). 137.9 (C), 136.9 (4 × CH), 135.8 (CH), 133.1 (CH), 130.0 (2 ×
1H NMR (500 MHz, CDCl3, minor isomer marked*):
δ
CH), 128.9 (4 × CH), 126.4 (t, J = 285.7 Hz, CF2), 126.0 (C),
7.68–7.61 (m, 4H, ArH of major and minor isomers), 7.51–7.46 125.9 (C and CH), 125.6 (CH), 125.1 (d, J = 2.2 Hz, CH), 124.9
(m, 2H, ArH of major and minor isomers), 7.44–7.38 (m, 4H, (t, J = 283.7 Hz, CF2) 124.6 (d, J = 2.1 Hz, CH), 106.8 (t, J =
ArH of major and minor isomers), 5.80–5.65 (m, 4H, 2 × CH of 30.2 Hz, C), 106.5 (t, J = 30.2 Hz, C), 51.9 (CH3), 51.8 (CH3),
major and minor isomers), 3.70 (s, 3H, OCH3), 3.69* (s, 3H, 22.1 (CH3), 21.4 (CH3). 19F NMR (470 MHz, CDCl3): δ −84.9 (d,
OCH3), 3.51* (d, J = 2.4, 5.8 Hz, 1H, CH), 3.46 (dt, J = 5.2, J = 212.9 Hz, 2F), −84.8 (d, J = 212.9 Hz, 1F), −84.0 (d, J = 212.9
11.2 Hz, 1H, CH), 3.13* (dt, J = 2.5, 5.8 Hz, 1H, CH), 3.02 (dt, Hz, 1F). IR (CHCl3): νmax 1787s, 1709w, 1615w, 1475w, 1442w,
J = 5.7, 11.2 Hz, 1H, CH), 2.74–2.64* (m, 2H, CH2), 2.63–2.50 1286m, 1164w, 1140w, 1114m, 991m, 948m, 909m cm−1. MS:
(m, 2H, CH2), 2.48–2.38* (m, 2H, CH2), 2.29–2.18 (m, 1H, m/z (% relative intensity) 337 (M+ + 1, 4), 317 (5), 305 (9), 191
CHH), 2.15–2.04 (m, 1H, CHH). 13C NMR (125 MHz, CDCl3, (4), 178 (9), 177 (100), 147 (4), 91 (5). HRMS (ESI-TOF) calcd.
minor isomer marked*): δ 199.0 (t, J = 28.4 Hz, C), 196.2* (t, J = C17H14F2O3SNa [M + Na]+: 359.0529; found: 359.0530.
27.6 Hz, C), 174.3 (C), 173.1* (C), 136.7 (2 × CH), 135.0* (C),
General procedure C for the preparation of compounds 6
130.4* (CH), 130.3* (2 × CH), 129.2 (2 × CH of major and
minor isomers), 127.9 (C), 125.5* (CH), 125.0 (2 × CH), 124.8
2-Benzyl-3-(difluoro(phenylsulfanyl)methyl)-3-hydroxyisoin-
(C), 124.5 (2 × CH), 123.7* (CH), 123.0* (dd, J = 287.4, 289.7 dolin-1-one (6a). A mixture of 5Aa (65 mg, 0.2 mmol), benzyl-
Hz, CF2), 122.7 (dd, J = 290.4, 292.4 Hz, CF2), 52.1 (CH3), 51.9* amine (43 mg, 0.4 mmol) and a catalytic amount of p-TsOH in
(CH3), 42.2 (CH), 41.2 (CH), 41.1* (CH), 39.5* (CH), 28.7 (CH2), toluene (4 mL) was heated at reflux for 15 h. The reaction
27.8 (CH2), 26.0* (CH2), 24.7* (CH2). 19F NMR (470 MHz, mixture was diluted with AcOEt (10 mL) and washed with
CDCl3, minor isomer marked*): δ −83.2 (d, J = 217.8 Hz, 1F), water (3 × 10 mL), brine (10 mL) and dried (anh. Na2SO4). Puri-
−82.6 (d, J = 217.8 Hz, 1F), −82.2* (d, J = 218.6 Hz, 1F), −81.1* fication of the crude product by column chromatography
(d, J = 218.6 Hz, 1F). IR (CHCl3): νmax 1796s, 1733s, 1562w, (SiO2, 20% AcOEt in hexanes) gave 6a (72 mg, 96% yield) as a
1475m, 1442m, 1398m, 1101m, 1042m cm−1. MS: m/z (% rela- white needle: m.p. 143–144 °C (CH2Cl2). 1H NMR (500 MHz,
tive intensity) 325 (M+ − 1, 8), 281 (12), 256 (23), 227 (13), 213 CDCl3): δ 7.86–7.83 (m, 1H, ArH), 7.72–7.68 (m, 1H, ArH),
(17), 199 (17), 179 (23), 178 (70), 161 (36), 149 (100), 125 (49), 7.60–7.58 (m, 2H, ArH), 7.35–7.25 (m, 3H, ArH), 7.20–7.10 (m,
111 (41), 97 (65), 79 (94), 69 (87), 55 (89). HRMS (ESI-TOF) 7H, ArH), 4.95 (d, J = 15.6 Hz, 1H, CHH), 4.45 (d, J = 15.6 Hz,
calcd C16H16F2O3SNa [M + Na]+: 349.0685; found: 349.0684.
1H, CHH), 3.85 (br, 1H, OH). 13C NMR (125 MHz, CDCl3): δ
Methyl 5,5-difluoro-4-oxo-5-(phenylsulfanyl)pentanoate 168.3 (C), 141.9 (C), 137.5 (2 × C), 136.7 (2 × CH), 132.8 (CH),
(5Bd). According to the general procedure B, the reaction of a 131.5 (C), 131.0 (2 × CH), 130.1 (CH), 129.2 (t, J = 187.5 Hz,
1 : 7 mixture of 3d and 4d (0.26 g, 1.0 mmol) with SOCl2 CF2), 129.0 (2 × CH), 128.5 (3 × CH), 127.4 (CH), 124.2 (CH),
(0.20 mL, 3.0 mmol) gave a pale yellow oil of 5Bd (0.25 g, 91% 123.8 (CH), 91.2 (t, J = 25.0 Hz, C), 43.5 (CH2). 19F NMR
yield) after column chromatography (SiO2, 10% AcOEt in (470 MHz, CDCl3): δ −81.6 (d, J = 211.0 Hz, 1F), −80.5 (d, J =
1
hexanes). H NMR (500 MHz, CDCl3): δ 7.63 (d, J = 7.1 Hz, 2H, 211.0 Hz, 1F). IR (nujol): νmax 3207br, 1682s, 1471s, 1456s,
ArH), 7.62–7.47 (m, 1H, ArH), 7.44–7.40 (m, 2H. ArH), 3.72 (s, 1455m, 1163s, 770s cm−1. MS: m/z (% relative intensity) 398
3H, OCH3), 3.04 (t, J = 6.6 Hz, 2H, CH2), 2.65 (t, J = 6.6 Hz, 2H, (M+, 10), 380 (7), 250 (6), 238 (47), 161 (11), 160 (100), 91 (20),
CH2).13C NMR (125 MHz, CDCl3): δ 194.7 (t, J = 29.1 Hz, C), 65 (7). HRMS (ESI-TOF) calcd. C22H17F2NO2SNa [M + Na]+:
172.1 (C), 136.7 (2 × CH), 130.5 (CH), 129.3 (2 × CH), 124.4 (d, 420.0846; found: 420.0851.
J = 2.1 Hz, C), 122.3 (t, J = 288.9 Hz, CF2), 51.9 (CH3), 31.5
2-Benzyl-3-(difluoro(phenylsulanyl)methyl)-3-hydroxyoctahy-
(CH2), 27.0 (CH2). 19F NMR (470 MHz, CDCl3): δ −85.3 (s, 2F). dro-1H-isoindol-1-one (6b). According to the general procedure
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C, the reaction of a 8 : 1 mixture of 5Bb (82 mg, 0.25 mmol), (t, J = 285.4 Hz, CF2), 129.2 (2 × CH), 128.9 (2 × CH), 128.2 (2 ×
and benzylamine (54 mg, 0.5 mmol) gave a single isomer of 6b CH), 127.9 (CH), 127.0 (CH), 125.9 (CH), 124.7 (C), 92.4 (dd, J =
(48 mg, 48% yield) as a white needle after column chromato- 23.6, 27.8 Hz, C), 44.0 (CH2), 42.7 (CH), 40.3 (CH), 25.5 (CH2),
graphy (SiO2, 20% AcOEt in hexanes): m.p. 171–172 °C 25.4 (CH2). 19F NMR (470 MHz, CDCl3): δ −81.4 (d, J =
(CH2Cl2). 1H NMR (500 MHz, CDCl3): δ 7.69–7.60 (m, 2H, ArH), 213.9 Hz, 1F), −80.8 (d, J = 213.9 Hz, 1F). IR (KBr): νmax 3219br,
7.52–7.46 (m, 1H, ArH), 7.45–7.37 (m, 4H, ArH), 7.36–7.31 (m, 1683s, 1499m, 1474m, 1443s, 1413s, 1349m, 1297m, 1212m,
2H, ArH), 7.31–7.25 (m, 1H, ArH), 5.04 (d, J = 15.4 Hz, 1H, 1183s, 1076s, 1046m cm−1. MS: m/z (% relative intensity) 402
CHH), 4.38 (d, J = 15.4 Hz, 1H, CHH), 2.97–2.85 (m, 2H, CH2), (M+ + 1, 3), 276 (5), 243 (18), 242 (100), 165 (9), 164 (57), 106
2.71 (d, J = 6.6 Hz, 1H, OH), 2.24–2.15 (m, 1H, CH), 1.80–1.69 (6), 93 (16), 91 (53), 79 (15), 77 (17), 65(12). HRMS (ESI-TOF)
(m, 2H, CH2), 1.69–1.53 (m, 2H, CH2), 1.32–1.07 (m, 3H, CH2 calcd. C22H21F2NO2SNa [M + Na]+: 424.1158; found: 424.1164.
and CH). 13C NMR (125 MHz, CDCl3): δ 176.3 (C), 138.6 (C),
1-Benzyl-5-(difluoro(phenylsulfanyl)methyl)-5-hydroxypyr-
136.7 (2 × CH), 130.7 (dd, J = 286.5, 289.9 Hz, CF2), 130.2 (CH), rolidin-2-one (6d). According to the general procedure C, the
129.1 (2 × CH), 128.6 (2 × CH), 128.0 (2 × CH), 127.3 (CH), reaction of 5Bd (55 mg, 0.2 mmol) and benzylamine (43 mg,
125.1 (C), 93.4 (dd, J = 22.8, 26.3 Hz, C), 44.0 (d, J = 3.3 Hz, 0.4 mmol) gave 6d (39 mg, 56% yield) as a white needle after
CH2), 39.5 (d, J = 3.6 Hz, CH), 39.4 (CH), 23.3 (CH2), 23.1 purification by column chromatography (SiO2, 20% AcOEt in
(CH2), 22.9 (CH2), 22.5 (CH2). 19F NMR (470 MHz, CDCl3): hexanes): m.p. 130–131 °C (CH2Cl2). 1H NMR (500 MHz,
δ −83.6 (d, J = 208.7 Hz, 1F), −81.4 (d, J = 208.7 Hz, 1F). CDCl3): δ 7.58 (d, J = 7.4 Hz, 2H, ArH), 7.51–7.45 (m, 1H, ArH),
IR (KBr): νmax 3171br, 1686s, 1448m, 1385w, 1360w, 1171m, 7.44–7.39 (m, 2H, ArH), 7.39–7.35 (m, 2H, ArH), 7.35–7.30 (m,
1141w, 1045m, 781w, 750m, 703w, 691w cm−1. MS: m/z (% rela- 2H, ArH), 7.30–7.24 (m, 1H, ArH), 4.95 (d, J = 15.5 Hz, 1H,
tive intensity) 404 (M+ + 1, 1), 334 (2), 278 (5), 245 (17), 244 CHH), 4.41 (d, J = 15.5 Hz, 1H, CHH), 3.82 (br, 1H, OH),
(100), 167 (12), 166 (97), 138 (16), 109 (9), 95 (42), 91 (75), 65 2.79–2.68 (m, 1H, CHH), 2.63–2.51 (m, 2H, CH2), 2.16 (dt, J =
(14). HRMS (ESI-TOF) calcd. C22H23F2NO2SNa [M + Na]+: 8.6, 15.5 Hz, 1H, CHH). 13C NMR (125 MHz, CDCl3): δ 175.7
426.1315; found: 426.1317.
(C), 137.5 (C), 136.7 (2 × CH), 130.2 (CH), 129.6 (t, J = 287.2 Hz,
2-Benzyl-3-(difluoro( phenylsulfanyl)methyl)-3-hydroxy- CF2), 129.1 (2 × CH), 128.5 (2 × CH), 128.2 (2 × CH), 127.4
2,3,3a,4,7,7a-hexahydro-1H-isoindol-1-one (6c). According to (CH), 124.7 (C), 93.2 (t, J = 25.5 Hz, C), 44.2 (C), 30.4 (CH2),
the general procedure C, the reaction of a 5.6 : 1 mixture of 5Bc 28.6 (CH2). 19F NMR (470 MHz, CDCl3): δ −84.9 (d, J = 207.7 Hz,
(0.33 g, 1.0 mmol) and benzylamine (0.14 g, 1.3 mmol) gave a 1F), −83.4 (d, J = 207.7 Hz, 1F). IR (nujol): νmax 3354br,
mixture of isomers of 6c (0.35 g, 87% yield) as a white solid 1678s, 1456m, 1441m, 1203m, 1152m, 1069s, 748m, 715s cm−1
.
after purification by column chromatography (SiO2, 50% MS: m/z (% relative intensity) 350 (M+, 12), 284 (7), 191 (13),
AcOEt in hexanes). Separation of the mixture of 6c was 190 (100), 168 (2), 165 (2), 160 (6), 140 (5), 121 (3), 112 (49),
achieved by preparative thin-layer chromatography (SiO2, 30% 106 (5), 92 (5), 91 (65), 84 (23), 77 (6), 65 (15). HRMS (ESI-TOF)
AcOEt in hexanes × 2) to give 6cA (more polar, 0.18 g, 45%, calcd. C18H17F2NO2SNa [M + Na]+: 372.0846; found: 372.0847.
m.p. 164–165 °C) and 6cB (less polar, 0.15 g, 37%,
A mixture of 2-benzyl-3-(difluoro(phenylsulfanyl)methyl)-3-
m.p. 170–171 °C). 6cA: 1H NMR (500 MHz, CDCl3): δ 7.52–7.44 hydroxy-6-methylisoindolin-1-one and 2-benzyl-3-(difluoro-
(m, 2H, ArH), 7.44–7.33 (m, 1H, ArH), 7.33–7.26 (m, 4H, ArH), (phenylsulfanyl)methyl)-3-hydroxy-5-methylisoindolin-1-one
7.26–7.11 (m, 3H, ArH), 5.76–5.61 (m, 2H, 2 × CH), 4.47 (d, J = (6e). According to the general procedure C, the reaction of a
15.7 Hz, 1H, CHH), 4.37 (d, J = 15.7 Hz, 1H, CHH), 3.34 (br, 1 : 1 mixture of 5Ae (71 mg, 0.2 mmol) and benzylamine
1H, OH), 2.68 (dt, J = 5.5, 12.3 Hz, 1H, CHH), 2.60–2.37 (m, 3H, (47 mg, 0.4 mmol) gave a 1 : 1 isomeric mixture of 6e (54 mg,
3 × CHH), 2.23–2.11 (m, 1H, CH), 2.11–2.00 (m, 1H, CH). 63% yield) as a white solid after purification by column chrom-
13C NMR (125 MHz, CDCl3): δ 175.5 (C), 138.2 (C), 136.8 (2 × atography (SiO2, 30% AcOEt in hexanes): m.p. 140–150 °C.
CH), 130.3 (CH), 129.4 (t, J = 286.1 Hz, CF2), 129.2 (2 × CH), 1H NMR (500 MHz, CDCl3): δ 7.74 (d, J = 7.7 Hz, 1H, ArH), 7.66
128.4 (2 × CH), 128.0 (2 × CH), 127.2 (CH), 126.9 (CH), 126.1 (br, 1H, ArH), 7.61 (dd, J = 1.7, 7.8 Hz, 1H, ArH), 7.51 (br, 1H,
(CH), 124.6 (C), 92.6 (t, J = 25.1 Hz, C), 49.6 (CH), 43.8 (CH2), ArH), 7.46–7.36 (m, 8H, ArH), 7.35–7.24 (m, 14H, ArH), 5.02 (d,
41.2 (CH), 27.2 (CH2), 26.8 (CH2). 19F NMR (470 MHz, CDCl3): J = 15.6 Hz, 1H, CHH), 5.01 (d, J = 15.6 Hz, 1H, CHH), 4.55 (d,
δ −79.5 (d, J = 213.6 Hz, 1F), −79.0 (d, J = 213.6 Hz, 1F). IR J = 15.6 Hz, 1H, CHH), 4.54 (d, J = 15.6 Hz, 1H, CHH), 3.81 (br,
(KBr): νmax 1683s, 1442m, 1412m, 1385m, 1065m cm−1. MS: m/z 1H, OH), 3.76 (br, 1H, OH), 2.49 (s, 3H, CH3), 2.47 (s, 3H,
(% relative intensity) 402 (M+ + 1, 9), 276 (6), 243 (17), 242 CH3).13C NMR (125 MHz, CDCl3): δ 168.5 (C), 168.4 (C), 143.8
(100), 166 (3), 164 (54), 106 (8), 93 (22), 91 (60), 79 (16), 77 (12). (C), 142.3 (C), 141.5 (C), 139.3 (C), 137.7 (C), 137.6 (C), 136.7
HRMS (ESI-TOF) calcd C22H21F2NO2SNa [M + Na]+: 424.1158; (2 × CH), 136.6 (2 × CH), 133.6 (2 × CH), 131.8 (2 × CH), 131.6
1
found: 424.1179. 6cB: H NMR (500 MHz, CDCl3): δ 7.62–7.50 (2 × C), 130.0 (2 × CH), 128.9 (2 × CH), 128.6 (t, J = 282.5 Hz,
(m, 2H, ArH), 7.46–7.39 (m, 1H, ArH), 7.39–7.27 (m, 2H, ArH), 2 × CF2), 128.4 (4 × CH), 127.3 (2 × CH), 125.0 (C), 124.9 (C),
7.27–7.15 (m, 5H, ArH), 5.76–5.65 (m, 2H, 2 × CH), 5.21 (d, J = 124.7 (CH), 124.6 (CH), 124.1 (2 × CH), 123.9 (CH), 123.8 (CH),
15.5 Hz, 1H, CHH), 4.25 (d, J = 15.5 Hz, 1H, CHH), 2.58–2.47 123.6 (2 × CH), 91.1 (t, J = 26.5 Hz, 2 × C), 43.5 (CH2), 43.4
(m, 3H, 2 × CH and OH), 2.41–2.30 (m, 1H, CHH), 2.30–2.21 (CH2), 22.0 (CH3), 21.5 (CH3). 19F NMR (470 MHz, CDCl3):
(m, 2H, CH2), 2.20–2.08 (m, 1H, CHH). 13C NMR (125 MHz, δ −81.8 (d, J = 210.3 Hz, 1F), −81.7 (d, J = 211.5 Hz, 1F), −80.6
CDCl3): δ 176.8 (C), 137.8 (C), 136.8 (2 × CH), 130.3 (CH), 129.8 (d, J = 211.5 Hz, 1F), −80.5 (d, J = 210.3 Hz, 1F). IR (KBr): νmax
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3362br, 1698s, 1684s, 1618m, 1443m, 1385s, 1358m, 1152m, (ESI-TOF) calcd C22H23F2NOSNa [M + Na]+: 410.1365; found:
1118m, 1067s, 1011m, 753m, 699s, 692m cm−1. MS: m/z (% rela- 410.1344.
tive intensity) 412 (M+ + 1, trace), 253 (8), 252 (45), 175 (12),
2-Benzyl-3-(difluoro(phenylsulfanyl)methyl)-2,3,3a,4,7,7a-
174 (100), 91 (26), 65 (9). HRMS (ESI-TOF) calcd hexahydro-1H-isoindol-1-one (7c). According to the general
C23H19F2NO2SNa [M + Na]+: 434.1002; found: 434.0979.
procedure D, reduction of 6cA (40 mg, 0.1 mmol) followed by
column chromatography (SiO2, 30% AcOEt in hexanes)
afforded a colorless oil of 7c (34 mg, 88% yield). 1H NMR
(500 MHz, CDCl3): δ 7.57–7.49 (m, 2H, ArH), 7.43–7.36 (m, 1H,
General procedure D for the preparation of compounds 7
2-Benzyl-3-(difluoro(phenylsulfanyl)methyl)isoindolin-1- ArH), 7.36–7.30 (m, 2H, ArH), 7.27–7.12 (m, 5H, ArH),
one (7a). To a solution of 6a (78 mg, 0.2 mmol) in dry CH2Cl2 5.77–5.69 (m, 1H, HC), 5.69–5.62 (m, 1H, CH), 5.25 (d, J =
(3 mL) at −78 °C was slowly added triethylsilane (0.3 mL, 15.1 Hz, 1H, CHH), 4.07 (dd, J = 2.2, 15.1 Hz, 1H, CHH), 3.61
2.0 mmol) and BF3·OEt2 (0.1 mL, 0.6 mmol) under an argon (dd, J = 9.4, 9.9 Hz, 1H, CH), 2.54–2.39 (m, 2H, CH, and CHH),
atmosphere. The reaction mixture was slowly warmed up to 2.23–2.04 (m, 3H, 3 × CHH), 2.04–1.92 (m, 1H, CH). 13C NMR
room temperature overnight (15 h) then quenched with satu- (125 MHz, CDCl3): δ 176.4 (C), 136.7 (2 × CH), 136.3 (C), 130.9
rated aqueous NaHCO3 and extracted with CH2Cl2 (3 × 5 mL). (t, J = 279.8 Hz, CF2), 130.1 (CH), 129.1 (2 × CH), 128.6 (2 ×
The combined organic phase was washed with water (3 mL), CH), 128.5 (2 × CH), 127.6 (CH), 126.7 (CH), 126.5 (CH), 124.8
brine (3 mL) and dried (anh. Na2SO4). Purification of the (C), 65.5 (dd, J = 23.5, 32.0 Hz, C), 45.2 (CH2), 43.6 (CH), 38.7
crude product by column chromatography (SiO2, 20% AcOEt (d, J = 2.4 Hz, CH), 29.8 (d, J = 3.3 Hz, CH2), 26.1 (CH2).
in hexanes) gave a white solid of 7a (66 mg, 87% yield): 19F NMR (470 MHz, CDCl3): δ −75.5 (d, J = 219.0 Hz, 1F), −66.9
m.p. 96–97 °C. 1H NMR (500 MHz, CDCl3): δ 8.01–7.96 (m, 1H, (dd, J = 10.1, 219.0 Hz, 1F). IR (CHCl3): νmax 1699s, 1603m,
ArH), 7.64–7.55 (m, 3H, ArH), 7.49–7.40 (m, 3H, ArH), 1404w, 1354w, 1270w, 1157w, 1009w cm−1. MS: m/z (% relative
7.39–7.26 (m, 7H, ArH), 5.54 (d, J = 15.1 Hz, 1H, CHH), 4.83 intensity) 385 (M+, 9), 309 (2), 276 (6), 240 (4), 227 (15),
(dd, J = 3.3, 7.8 Hz, 1H, CH), 4.25 (dd, J = 1.9, 15.1 Hz, 1H, 226 (88), 198 (5), 167 (7), 109 (7), 106 (15), 93 (27), 91 (100),
CHH). 13C NMR (125 MHz, CDCl3): δ 169.1 (C), 138.5 (d, J = 77 (28). HRMS (ESI-TOF) calcd C22H21F2NOSNa [M + Na]+:
6.6 Hz, C), 136.7 (2 × CH), 136.4 (C), 132.4 (C), 132.2 (CH), 408.1209; found: 408.1202.
130.0 (CH), 129.7 (CH), 129.6 (dd, J = 282.1, 284.6 Hz, CF2),
1-Benzyl-5-(difluoro(phenylsulfanyl)methyl)pyrrolidin-2-one
129.0 (2 × CH), 128.8 (2 × CH), 128.6 (2 × CH), 127.7 (CH), (7d). According to the general procedure D, reduction of 6d
124.8 (C), 124.60 (d, J = 3.8 Hz, CH), 124.1 (CH), 63.4 (dd, J = (0.18 g, 0.5 mmol) followed by column chromatography (SiO2,
25.9, 26.1 Hz, C), 44.9 (d, J = 3.4 Hz, CH2). 19F NMR (470 MHz, 50% EtOAc in hexanes) afforded an off-white solid of 7d
CDCl3): δ −73.4 (d, J = 221.8 Hz, 1F), −67.5 (dd, J = 7.1, (0.16 g, 96% yield): m.p. 112–113 °C. 1H NMR (500 MHz,
221.8 Hz, 1F). IR (neat): νmax 1705s, 1471m, 1442m, 1393s, CDCl3): δ 7.64–7.58 (m, 2H, ArH), 7.51–7.44 (m, 1H, ArH),
1130s, 1033s, 705s, 694s cm−1. MS: m/z (% relative intensity) 7.44–7.39 (m, 2H, ArH), 7.36–7.27 (m, 3H, ArH), 7.26–7.20 (m,
382 (M+ + 1, 7), 381 (M+, 10), 223 (17), 222 (98), 167 (13), 2H, ArH), 5.27 (d, J = 14.9 Hz, 1H, CHH), 3.99 (d, J = 14.9 Hz,
139 (4), 109 (3), 92 (100), 65 (13). HRMS (ESI-TOF) calcd. 1H, CHH), 3.86 (ddd, J = 3.2, 7.1, 16.5 Hz, 1H, CH), 2.75 (dt, J =
C22H17F2NOSNa [M + Na]+: 404.0896; found: 404.0912.
9.8, 18.2 Hz, 1H, CHH), 2.45 (ddd, J = 2.9, 10.5, 12.0 Hz, 1H,
2-Benzyl-3-(difluoro(phenylsulfanyl)methyl)octahydro-1H- CHH), 2.31 (m, 1H, CHH), 2.16 (dq, J = 10.1, 14.0 Hz, 1H,
isoindol-1-one (7b). According to the general procedure D, CHH). 13C NMR (125 MHz, CDCl3): δ 175.6 (C), 136.5 (2 × CH),
reduction of 6b (0.20 g, 0.5 mmol) followed by column chrom- 135.8 (C), 130.9 (t, J = 283.6 Hz, CF2), 130.1 (CH), 129.2 (2 ×
atography (SiO2, 1 : 3 : 6 CH2Cl2 : AcOEt : hexanes) afforded a CH), 128.7 (2 × CH), 128.5 (2 × CH), 127.7 (CH), 125.0 (C), 61.0
white solid of 7b (0.16 g, 83% yield): m.p. 165–166 °C. 1H NMR (t. J = 25.3 Hz, C), 45.6 (CH2), 29.3 (CH2), 20.5 (CH2). 19F NMR
(500 MHz, CDCl3): δ 7.59–7.52 (m, 2H, ArH), 7.41–7.37 (m, 1H, (470 MHz, CDCl3): δ −77.1 (d, J = 211.7 Hz, 1F), −77.0 (d, J =
ArH), 7.37–7.30 (m, 2H, ArH), 7.26–7.15 (m, 3H, ArH), 211.7 Hz, 1F). IR (KBr): νmax 1699s, 1457w, 1450w, 1410m,
7.15–7.11 (m, 2H, ArH), 5.22 (d, J = 15.1 Hz, 1H, CHH), 4.06 1232m, 1063m, 989m, 755m, 698m cm−1. MS: m/z (% relative
(dd, J = 2.3, 15.1 Hz, 1H, CHH), 3.53 (dd, J = 9.6, 10.3 Hz, 1H, intensity) 333 (M+, 4), 175 (12), 174 (100), 109 (4), 92 (7), 91
CH), 2.23–2.15 (m, 1H, CH), 2.13–1.95 (m, 1H, CH), 1.93–1.69 (92), 77 (4), 65 (14). HRMS (ESI-TOF) calcd C18H17F2NOSNa
(m, 5H, CHH), 1.36–1.24 (m, 2H, 2 × CHH), 1.24–1.11 (m, 1H, [M + Na]+: 356.0896; found: 356.0889.
5 × CHH). 13C NMR (125 MHz, CDCl3): δ 176.7 (C), 136.7 (2 ×
A mixture of 2-benzyl-3-(difluoro(phenylsulfanyl)methyl)-6-
CH), 136.5 (C), 131.0 (t, J = 281.3 Hz, CF2), 130.0 (CH), 129.1 methylisoindolin-1-one and 2-benzyl-3-(difluoro(phenylsulfa-
(2 × CH), 128.6 (2 × CH), 128.5 (2 × CH), 127.5 (CH), 125.0 (C), nyl)methyl)-5-methyl isoindolin-1-one (7e). According to the
65.0 (t, J = 29.1 Hz, C), 48.0 (CH), 45.2 (CH2), 43.2 (CH), 29.3 general procedure D, reduction of a 1 : 1 mixture of 6e (30 mg,
(CH2), 25.9 (CH2), 25.8 (CH2), 25.6 (CH2). 19F NMR (470 MHz, 0.07 mmol) followed by column chromatography (SiO2, 50%
CDCl3): δ −75.1 (d, J = 220.2 Hz, 1F), −65.8 (dd, J = 9.9, AcOEt in hexanes) gave a pale yellow oil of a 1 : 1 isomeric
1
220.2 Hz, 1F). IR (KBr): νmax 1706s, 1474w, 1449w, 1390m, mixture of 7e (24 mg, 83% yield). H NMR (500 MHz, CDCl3):
1246w, 1155w, 1111w, 706m cm−1. MS: m/z (% relative inten- δ 7.74 (d, J = 7.8 Hz, 1H, ArH), 7.67 (s, 1H, ArH), 7.38–7.12 (m,
sity) 388 (M+ + 1, 7), 387 (M+, 20), 278 (9), 229 (17), 228 (100), 24H, ArH), 5.40 (dd, J = 3.0, 15.0 Hz, 2H, 2 × CHH), 4.66 (dt, J =
200 (5), 109 (6), 106 (18), 95 (34), 91 (44), 65 (10). HRMS 3.1, 11.2 Hz, 2H, 2 × CH), 4.12 (ddd, J = 1.6, 4.5, 15.0 Hz, 2H,
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2 × CHH), 2.38 (s, 3H, CH3), 2.33 (s, 3H, CH3). 13C NMR (CH), 45.0 (d, J = 1.9 Hz, CH2), 41.4 (t, J = 3.4 Hz, CH), 28.8 (d,
(125 MHz, CDCl3): δ 169.2 (C), 169.1 (C), 142.9 (C), 140.0 (C), J = 2.0 Hz, CH2), 25.8 (CH2), 25.7 (CH2), 25.5 (CH2). 19F NMR
138.8 (d, J = 6.6 Hz, C), 137.7 (d, J = 6.6 Hz, C), 136.7 (2 × CH), (470 MHz, CDCl3): δ −124.6 (ddd, J = 8.9, 54.7, 293.3 Hz, 1F),
136.6 (CH), 136.5 (C), 136.4 (C), 135.7 (d, J = 6.6 Hz, C), 133.2 −120.3 (ddd, J = 9.9, 54.7, 293.3 Hz, 1F). IR (CHCl3): νmax
(CH), 132.5 (C), 130.7 (CH), 129.9 (2 × CH), 129.7 (dd, J = 1695s, 1456w, 1395w, 1377w, 1252w, 1134w, 1113w, 1068w
282.8, 284.9 Hz, CF2), 129.6 (t, J = 283.9 Hz, CF2), 129.6 (C), cm−1. MS: m/z (% relative intensity) 279 (M+, 69), 229 (24), 228
129.0 (2 × CH), 128.9 (2 × CH), 128.7 (4 × CH), 128.5 (2 × CH), (100), 202 (11), 107 (21), 106 (51), 92 (85), 79 (17). HRMS
128.0 (C), 127.7 (CH), 125.1 (CH), 125.1 (CH), 125.0 (CH), 124.9 (ESI-TOF) calcd C16H19F2NONa [M + Na]+: 302.1332; found:
(CH), 124.4 (CH), 124.3 (CH), 124.3 (CH), 123.9 (CH), 63.3 (dd, 302.1350.
J = 9.0, 25.9 Hz, C), 63.0 (dd, J = 9.0, 26.0 Hz, C), 44.9 (CH2),
2-Benzyl-3-(difluoromethyl)-2,3,3a,4,7,7a-hexahydro-1H-isoin-
44.8 (CH2), 21.9 (CH3), 21.4 (CH3). 19F NMR (470 MHz, CDCl3): dol-1-one (8c). According to the general procedure E, reductive
δ −73.8 (d, J = 222.3 Hz, 1F), −73.7 (d, J = 220.9 Hz, 1F), −67.8 cleavage of 7c (39 mg, 0.1 mmol) provided a colorless oil of 8c
(dd, J = 7.1, 220.9 Hz, 1F), −67.5 (dd, J = 7.1, 222.3 Hz, 1F). IR (27 mg, 97% yield) after column chromatography (SiO2, 20%
(CHCl3): νmax 1698s, 1496w, 1475w, 1456w, 1442w, 1396w, AcOEt in hexanes). 1H NMR (500 MHz, CDCl3): δ 7.30–7.04 (m,
1035w cm−1. MS: m/z (% relative intensity) 396 (M+ + 1, 4), 395 5H, ArH), 5.75–5.69 (m, 1H, CH), 5.68 (dt, J = 4.4, 54.9 Hz, 1H,
(16), 252 (4), 237 (18), 236 (100), 182 (3), 181 (13), 174 (6), 109 CF2H), 5.67–5.61 (m, 1H, CH), 4.98 (d, J = 14.7 Hz, 1H, CHH),
(6), 91 (62), 65 (11). HRMS (ESI-TOF) calcd C23H19F2NOSNa 4.07 (d, J = 14.7 Hz, 1H, CHH), 3.37 (dq, J = 4.5, 9.3 Hz, 1H,
[M + Na]+: 418.1052; found: 418.1050.
CH), 2.54–2.41 (m, 1H, CH), 2.39–2.24 (m, 1H, CH), 2.21–2.05
(m, 2H, CH2), 2.05–1.85 (m, 2H, CH2). 13C NMR (125 MHz,
CDCl3): δ 176.2 (C), 136.4 (C), 128.8 (2 × CH), 128.1 (2 × CH),
General procedure E for the preparation of compounds 8
2-Benzyl-3-(difluoromethyl)isoindolin-1-one (8a). A solution 127.7 (CH), 126.6 (CH), 126.4 (CH), 115.8 (t, J = 242.8 Hz,
of 7a (77 mg, 0.2 mmol) in toluene (3 mL) was bubbled with CF2H), 62.1 (t, J = 24.9 Hz, C), 45.1 (CH2), 43.3 (CH), 36.9 (CH),
argon gas. The deoxygenated solution of AIBN (6 mg, 29.3 (CH2), 26.0 (CH2). 19F NMR (470 MHz, CDCl3): δ −125.1
0.03 mmol) in toluene (4 mL) and Bu3SnH (0.04 mL, (ddd, J = 8.9, 54.5, 294.7 Hz, 1F), −119.9 (ddd, J = 8.9, 54.5,
0.35 mmol) was then added dropwise. The reaction mixture 294.7 Hz, 1F). IR (CHCl3): νmax 1696s, 1398w, 1271w, 1122w,
was heated at reflux overnight (15 h). Toluene was evaporated 1072w, 909m cm−1. MS: m/z (% relative intensity) 278 (M+ + 1,
to provide a crude product, which was purified by column 27), 277 (M+, 100), 276 (6), 227 (12), 226 (66), 186 (7), 146 (13),
chromatography (SiO2, 20% AcOEt in hexanes) to give a color- 106 (14), 93 (18), 91 (75), 77 (24). HRMS (ESI-TOF) calcd
1
less oil of 8a (45 mg, 82% yield). H NMR (500 MHz, CDCl3): δ C16H17F2NONa [M + Na]+: 300.1175; found: 300.1175.
7.99–7.93 (m, 1H, ArH), 7.64–7.57 (m, 2H, ArH), 7.57–7.52 (m,
1-Benzyl-5-(difluoromethyl)pyrrolidin-2-one (8d). According
1H, ArH), 7.39–7.33 (m, 2H, ArH), 7.33–7.29 (m, 3H, ArH), 5.71 to the general procedure E, reductive cleavage of 7d (0.30 g,
(dt, J = 5.5, 55.7 Hz, 1H, CF2H), 5.49 (d, J = 15.1 Hz, 1H, CHH), 0.9 mmol) provided a colorless oil of 8d (0.14 g, 69% yield)
4.58 (ddd, J = 5.5, 8.5, 8.5 Hz, 1H, CH), 4.40 (d, J = 15.1 Hz, 1H, after column chromatography (SiO2, 20% AcOEt in hexanes).
CHH). 13C NMR (125 MHz, CDCl3): δ 169.1 (C), 138.0 (d, J = 1H NMR (500 MHz, CDCl3): δ 7.40–7.35 (m, 2H, ArH),
7.0 Hz, C), 136.5 (C), 132.4 (CH), 132.2 (CH), 129.7 (CH), 128.9 7.35–7.30 (m, 1H, ArH), 7.30–7.25 (m, 2H, ArH), 5.72 (dt, J =
(2 × CH), 128.4 (2 × CH), 127.9 (CH), 124.3 (CH), 124.2 (d, J = 3.4, 55.3 Hz, 1H, CF2H), 5.08 (d, J = 15.0 Hz, 1H, CHH), 4.17 (d,
1.9 Hz, CH), 115.6 (t, J = 246.5 Hz, CF2H), 59.9 (dd, J = 23.5, J = 15.0 Hz, 1H, CHH), 3.73–3.65 (m, 1H, CH), 2.61 (dt, J = 8.6,
27.0 Hz, C), 45.5 (CH2). 19F NMR (470 MHz, CDCl3): δ −120.2 9.5 Hz, 1H, CHH), 2.45 (ddd, J = 4.7, 9.1, 17.2 Hz, 1H, CHH),
(ddd, J = 8.2, 54.6, 293.0 Hz, 1F), −118.1 (ddd, J = 8.9, 55.8, 2.17–2.05 (m, 2H, CH2). 13C NMR (125 MHz, CDCl3): δ 175.4
293.0 Hz, 1F). IR (neat): νmax 1694s, 1456m, 1470w, 1409m, (C), 136.0 (C), 128.8 (2 × CH), 128.2 (2 × CH), 127.9 (CH), 115.4
1120s, 1060s, 752s, 720s, 702s cm−1. MS: m/z (% relative inten- (t, J = 244.1 Hz, CF2H), 57.8 (t, J = 23.9 Hz, C), 45.7 (CH2), 29.3
sity) 274 (M+ + 1, 37), 273 (58), 223 (20), 222 (77), 196 (11), 169 (CH2), 18.5 (CH2). 19F NMR (470 MHz, CDCl3): δ −126.6 (ddd,
(6), 149 (17), 129 (5), 93 (10), 92 (100), 66 (14). HRMS (ESI-TOF) J = 10.8, 55.3, 288.0 Hz, 1F), −125.7 (ddd, J = 12.2, 55.3, 288.0 Hz,
calcd C16H13F2NONa [M + Na]+: 296.0862; found: 296.0864.
1F). IR (neat): νmax 1682s, 1446w, 1418m, 1237m, 1072m,
2-Benzyl-3-(difluoromethyl)octahydro-1H-isoindol-1-one (8b). 1059m, 703s cm−1. MS: m/z (% relative intensity) 226 (M+ + 1,
According to the general procedure E, reductive cleavage of 7b 25), 225 (M+, 50), 223 (7), 175 (10), 174 (75), 146 (19), 104 (14),
(59 mg, 0.15 mmol) provided a colorless oil of 8b (41 mg, 98% 91 (100), 65 (16). HRMS (ESI-TOF) calcd C12H13F2NONa
yield) after column chromatography (SiO2, 20% AcOEt in [M + Na]+: 248.0862; found: 248.0862.
hexanes). 1H NMR (300 MHz, CDCl3): δ 7.31–7.08 (m, 5H,
A mixture of 2-benzyl-3-(difluoromethyl)-6-methyl isoindo-
ArH), 5.65 (dt, J = 4.2, 54.8 Hz, 1H, CF2H), 4.95 (d, J = 15.2 Hz, lin-1-one and 2-benzyl-3-(difluoromethyl)-5-methyl isoindolin-
1H, CHH), 4.04 (d, J = 15.2 Hz, 1H, CHH), 3.28 (dq, J = 4.2, 1-one (8e). According to the general procedure E, reductive clea-
9.7 Hz, 1H, CH), 2.27–2.08 (m, 1H, CH), 2.04–1.92 (m, 1H, CH), vage of 1 : 1 mixture of 7e (19 mg, 0.05 mmol) provided color-
1.92–1.69 (m, 3H, CH2, and CHH), 1.69–1.58 (m, 1H, CHH), less oil of a 1 : 1 isomeric mixture of 8e (12 mg, 79% yield)
1.39–1.04 (m, 4H, 2 × CH2). 13C NMR (75 MHz, CDCl3): δ 176.4 after column chromatography (SiO2, 50% AcOEt in hexanes).
(C), 136.5 (C), 128.7 (2 × CH), 128.0 (2 × CH), 127.6 (CH), 115.8 1H NMR (300 MHz, CDCl3): δ 7.78–7.70 (m, 1H, ArH),
(t, J = 243.2 Hz, CF2H), 61.5 (dd, J = 23.0, 25.2 Hz, C), 47.6 7.70–7.60 (m, 2H, ArH), 7.39–7.10 (m, 13H, ArH), 5.58 (tt, J =
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5.5, 55.6 Hz, 2H, 2 × CF2H), 5.38 (d, J = 14.3 Hz, 2H, 2 × CHH),
4.52–4.36 (m, 2H, 2 × HC), 4.29 (d, J = 14.3 Hz, 2H, 2 × CHH),
1.20 (s, 3H, CH3), 1.19 (s, 3H, CH3). 13C NMR (75 MHz, CDCl3):
δ 169.3 (2 × C), 155.5 (C), 152.8 (C), 143.0 (C), 140.0 (C), 136.5
(C), 135.2 (C), 133.2 (CH), 132.5 (C), 130.6 (CH), 129.8 (C),
128.8 (3 × CH), 128.3 (2 × CH), 127.8 (CH), 124.7 (CH), 124.5
(3 × CH), 124.0 (2 × CH), 123.9 (2 × CH), 115.7 (t, J = 246.4 Hz,
2 × CF2), 59.7 (t, J = 25.4 Hz, 2 × CH), 45.4 (2 × CH2), 21.9
(CH3), 21.4 (CH3). 19F NMR (470 MHz, CDCl3) δ −120.2 (dd, J =
54.5, 292.3 Hz, 1F), −120.1 (dd, J = 54.5, 292.6 Hz, 1F), −118.6
(ddd, J = 8.9, 55.9, 292.6 Hz, 1F), −118.5 (ddd, J = 8.9, 55.9,
292.3 Hz, 1F). IR (CHCl3): νmax 1697s, 1603m, 1559w, 1542w,
1508w, 1497w, 1457w, 1077m cm−1. MS: m/z (% relative inten-
sity) 288 (M+ + 1, 11), 287 (61), 286 (4), 237 (17), 236 (93), 210
(6), 178 (7), 163 (21), 115 (12), 91 (100), 65 (18). HRMS
(ESI-TOF) calcd. C17H15F2NONa [M + Na]+: 310.1019; found:
310.1020.
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Acknowledgements
We acknowledge financial supports from the Thailand
Research Fund (BRG 5380019), the Office of the Higher Edu-
cation Commission and Mahidol University under the
National Research Universities Initiative, and the Center of
Excellence for Innovation in Chemistry (PERCH-CIC).
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