α,α-Difluoro-α-phenylsulfanyl-α- trimethylsilylmethane as "cF2-" synthetic building block for the preparation of gem-difluoromethylenated cyclopentanols

Article abstract of DOI:10.1016/j.jfluchem.2011.10.009

A general strategy for the preparation of gem-difluoromethylenated cyclopentanols has been demonstrated; it involves sequential fluoride-catalyzed nucleophilic addition of α,α-difluoro-α-phenylsulfanyl- α-trimethylsilylmethane (PhSCF₂SiMe₃

Full text of DOI:10.1016/j.jfluchem.2011.10.009

Journal of Fluorine Chemistry 135 (2012) 367–372
Contents lists available at SciVerse ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Short communication
a,a-Difluoro-a-phenylsulfanyl-a
-trimethylsilylmethane as ‘‘ꢀCF2 ’’ synthetic
À
building block for the preparation of gem-difluoromethylenated cyclopentanols
Krisana Peewasan, Chutima Kuhakarn, Darunee Soorukram, Patoomratana Tuchinda,
*
Vichai Reutrakul, Manat Pohmakotr
Center of Excellence for Innovation in Chemistry (PERCH-CIC) and Department of Chemistry, Faculty of Science, Mahidol University, Rama VI Road, Bangkok 10400, Thailand
A R T I C L E I N F O
A B S T R A C T
Article history:
A
general strategy for the preparation of gem-difluoromethylenated cyclopentanols has been
demonstrated; it involves sequential fluoride-catalyzed nucleophilic addition of -difluoro-
phenylsulfanyl- -trimethylsilylmethane (PhSCF2SiMe3; 1) to homoallyl ketones followed by intramo-
lecular radical cyclization.
Received 29 August 2011
a
,
a
a-
Received in revised form 10 October 2011
Accepted 12 October 2011
Available online 2 November 2011
a
ß 2011 Elsevier B.V. All rights reserved.
Keywords:
a,
a-Difluoro-
a-phenylsulfanyl-a-
trimethylsilylmethane
gem-Difluoromethylenated cyclopentanols
Radical cyclization
1. Introduction
cyclization, providing the desired gem-difluoromethylenated
cyclopentanol 5 (Scheme 1).
Organofluorine compounds are of importance due to their
unique physical properties. More importantly, they are widely
used in pharmaceutical chemistry and material sciences [1,2]. The
presence of gem-difluoromethylene moiety in organic compounds
led to the enhancement of biological properties of drug molecules
[3]. Consequently, the development of general and efficient
methodologies for the preparation of structurally different fluorine
containing molecules has attracted considerable attention in
organic communities [4,5].
2. Results and discussion
To begin with, treatment of 1 with homoallyl ketone 2a in the
presence of 10 mol% of anhydrous tetrabutylammonium fluoride
(TBAF) in THF at À78 8C to room temperature overnight (16 h)
followed by acidic workup (1 M HCl) afforded the expected adduct
3a in 93% yield (Table 1, entry 1). Under similar reaction conditions
as for 3a, the reaction of 1 with 2d–g provided the corresponding
adducts 3d–g in moderate to good yields (Table 1, entries 4–7).
Alternatively, compounds 3b, 3c, and 3h were prepared in high
yields (entries 2, 3, and 8) by cross-olefin metathesis of 3a and 3g
with styrene or methyl acrylate, respectively, employing Grubbs
second-generation catalyst in refluxing CH2Cl2 for 20 h.
Having succeeded in preparing adducts 3a–h, reductive
desulfenylation of 3 employing Bu3SnH/AIBN should provide
gem-difluoromethylenated radical intermediate 4, which should
then be trapped intramolecularly by an alkenyl moiety to afford
gem-difluoromethylenated cyclopentanols 5. Under the standard
reaction conditions (1.75 equiv. Bu3SnH, 15 mol% AIBN, toluene,
reflux, 5 h), reductive desulfenylation followed by radical cycliza-
tion of 3a yielded 5a in 68% yield as a mixture of two diastereomers
(Table 1, entry 1). Pure trans-5a was partially obtained in 40% yield
by chromatography. The relative yields of the two diastereomers
were carefully determined by 1H NMR (500 MHz) to be approxi-
mately 2:1. Under the standard radical reaction conditions, a
Recently, PhSCF2SiMe3 (1) has been shown to react with
carbonyl compounds [6],
and alkyl bromides [9] to provide the corresponding gem-
difluoromethylenated alcohols, -lactones, amines, 1-azabicyclic
g-ketoesters [7], imines [8], imides [5d],
g
compounds, and alkanes, respectively. In continuation with our
research work on using 1 as a gem-difluoromethylene building
block [10], we now wish to report a general synthetic entry to gem-
difluoromethylenated cyclopentanols [11]. Since it has been
demonstrated that carbonyl compounds can undergo fluoride-
catalyzed nucleophilic difluoro(phenylsulfanyl)methylation reac-
tion using 1, it is anticipated that 1 would similarly react with
homoallyl ketones 2 leading to adducts 3. Subsequent reductive
cleavage of the phenylsulfanyl moiety should provide radical
intermediate 4 that should then undergo intramolecular radical
* Corresponding author. Tel.: +66 2201 5158; fax: +66 2644 5126.
E-mail address: scmpk@mahidol.ac.th (M. Pohmakotr).
0022-1139/$ – see front matter ß 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2011.10.009

368
K. Peewasan et al. / Journal of Fluorine Chemistry 135 (2012) 367–372
PhSCF2SiMe3
region than those of the cis-isomers. The trans-isomers of 5f and 5h
were also proposed, based on the transition structure in Scheme 2,
to be the major isomers.
In conclusion, we have demonstrated a convenient two-step
synthesis of gem-difluoromethylenated cyclopentanols. The syn-
thetic approach entails fluoride-catalyzed nucleophilic addition of
PhSCF2SiMe3 to homoallyl ketones followed by intramolecular
radical cyclization.
F
F
1. TBAF (10 mol%)
THF, −78 oC to rt
2. HCl, H2O
1
SPh
HO
R1
+
R2
O
3
R2
R1
2
Bu3SnH, AIBN
toluene, reflux
3. Experimental
F
F
F
HO
R1
F
R2
The 1H NMR (500 MHz) and 13C NMR (125 MHz) spectra were
recorded on a Bruker Advance-500 spectrometer in CDCl3 using
tetramethylsilane as an internal standard. The 19F NMR (470 MHz)
spectra were recorded on a Bruker Advance-500 spectrometer and
HO
R1
R2
5
4
chemical shifts (
d) were measured with fluorotrichloromethane
Scheme 1.
(
d
= 0) as an internal standard. The IR spectra were recorded on
either a Jasco A-302 or a Perkin Elmer 683 infrared spectrometer.
The electron impact mass spectra were recorded by using Thermo
Finnigan Polaris Q mass spectrometer. The high resolution mass
spectra were recorded using TOF mode on a Micromass model VQ-
TOF2 mass spectrometer. Elemental analyses were performed
using a Perkin Elmer Elemental Analyzer 2400 CHN. Melting points
were recorded on a Buchi 501 melting point apparatus and are
uncorrected. Tetrahydrofuran (THF) was distilled from sodium-
benzophenone ketyl. Column chromatography was performed by
using Merck silica gel 60H (mesh Art. 7736). Preparative TLC plates
were prepared by using Merck silica gel 60 PF254 (mesh Art. 7747).
collection of gem-difluoromethylenated cyclopentanols 5b–h, each
as mixtures of isomers, were synthesized in moderate to good
yields (56–87%) (Table 1, entries 2–8). Unfortunately, attempts to
separate each isomer of compounds 5b–h by chromatographic
techniques were unsuccessful.
The proposed transition structure for radical cyclization was
shown in Scheme 2. Based on Zimmermann–Beckwith–Houk
Model [12], we assumed that the preferred transition structure for
cyclization that proceeds through an exo-1,5-ring closure mode
was found to be cyclopentane chair-like transition state with
substituent occupied at pseudoequatorial position. Therefore, for
radical cyclization of compound 3a to yield compound 5a, a chair-
like transition structure 4a-A should be more favorable, giving rise
to the trans-5a as a major isomer. On the contrary, the minor cis-5a
should occur through a less favorable boat-like transition structure
4a-B. Additionally, for compounds 5a–e, the evidence in support-
ing the trans-isomer as the major isomer was the 1H NMR chemical
shifts of the methine protons of compounds 5a–e. The influence
caused by anisotropic effect of the phenyl ring [13] made the
methine protons of the trans-isomers 5a–e to appear at higher field
3.1. General procedure for the synthesis of compound 3
To a mixture of PhSCF2SiMe3 (1) (1.39 g, 6 mmol) and 2a
(481 mg, 3 mmol) in dry THF (6 mL), was added 10 mol% TBAF
(0.6 mL, 0.6 mmol, 1 M solution in THF) at À78 8C. The reaction
mixture was stirred and slowly warmed up to room temperature
overnight (16 h), then quenched with 1 M HCl (3 mL) and extracted
with EtOAc (3Â 50 mL). The organic layer was washed with water
(10 mL), brine (10 mL), and dried (anh. Na2SO4). Purification by
preparative TLC (SiO2, 15% EtOAc-hexanes) afforded 3a.
3.1.1. 1,1-Difluoro-2-phenyl-1-(phenylsulfanyl)hex-5-en-2-ol (3a)
A colorless oil (894 mg, 93% yield); IR (neat): 3543s, 1642m,
. d
1475m, 1449s, 1441s, 1047s cmÀ1 1H NMR (500 MHz, CDCl3):
HO CF2SPh
7.63 (d, J = 8.0 Hz, 2H, PhH), 7.59–7.54 (m, 2H, PhH), 7.48–7.33 (m,
6H, PhH), 5.83 (ddt, J = 17.0, 10.4, 6.5 Hz, 1H, CH55CHH), 5.04–4.94
(m, 2H, CH55CHH), 2.69 (s, 1H, OH), 2.44–2.35 (m, 1H, CHH–CHH),
2.28–2.10 (m, 2H, CHH–CHH), 1.85–1.75 (m, 1H, CHH–CHH). 13C
3a
Bu3SnH, AIBN
NMR (125 MHz, CDCl3): d 138.0 (CH), 137.9 (C), 136.6 (2CH), 131.3
(t, J = 288.5 Hz, CF2), 129.6 (2CH), 128.8 (2CH), 128.1 (2CH), 126.7
(2CH), 126.2, (C), 115.1 (CH2), 80.4 (t, J = 23.6 Hz, C), 34.6 (CH2),
F
F
27.2 (CH2). 19F NMR (470 MHz, CDCl3):
d
À81.55 (d, J = 204.5 Hz, F),
+
F
À84.02 (d, J = 204.5 Hz, F). MS (EI): m/z (%) = 320 [M]+ (1), 303 (45),
F
225 (20), 161 (95), 105 (100), 77 (19). HRMS (ESI-TOF): calcd. for
18H18F2OSNa [M+Na]+: 343.0944; Found: 343.1002.
OH
OH
4a-B
C
4a-A (favored TS)
3.1.2. (E)-1,1-Difluoro-2,6-diphenyl-1-(phenylsulfanyl)hex-5-en-2-
ol (3b)
Cross-olefin metathesis of 3a (665 mg, 2 mmol) with styrene
(0.9 mL, 8 mmol) using Grubbs’ catalyst (2nd generation, 5 mol%)
in reflux CH2Cl2 (10 mL) for 20 h gave 3b (681 mg, 86% yield) as a
colorless oil after purification by preparative TLC (SiO2, 10% EtOAc-
F
F
OH
OH
F
F
H
Me
Me
H
hexanes); IR (neat): 3473s, 1496s, 1475s, 1449s, 1048s cmÀ1
.
1H
NMR (500 MHz, CDCl3): 7.62 (d, J = 7.9 Hz, 2H, PhH), 7.54–7.50
d
(m, 2H, PhH), 7.45–7.35 (m, 5H, PhH), 7.35–7.29 (m, 2H, PhH),
7.29–7.23 (m, 3H, PhH), 7.21–7.15 (m, 1H, PhH), 6.30 (d, J = 15.8 Hz,
1H, 55CHPh), 6.14 (dt, J = 15.8, 6.7 Hz, 1H, CH55CHPh), 2.67 (s, 1H,
trans-5a (major)
cis-5a (minor)
Scheme 2.

K. Peewasan et al. / Journal of Fluorine Chemistry 135 (2012) 367–372
369
Table 1
Preparation of gem-difluoromethylenated cyclopentanols 5.
Entry
1
2
3 (%)a
5 (%;a trans:cis)
O
HO CF2SPh
F
OH
F
Me
3a (93%)
5a (68%; 66:34)b
2a
2
–
HO CF2SPh
F
OH
F
5b (56%; 65:35)b
3bc (86%)
3
–
HO CF2SPh
F
OH
F
CO2Me
CO2Me
5c (73%; 61:39)b
3cc (82%)
4
O
HO CF2SPh
MeO
F
OH
F
MeO
MeO
5d (87%; 63:37)b
3d (60%)
2d
5
O
HO CF2SPh
OMe
MeO
MeO
MeO
MeO
MeO
MeO
F
OH
F
OMe
OMe
5e (63%; 60:40)b
3e (89%)
2e
6
HO CF2SPh
Me
O
F
OH
Me
F
CO2Me
Me
CO2Me
CO2Me
3f (67%)
5f (77%; 66:34)b
2f
d
7
8
–
O
HO CF2SPh
Me
Me
3g (77%)
2g
–
F
HO CF2SPh
OH
Me
F
Me
3h (75%)e
5h (71%; 52:48)b
aIsolated yields by chromatography on silica gel.
bDetermined by 1H NMR spectrum.
cCompounds 3b and 3c were prepared by cross-olefin metathesis between 3a and styrene and methyl acrylate, respectively.
dThe reaction was not performed.
ePrepared by cross-olefin metathesis between 3g and styrene.

370
K. Peewasan et al. / Journal of Fluorine Chemistry 135 (2012) 367–372
OH), 2.48–2.36 (m, 1H), 2.33–2.20 (m, 2H), 1.96–1.85 (m, 1H). 13
NMR (125 MHz, CDCl3): 137.8 (C), 137.4 (C), 136.6 (2CH), 131.3 (t,
J = 288.6 Hz, CF2), 130.5 (2CH), 129.7 (CH), 129.6 (CH), 129.0 (2CH),
128.5 (2CH), 128.2 (2CH), 127.0 (CH), 126.7 (2CH), 126.2 (C), 126.9
(2CH), 80.3 (t, J = 23.3 Hz, C), 35.1 (CH2), 26.5 (CH2). 19F NMR
C
(CH), 129.6 (CH), 128.9 (2CH), 128.5 (2CH), 127.1 (CH), 126.2 (C),
125.9 (2CH), 104.3 (2CH), 80.3 (t, J = 23.5 Hz, C), 60.9 (OCH3), 56.2
(2OCH3), 35.3 (CH2), 26.5 (CH2). 19F NMR (470 MHz, CDCl3):
d
À81.3 (d, J = 205.4 Hz, F), À83.5 (d, J = 205.4 Hz, F). MS (EI): m/z
(%) = 486 [M]+ (20), 355 (27), 327 (100), 251 (18), 195 (57), 117
(36). HRMS (ESI-TOF) calcd. for C27H28F2O4SNa [M+Na]+:
509.1574; Found: 509.1616. Anal. Calcd. for C27H28F2O4S: C,
66.65; H, 5.80; Found: C, 66.44; H, 5.49.
d
(470 MHz, CDCl3):
d
À81.6 (d, J = 204.2 Hz, F), À84.0 (d,
J = 204.2 Hz, F). MS (EI): m/z (%) = 396 [M]+ (1), 253 (46), 237
(100), 117 (90), 105 (54), 91 (38), 77 (48). Anal. Calcd. for
C
24H22F2OS: C, 72.70; H, 5.59; Found: C, 72.55; H, 5.56.
3.1.6. 7,7-Difluoro-6-hydroxy-6-methyl-7-(phenylsulfanyl)hept-2-
enoic acid methyl ester (3f)
3.1.3. 7,7-Difluoro-6-hydroxy-6-phenyl-7-(phenylsulfanyl)hept-2-
enoic acid methyl ester (3c)
The reaction of 1 (1.39 g, 6 mmol) with 2f (469 mg, 3 mmol)
and purification by column chromatography (SiO2, 5% EtOAc-
hexanes) gave 3f (636 mg, 67% yield) as a colorless oil. IR (neat):
Cross-olefin metathesis of 3a (665 mg, 2 mmol) with methyl
acrylate (0.7 mL, 8 mmol) using Grubbs’ catalyst (2nd generation,
5 mol%) in reflux CH2Cl2 (10 mL) gave 3c (620 mg, 82% yield) as a
white solid after purification by preparative TLC (SiO2, 15% EtOAc-
hexanes); m.p. 127–128 8C. IR (KBr): 3439s, 1709s, 1702s, 1655s,
3445s, 1723s, 1714s, 1699s, 1659s, 1440s cmÀ1
.
1H NMR
7.65–7.58 (m, 2H, PhH), 7.46–7.40 (m, 1H,
(500 MHz, CDCl3):
d
PhH), 7.40–7.34 (m, 2H, PhH), 7.02 (dt, J = 15.7, 6.7 Hz, 1H, –
CH55CH), 5.89 (dt, J = 15.7, 1.5 Hz, 1H, CH55C(O)), 3.73 (s, 3H,
OCH3), 2.66–2.50 (br. s, 1H, OH), 2.50–2.41 (m, 1H), 2.41–2.30 (m,
1H), 2.01–1.91 (m, 1H), 1.89–1.80 (m, 1H), 1.42 (s, 3H, CH3). 13C
1436s, 1331s, 1257s, 1214s, 1053s, 1014s cmÀ1
.
1H NMR
(500 MHz, CDCl3): 7.60 (d, J = 8.0 Hz, 2H, PhH), 7.56–7.51 (m,
d
2H, PhH), 7.46–7.38 (m, 4H, PhH), 7.38–7.33 (m, 2H, PhH), 6.93 (dt,
J = 15.6, 6.7 Hz, 1H, –CH55), 5.78 (dt, J = 15.6, 1.5 Hz, 1H, CH55C(O)),
3.73 (s, 3H, CH3), 2.80 (s, 1H, OH), 2.44–2.36 (m, 1H), 2.36–2.21 (m,
NMR (125 MHz, CDCl3):
d 167.0 (CO), 148.6 (CH), 136.6 (2CH),
131.8 (t, J = 286.0 Hz, CF2), 129.7 (CH), 128.9 (2CH), 125.8, (C),
121.2 (CH), 76.5 (t, J = 23.1 Hz, C), 51.4 (OCH3), 34.4 (CH2), 26.0
2H), 1.94–1.83 (m, 1H). 13C NMR (125 MHz, CDCl3):
d 166.9 (CO),
148.4 (CH), 137.4 (C), 136.6 (2CH), 131.2 (t, J = 288.9 Hz, CF2), 129.7
(CH), 128.9 (2CH), 128.4 (2CH), 128.3 (2CH), 126.6 (CH), 126.0 (C),
121.2 (CH), 80.0 (t, J = 23.1 Hz, C), 51.4 (OCH3), 33.9 (CH2), 25.8
(CH2), 21.0 (CH3). 19F NMR (470 MHz, CDCl3):
d
À85.0 (s, 2F). MS
(EI): m/z (%) = 316 [M]+ (3), 297 (11), 278 (8), 249 (11), 184 (89),
157 (44), 141 (70), 129 (84), 125 (63), 109 (48), 97 (47), 79 (100).
HRMS (ESI-TOF) calcd. for C15H18F2O3SNa [M+Na]+: 339.0843;
Found: 339.0842.
(CH2). 19F NMR (470 MHz, CDCl3):
d
À81.6 (d, J = 204.9 Hz, F),
À84.1 (d, J = 204.9 Hz, F). MS (EI): m/z (%) = 378 [M]+ (1), 341 (13),
219 (51), 187 (100), 169 (90), 141 (89), 128 (36), 115 (18), 105 (22),
77 (27). HRMS (ESI-TOF) calcd. for C20H20F2O3SNa [M+Na]+:
401.0999; Found: 401.0997.
3.1.7. 1,1-Difluoro-2-methyl-1-(phenylsulfanyl)hex-5-en-2-ol (3g)
The reaction of 1 (1.39 g, 6 mmol) with hex-5-en-2-one
(295 mg, 3 mmol) and purification by column chromatography
(SiO2, 5% EtOAc-hexanes) gave 3g (596 mg, 77% yield) as a
colorless oil. IR (neat): 3441s, 1710s, 1642s, 1475s, 1441s,
3.1.4. 1,1-Difluoro-2-(4-methoxyphenyl)-6-phenyl-1-
(phenylsulfanyl)hex-5-en-2-ol (3d)
The reaction of 1 (1.39 g, 6 mmol) with 2d (799 mg, 3 mmol)
and purification by preparative TLC (SiO2, 5% EtOAc-hexanes) gave
3d (768 mg, 60% yield) as a colorless oil. IR (neat): 3479s, 1612s,
1515s, 1254s, 1181s, 1038s cmÀ1 1H NMR (500 MHz, CDCl3):
. d
7.61–7.50 (m, 4H, PhH), 7.45–7.39 (m, 1H, PhH), 7.39–7.33 (m, 2H,
PhH), 7.33–7.27 (m, 4H, PhH), 7.25–7.18 (m, 1H, PhH), 7.00–6.94
(m, 2H, ArH), 6.34 (d, J = 15.8 Hz, 1H, 55CHPh), 6.18 (dt, J = 15.8,
6.7 Hz, 1H, CH55CH), 3.87 (s, 3H, CH3), 2.64 (s, 1H, OH), 2.47–2.38
(m, 1H), 2.36–2.22 (m, 2H), 2.02–1.92 (m, 1H). 13C NMR (125 MHz,
1381s cmÀ1 1H NMR (500 MHz, CDCl3):
. d 7.46–7.41 (m, 2H,
PhH), 7.27–7.22 (m, 1H, PhH), 7.22–7.16 (m, 2H, PhH), 5.68 (ddt,
J = 17.1, 10.2, 6.6 Hz, 1H, CH55CHH), 4.90 (ddt, J = 1.7, 17.1, 1.7 Hz,
1H, 55CHH), 4.82 (ddt, J = 1.7, 10.2, 1.4 Hz, 1H, 55CHH), 2.16–1.98
(m, 2H, CH2), 1.88 (s, 1H, OH), 1.74–1.66 (m, 1H), 1.66–1.58 (m,
1H), 1.23 (s, 3H, CH3). 13C NMR (125 MHz, CDCl3):
d 138.1 (CH),
136.7 (2CH), 132.0 (t, J = 285.0 Hz, CF2), 129.7 (CH), 128.9 (2CH),
126.1, (C), 115.0 (CH2), 76.9 (t, J = 23.0 Hz, C), 35.4 (CH2), 27.4
(CH2), 21.1 (CH3). 19F NMR (470 MHz, CDCl3):
d
À85.1 (s, 2F). MS
CDCl3):
d
159.5 (C), 137.5 (2C), 136.5 (2CH), 131.5 (t, J = 288.4 Hz,
(EI): m/z (%) = 258 [M]+ (66), 240 (32), 201 (16), 160 (22), 131
(100), 109 (40). HRMS (ESI-TOF) calcd. for C13H16F2OSNa [M+Na]+:
281.0788; Found: 281.0787.
CF2), 130.4 (CH), 129.8 (CH), 129.6 (CH), 128.8 (2CH), 128.5 (2CH),
128.0 (2CH), 127.0 (CH), 126.3 (C), 125.9 (2CH), 113.5 (2CH), 80.1
(t, J = 23.6 Hz, C), 55.2 (OCH3), 35.1 (CH2), 26.6 (CH2). 19F NMR
(470 MHz, CDCl3):
d
À81.7 (d, J = 203.7 Hz, F), À84.3 (d,
3.1.8. 1,1-Difluoro-2-methyl-6-phenyl-1-(phenylsulfanyl)hex-5-en-
2-ol (3h)
J = 203.7 Hz, F). MS (EI): m/z (%) = 426 [M]+ (2), 295 (7), 267
(100), 135 (97), 117 (55), 77 (25). HRMS (ESI-TOF) calcd. for
C
for C25H24F2O2S: C, 70.40; H, 5.67; Found: C, 70.28; H, 5.89.
Cross-olefin metathesis of 3g (512 mg, 2 mmol) with styrene
(0.9 mL, 8 mmol) using Grubbs’ catalyst (2nd generation, 5 mol%)
in reflux CH2Cl2 (10 mL) gave 3h (496 mg, 75% yield) as a colorless
oil after purification by column chromatography (SiO2, 5% EtOAc-
25H24F2O2SNa [M+Na]+: 449.1363; Found: 449.1397. Anal. Calcd.
3.1.5. 1,1-Difluoro-6-phenyl-1-(phenylsulfanyl)-2-(3,4,5-
trimethoxyphenyl)hex-5-en-2-ol (3e)
hexanes); IR (neat): 3436s, 1475s, 1441s, 1380s, 1047s cmÀ1
.
1H
NMR (500 MHz, CDCl3): 7.75 (d, J = 8.1 Hz, 2H, PhH), 7.53–7.43
d
The reaction of 1 (1.39 g, 6 mmol) with 2e (979 mg, 3 mmol)
and purification by preparative TLC (SiO2, 15% EtOAc-hexanes)
gave 3e (1.30 g, 89% yield) as a white solid. m.p. 141–143 8C. IR
(KBr): 3407s, 1592s, 1506s, 1461s, 1451s, 1417s, 1318s, 1244s,
(m, 5H, PhH), 7.43–7.37 (m, 2H, PhH), 7.34–7.28 (m, 1H, PhH), 6.56
(d, J = 15.8 Hz, 1H, 55CHPh), 6.35 (dt, J = 15.8, 6.9 Hz, 1H,
CH55CHPh), 2.63–2.42 (m, 3H), 2.14–2.04 (m, 1H), 2.04–1.96
(m, 1H), 1.56 (s, 3H, CH3). 13C NMR (125 MHz, CDCl3):
d 137.5 (C),
1126s, 1060s cmÀ1. 1H NMR (500 MHz, CDCl3):
d
7.56–7.50 (m, 2H,
136.6 (2CH), 132.0 (t, J = 286.1 Hz, CF2), 130.4 (CH), 129.8 (CH),
PhH), 7.43–7.37 (m, 1H, PhH), 7.37–7.31 (m, 2H, PhH), 7.31–7.26
(m, 4H, PhH), 7.22–7.16 (m, 1H, PhH), 6.82 (s, 2H, ArH), 6.32 (d,
J = 15.8 Hz, 1H,55CHPh), 6.15 (dt, J = 15.8, 6.5 Hz, 1H, CH55CH), 3.89
(s, 9H, 3OCH3), 2.67 (s, 1H, OH), 2.41–2.20 (m, 3H), 2.03–1.91 (m,
129.6 (CH), 128.9 (2CH), 128.4 (2CH), 126.9 (CH), 126.0 (C), 125.9
(2CH), 76.8 (t, J = 23.0 Hz, C), 35.7 (CH2), 26.6 (CH2), 20.9 (CH3). 19
F
NMR (470 MHz, CDCl3):
d
À84.7 (s, 2F). MS (EI): m/z (%) = 335
[M+H]+ (30), 243 (55), 187 (69), 175 (100), 117 (67), 91 (28). HRMS
(ESI-TOF) calcd. for C19H20F2OSH [M+H]+: 335.1281; Found:
335.1288.
1H). 13C NMR (125 MHz, CDCl3):
136.6 (2CH), 133.3 (C), 131.2 (t, J = 289.5 Hz, CF2), 130.5 (CH), 130.0
d 152.9 (2C), 138.0 (C), 137.4 (C),

K. Peewasan et al. / Journal of Fluorine Chemistry 135 (2012) 367–372
371
3.2. General procedure for the synthesis of compound 5
J = 16.4, 5.9 Hz, 1H, CHH–CO), 2.69 (dd, J = 16.2, 4.7 Hz, 1H,
CHHCO), 2.53* (dd, J = 16.4, 8.7 Hz, 1H, CHHCO), 2.40 (dd,
J = 16.2, 10.3 Hz, 1H, CHH–CO), 2.45–2.36 (m, 1H, CHH), 2.36–
2.27 (m, 2H, CHH of trans- and cis-isomers), 2.25–2.12* (m, 1H,
CHH), 2.12–2.03 (m, 2H, CHH of trans- and cis-isomers), 1.85–1.73*
(m, 1H, CHH), 1.56–1.45 (m, 1H, CHH). 13C NMR (125 MHz, CDCl3,
Argon was bubbled through a solution of 3a (320 mg, 1 mmol)
in toluene (5 mL) for 30 min. Bu3SnH (0.47 mL, 1.75 mmol) was
added to the solution and deoxygenation was continued for 5 min.
AIBN (25 mg, 0.15 mmol) was added and the solution was heated
to reflux for 5 h. Evaporation and purification by column
chromatography (SiO2, 10% EtOAc-hexanes) gave a colorless oil
of 5a (144 mg, 68% yield) as a 66:34 mixture of trans- and cis-
isomers. The major trans-isomer was obtained in 40% yield by
column chromatography (SiO2, 5% EtOAc-hexanes).
trans-isomer marked*): d 172.6* (CO), 172.5 (CO), 138.8* (C), 138.6
(C), 128.4 (dd, J = 265.1, 253.0 Hz, CF2), 128.3* (dd, J = 264.6,
255.1 Hz, CF2), 128.2* (2CH), 128.1 (2CH), 128.0 (2CH), 126.5
(2CH), 126.4* (2CH) 81.1* (dd, J = 28.4, 20.4 Hz, C), 80.3 (dd,
J = 27.9, 20.3 Hz, C), 51.7 (OCH3), 51.6* (OCH3), 40.4* (dd, J = 26.4,
20.3 Hz, CH), 38.5 (t, J = 21.1 Hz, CH), 35.5* (dd, J = 6.6, 4.7 Hz, CH2),
33.9 (2CH2), 32.4 (d, J = 7.9 Hz, CH2), 25.8* (t, J = 3.8 Hz, CH2), 24.0
(d, J = 8.6 Hz, CH2). 19F NMR (470 MHz, CDCl3, trans-isomer
3.2.1. 2,2-Difluoro-3-methyl-1-phenylcyclopentanol (5a)
IR (neat): 3450s, 1460s, 1455s, 1449s, 1204s, 1122s,
1059s cmÀ1
.
1H NMR (500 MHz, CDCl3):
d
7.55–7.48 (m, 2H,
marked*):
d
À94.9* (dd, J = 233.6, 24.4 Hz, F), À118.1 (dd,
PhH), 7.40–7.28 (m, 3H, PhH), 2.60–2.28 (m, 3H, OH, CH, and CHH),
2.15–2.04 (m, 2H, CHH), 1.79–1.68 (m, 1H, CHH), 1.17 (dd, J = 7.2,
2.0 Hz, 3H, CH3). 13C NMR (125 MHz, CDCl3):
d 139.5 (C), 128.8 (dd,
J = 261.3, 255.4 Hz, CF2), 128.2 (2CH), 128.1 (CH), 126.5 (2CH), 81.4
(dd, J = 27.4, 20.7 Hz, C), 38.7 (dd, J = 24.1, 22.4 Hz, CH), 34.4 (d,
J = 2.3 Hz, CH2), 27.6 (dd, J = 4.9, 3.2 Hz, CH2), 15.1 (dd, J = 7.9,
J = 230.3, 25.3 Hz, F), À125.0* (d, J = 233.6 Hz, F), À125.7 (dt,
J = 230.3, 3.4 Hz, F). MS (EI): m/z (%) = 270 [M]+ (11), 233 (100), 199
(8), 171 (8), 157 (22), 133 (22), 115 (13), 105 (15), 77 (16). HRMS
(ESI-TOF): calcd. for C14H16F2O3Na [M+Na]+: 293.0966; Found:
293.0936. Anal. Calcd. for C14H16F2O3: C, 62.22; H, 5.97; Found: C,
62.18; H, 5.84.
3.6 Hz, CH3). 19F NMR (470 MHz, CDCl3):
d
À98.1 (dd, J = 230.9,
23.3 Hz, F), À126.3 (d, J = 230.9 Hz, F). MS (EI): m/z (%) = 212 [M]+
(18), 161 (14), 149 (14), 133 (100), 115 (43), 105 (36), 91 (24), 77
(54). HRMS (ESI-TOF): calcd. for C12H14F2ONa [M+Na]+: 235.0911;
Found: 235.0863.
3.2.4. 3-Benzyl-2,2-difluoro-1-(4-methoxyphenyl)cyclopentanol (5d)
Radical cyclization of 3d (427 mg, 1 mmol) afforded a white
solid of 5d (277 mg, 87% yield) as a 63:37 mixture of trans- and cis-
isomers after purification by PLC (SiO2, 15% EtOAc-hexanes).
m.p. = 90–93 8C. IR (neat): 3461s, 1612s, 1515s, 1455s, 1252s,
3.2.2. 3-Benzyl-2,2-difluoro-1-phenylcyclopentanol (5b)
1183s, 1035s cmÀ1
.
1H NMR (500 MHz, CDCl3, trans-isomer
Radical cyclization of 3b (396 mg, 1 mmol) afforded a colorless
oil of 5b (161 mg, 56% yield) as a 65:35 mixture of trans- and cis-
isomers after purification by column chromatography (SiO2, 5%
EtOAc-hexanes). IR (neat): 3550s, 1498s, 1455s, 1447s, 1190s,
marked*): 7.55–7.46 (m, 4H, ArH of trans- and cis-isomers),
d
7.38–7.31 (m, 4H, PhH of trans- and cis-isomers), 7.31–7.23 (m, 6H,
PhH of trans- and cis-isomers), 6.98–6.92 (m, 4H, ArH of trans- and
cis-isomers), 3.86 (s, 3H, OCH3), 3.85* (s, 3H, OCH3), 3.21* (dd,
J = 13.3, 4.3 Hz, 1H, CHHPh), 3.13 (dd, J = 13.5, 5.2 Hz, 1H, CHHPh),
3.14–3.00 (m, 1H, CH), 2.78–2.55 (m, 3H), 2.55–2.50* (br.s, 1H, OH),
2.50–2.41 (m, 2H, OH and CHH), 2.39–2.28* (m, 1H, CHH), 2.18–
2.05 (m, 3H), 1.97–1.85* (m, 2H, CH2), 1.67–1.58 (m, 1H). 13C NMR
1065s cmÀ1 1H NMR (500 MHz, CDCl3, trans-isomer marked*):
. d
7.57–7.50 (m, 4H, PhH of trans- and cis-isomers), 7.42–7.26 (m,
10H, PhH of trans- and cis-isomers), 7.26–7.19 (m, 6H, PhH of trans-
and cis-isomers), 3.17* (dd, J = 13.1, 4.2 Hz, 1H, CHHPh), 3.12–2.97
(m, 2H, CHHPh and CH), 2.74–2.55 (m, 3H of trans- and cis-
isomers), 2.50–2.28 (m, 3H of trans- and cis-isomers), 2.16–2.03
(m, 4H of trans- and cis-isomers), 1.94–1.84* (m, 2H, CH2), 1.66–
1.52 (m, 1H, CHH). 13C NMR (125 MHz, CDCl3, trans-isomer
(125 MHz, CDCl3, trans-isomer marked*):
d 159.5* (C), 159.4 (C),
139.7 (C), 139.6* (C), 131.4* (C), 131.1 (C), 128.6 (dd, J = 262.5,
255.0 Hz, CF2), 128.5* (dd, J = 262.3, 255.8 Hz, CF2), 128.8 (4CH),
128.4 (4CH), 128.3 (2CH), 128.0 (2CH), 127.8* (2CH), 126.2 (4CH),
113.6 (4CH), 81.1* (dd, J = 27.4, 20.6 Hz, C), 80.7 (dd, J = 27.9,
21.1 Hz, C), 55.2 (2OCH3), 45.3* (dd, J = 23.6, 20.9 Hz, CH), 43.5 (t,
J = 21.4 Hz, CH), 36.3* (dd, J = 7.3, 3.4 Hz, CH2), 34.2* (CH2), 33.9 (d,
J = 3.9 Hz, CH2), 33.7 (d, J = 7.6 Hz, CH2), 25.6* (CH2), 24.0 (d,
J = 9.4 Hz, CH2). 19F NMR (470 MHz, CDCl3, trans-isomer marked*):
marked*): d 139.7 (C), 139.6* (C), 139.3* (C), 138.9 (C), 128.4 (4CH),
128.7 (t, J = 251.9 Hz, CF2), 128.5* (dd, J = 262.5, 256.5 Hz, CF2),
128.4 (4CH), 128.3 (2CH), 128.2 (4CH), 128.1 (CH), 126.6 (CH),
126.5 (2CH), 126.2 (2CH), 81.5* (dd, J = 27.5, 20.6 Hz, C), 80.9 (dd,
J = 28.3, 20.6 Hz, C), 45.5* (dd, J = 23.7, 20.7 Hz, CH), 43.6 (t,
J = 21.1 Hz, CH), 36.3* (dd, J = 7.1, 3.3 Hz, CH2), 34.2* (d, J = 2.4 Hz,
CH2), 33.9 (d, J = 3.5 Hz, CH2), 33.7 (d, J = 7.4 Hz, CH2), 25.7* (dd,
J = 4.3, 3.4 Hz, CH2), 24.0 (d, J = 9.4 Hz, CH2). 19F NMR (470 MHz,
d
À97.0* (dd, J = 230.3, 23.5 Hz, F), À118.5 (dd, J = 230.3, 28.2 Hz, F),
À124.9* (d, J = 230.3 Hz, F), À125.1 (d, J = 230.3 Hz, F). MS (EI): m/z
(%) = 318 [M]+ (56), 300 (98), 191 (19), 163 (58), 150 (86), 135
(100), 91 (37), 77 (30). HRMS (ESI-TOF): calcd. for C19H20F2O2Na
[M+Na]+: 341.1329; Found: 341.1364.
CDCl3, trans-isomer marked*):
d
À96.6* (dd, J = 232.3, 22.3 Hz, F),
À118.7 (dd, J = 230.2, 25.6 Hz, F), À124.6* (d, J = 232.3 Hz, F),
À124.8 (d, J = 230.2 Hz, F). MS (EI): m/z (%) = 288 [M]+ (1), 270 (79),
161 (100), 133 (48), 129 (35), 115 (30), 105 (71), 91 (54), 77 (76).
HRMS (ESI-TOF): calcd. for C18H18F2ONa [M+Na]+: 311.1224;
Found: 311.1182.
3.2.5. 3-Benzyl-2,2-difluoro-1-(3,4,5-trimethoxyphenyl)cyclo
pentanol (5e)
Radical cyclization of 3e (487 mg, 1 mmol) afforded a white
solid of 5e (238 mg, 63% yield) as a 60:40 mixture of trans- and cis-
isomers after purification by PLC (SiO2, 20% EtOAc-hexanes).
m.p. = 116–120 8C. IR (neat): 3502s, 1591s, 1507s, 1462s, 1413s,
3.2.3. (2,2-Difluoro-3-hydroxy-3-phenylcyclopentyl)acetic acid
methyl ester (5c)
Radical cyclization of 3c (378 mg, 1 mmol) afforded a colorless
oil of 5c (197 mg, 73% yield) as a 61:39 mixture of trans- and cis-
isomers after purification by column chromatography (SiO2, 15%
EtOAc-hexanes). IR (neat): 3472s, 1732s, 1440s, 1280s, 1209s,
1338m, 1127s cmÀ1
.
1H NMR (500 MHz, CDCl3, trans-isomer
7.34–7.27 (m, 4H, PhH of trans- and cis-isomers),
marked*):
d
7.27–7.18 (m, 6H, PhH of trans- and cis-isomers), 6.78 (s, 2H, ArH),
6.76* (s, 2H, ArH), 3.87* (s, 9H, OCH3), 3.86 (s, 9H, OCH3), 3.24–
3.13* (m, 1H, CHHPh), 3.13–2.99 (m, 2H), 2.75–2.57 (m, 3H), 2.47–
2.34 (m, 3H), 2.34–2.24* (m, 1H), 2.15–2.02 (m, 3H), 1.94–1.81* (m,
2H, CH2), 1.66–1.54 (m, 1H). 13C NMR (125 MHz, CDCl3, trans-
.
1106s, 1066s cmÀ1 1H NMR (500 MHz, CDCl3, trans-isomer
marked*): 7.55–7.46 (m, 4H, PhH of trans- and cis-isomers),
d
7.39–7.27 (m, 6H, PhH of trans- and cis-isomers), 3.65 (s, 6H, OCH3
of trans- and cis-isomers), 3.28–3.11 (m, 1H, CH), 3.11–2.96 (s, 2H,
OH of trans- and cis-isomers), 2.89–2.75* (m, 1H, CH), 2.75* (dd,
isomer marked*):
d 152.9 (2C), 139.6 (C), 139.5* (C), 138.2* (C),
138.1 (C), 134.8* (C), 134.6 (C), 128.8 (4CH), 128.7 (dd, J = 262.5,

372
K. Peewasan et al. / Journal of Fluorine Chemistry 135 (2012) 367–372
255.3 Hz, CF2), 128.6* (dd, J = 262.5, 255.2 Hz, CF2), 128.5* (2CH),
128.4 (2CH), 126.2 (2CH), 104.2 (4CH), 81.5* (dd, J = 27.7, 20.4 Hz,
C), 80.9 (dd, J = 27.9, 20.6 Hz, C), 60.9 (2OCH3), 56.3 (2OCH3), 56.2
(2OCH3), 45.7* (dd, J = 23.9, 20.9 Hz, CH), 43.5 (t, J = 21.0 Hz, CH),
36.5* (dd, J = 7.2, 3.7 Hz, CH2), 34.4* (d, J = 2.9 Hz, CH2), 34.1 (d,
J = 3.8 Hz, CH2), 33.7 (d, J = 7.8 Hz, CH2), 25.8* (t, J = 3.8 Hz, CH2),
23.9 (d, J = 9.3 Hz, CH2). 19F NMR (470 MHz, CDCl3, trans-isomer
(2CH), 128.4* (2CH), 128.3 (2CH), 126.1* (CH), 126.0 (CH), 78.1*
(dd, J = 25.8, 21.0 Hz, C), 78.0 (dd, J = 27.6, 21.8 Hz, C), 44.6* (t,
J = 21.8 Hz, CH), 43.0 (t, J = 21.1 Hz, CH), 35.5* (dd, J = 6.9, 1.8 Hz,
CH2), 35.1* (CH2), 33.9 (d, J = 4.3 Hz, CH2), 33.6 (d, J = 7.4 Hz, CH2),
24.8* (dd, J = 5.9, 1.6 Hz, CH2), 24.1 (d, J = 9.3 Hz, CH2), 21.5* (d,
J = 3.8 Hz, CH3), 20.0 (d, J = 3.6 Hz, CH3). 19F NMR (470 MHz, CDCl3,
trans-isomer marked*):
d
À108.9* (dd, J = 229.4, 18.3 Hz, F), À123.1
marked*):
d
À94.8* (dd, J = 230.3, 23.5 Hz, F), À118.6 (dd, J = 230.3,
(dd, J = 228.6, 25.1 Hz, F), À127.3* (dd, J = 229.4, 13.2 Hz, F), À128.0
(dd, J = 228.6, 8.5 Hz, F). MS (EI): m/z (%) = 226 [M]+ (28), 208 (60),
129 (36), 117 (98), 91 (100), 77 (19). HRMS (ESI-TOF): calcd. for
13H16F2ONa [M+Na]+: 249.1067; Found: 249.1076.
23.5 Hz, F), À124.1* (d, J = 230.3 Hz, F), À125.0 (d, J = 230.3 Hz, F).
MS (EI): m/z (%) = 378 [M]+ (100), 257 (29), 223 (25), 210 (56), 195
(53), 91 (19). HRMS (ESI-TOF): calcd. for C21H24F2O4Na [M+Na]+:
401.1541; Found: 401.1550.
C
Acknowledgements
3.2.6. (2,2-Difluoro-3-hydroxy-3-methylcyclopentyl)acetic acid
methyl ester (5f)
We acknowledge financial supports from the Thailand Research
Fund (BRG 5380019), the Office of the Higher Education Commis-
sion and Mahidol University under the National Research
Universities Initiative, and the Center of Excellence for Innovation
in Chemistry (PERCH-CIC).
Radical cyclization of 3f (281 mg, 1 mmol) afforded a colorless
oil of 5f (161 mg, 77% yield) as a 66:34 mixture of trans- and cis-
isomers after purification by column chromatography (SiO2, 5%
EtOAc-hexanes). IR (neat): 3461s, 1732s, 1440m, 1310s, 1212s,
1175s, 1116s, 1068s cmÀ1. 1H NMR (500 MHz, CDCl3, trans-isomer
marked*): d 3.70 (s, 6H, 2OCH3 of trans- and cis-isomers), 3.09–2.92
(m, 1H, CH), 2.81–2.64 (m, 3H, CH*, CH*HCO, and CHHCO), 2.46*
(dd, J = 17.2, 10.1 Hz, 1H, CHHCO), 2.37 (dd, J = 16.0, 10.0 Hz, 1H,
CHHCO), 2.24–2.13 (m, 2H, OH and CHH), 2.13–2.00* (m, 2H, OH
and CHH), 1.91–1.69 (m, 4H), 1.66–1.54* (m, 1H), 1.45–1.29 (m,
1H, CHH), 1.34* (d, J = 2.3 Hz, 3H, CH3), 1.33 (d, J = 2.5 Hz, 3H, CH3).
References
[1] (a) T. Hiyama (Ed.), Organofluorine Compounds, Chemistry and Applications,
Springer, New York, 2000;
(b) M. Shimizu, T. Hiyama, Angew. Chem. Int. Ed. 44 (2005) 214–231, and
references cited.
[2] See for examples:
13C NMR (125 MHz, CDCl3, trans-isomer marked*):
d 172.5* (CO),
172.4 (CO), 128.4 (dd, J = 260.9, 253.1 Hz, CF2), 128.3* (t,
J = 257.5 Hz, CF2), 78.0* (dd, J = 26.4, 20.9 Hz, C), 77.5 (dd,
J = 27.6, 21.6 Hz, C), 51.7 (2OCH3), 39.6* (dd, J = 25.1, 20.4 Hz,
CH), 38.0 (t, J = 21.4 Hz, CH), 34.9* (CH2), 34.8* (dd, J = 7.0, 3.3 Hz,
CH2), 34.0 (d, J = 3.9 Hz, CH2), 32.4 (d, J = 7.3 Hz, CH2), 25.3* (dd,
J = 4.5, 2.4 Hz, CH2), 24.2 (d, J = 8.8 Hz, CH2), 20.9* (d, J = 3.3 Hz,
CH3), 19.9 (d, J = 3.4 Hz, CH3). 19F NMR (470 MHz, CDCl3, trans-
(a) J.T. Welch (Ed.), Selective Fluorination in Organic and Bioorganic Chemistry,
American Chemical Society, Washington, D.C., 1991;
(b) J. Fried, D.K. Mitra, M. Nagarajan, M.M. Mehrotra, J. Med. Chem. 23 (1980)
234–237.
[3] V.A. Soloshonok (Ed.), Enantiocontrolled Synthesis of Fluoro-organic Compounds,
Stereochemical Challenges and Biomedicinal Targets, John Wiley and Sons, Ltd.,
New York, 1999.
[4] X.-L. Qiu, F.-L. Qing, Eur. J. Chem. (2011) 3261–3278, and references cited.
[5] See for examples:
(a) L.A. Buttle, W.B. Motherwell, Tetrahedron Lett. 35 (1994) 3995–3998;
(b) C. Audouard, J. Fawcett, G.A. Griffith, E. Ke´roure´dan, A. Miah, J.M. Percy, H.
Yang, Org. Lett. 43 (2004) 4269–4272;
(c) A. Deleuze, C. Menozzi, M. Sollogoub, P. Sinay¨, Angew. Chem. Int. Ed. 43 (2004)
6680–6683;
(d) T. Bootwicha, D. Panichakul, C. Kuhakarn, S. Prabpai, P. Kongsaeree, P.
Tuchinda, V. Reutrakul, M. Pohmakotr, J. Org. Chem. 74 (2009) 3798–3805,
and references cited.
isomer marked*):
d
À106.6* (dd, J = 230.3, 18.8 Hz, F), À122.6 (dd,
J = 230.3, 28.2 Hz, F), À127.9 (dd, J = 230.3, 7.1 Hz, F), À128.7 (dd,
J = 230.3, 7.1 Hz, F). MS (EI): m/z (%) = 209 [M+H]+ (7), 201 (21), 193
(31), 184 (66), 149 (92), 141 (53), 125 (69), 109 (62), 79 (100).
HRMS (ESI-TOF): calcd. for C9H14F2O3Na [M+Na]+: 231.0809;
Found: 231.0837.
[6] (a) G.K.S. Prakash, J. Hu, Y. Wang, G.A. Olah, J. Fluorine Chem. 126 (2005) 527–
532;
3.2.7. 3-Benzyl-2,2-difluoro-1-methylcyclopentanol (5h)
(b) M. Pohmakotr, K. Boonkitpattarakul, W. Ieawsuwan, S. Jarussophon, N.
Duangdee, P. Tuchinda, V. Reutrakul, Tetrahedron 62 (2006) 5973–5985;
(c) S. Mizuta, N. Shibata, S. Ogawa, H. Fujimoto, S. Nakamura, T. Toru, Chem.
Commun. (2006) 2575–2577.
Radical cyclization of 3h (334 mg, 1 mmol) afforded a colorless
oil of 5h (161 mg, 71% yield) as a 52:48 mixture of trans- and cis-
isomers after purification by column chromatography (SiO2, 5%
EtOAc-hexanes). IR (neat): 3418s, 1497m, 1455s, 1380s, 1177s,
[7] M. Pohmakotr, D. Panichakul, P. Tuchinda, V. Reutrakul, Tetrahedron 63 (2007)
9429–9436.
1101s, 1071s cmÀ1
.
1H NMR (500 MHz, CDCl3, trans-isomer
[8] Y. Li, J. Hu, Angew. Chem. Int. Ed. 44 (2005) 5882–5886.
[9] Y. Li, J. Hu, J. Fluorine Chem. 129 (2008) 382–385.
[10] (a) G.K.S. Prakash, J. Hu, Acc. Chem. Res. 40 (2007) 921–930, and references cited;
(b) G.K.S. Prakash, J. Hu, G.A. Olah, J. Org. Chem. 68 (2003) 4457–4463.
[11] Leclerc and co-workers have recently reported syntheses of difluorinated carbo-
cyclic analogues of 5-deoxypentofuranoses employing PhSeCF2SiMe3, see:
marked*): 7.31–7.25 (m, 4H, PhH of trans- and cis-isomers),
d
7.23–7.16 (m, 6H, PhH of trans- and cis-isomers), 3.09* (dd, J = 13.7,
4.6 Hz, 1H, CHHPh), 3.03 (dd, J = 13.7, 5.1 Hz, 1H, CHHPh), 2.90–
2.73 (m, 1H, CH), 2.60* (dd, J = 13.7, 3.8 Hz, 1H, CHHPh), 2.58 (dd,
J = 13.7, 3.4 Hz, 1H, CHHPh), 2.55–2.42* (m, 1H, CH), 2.13–2.00*
(br.s, 1H, OH), 1.99–1.75 (m, 5H), 1.75–1.66* (m, 2H, CH2), 1.66–
1.56* (m, 1H, CHH), 1.46–1.35 (m, 1H, CHH), 1.33* (d, J = 2.4 Hz, 3H,
CH3), 1.32 (d, J = 2.4 Hz, 3H, CH3). 13C NMR (125 MHz, CDCl3, trans-
`
(a) G. Fourriere, J. Lalot, N. Van Hijfte, J.-C. Quirion, E. Leclerc, Tetrahedron Lett. 50
(2009) 7048–7050;
(b) G. Fourrie`re, N. Van Hijfte, J. Lalot, G. Dutech, B. Fragnet, G. Coadou, J.-C.
Quirion, E. Leclerc, Tetrahedron 66 (2010) 3963–3972.
[12] (a) A.L.J. Beckwith, J. Zimmermann, J. Org. Chem. 56 (1991) 5791–5796;
(b) A.L.J. Beckwith, C.H. Schiesser, Tetrahedron 41 (1985) 3925–3941;
(c) D.C. Spellmeyer, K.N. Houk, J. Org. Chem. 52 (1987) 959–974.
[13] P.A. Bartlett, D.J. Tanzella, J.F. Barstow, J. Org. Chem. 47 (1982) 3941–3945.
isomer marked*):
d 139.8* (C), 139.6 (C), 128.7 (dd, J = 260.6,
252.8 Hz, CF2), 128.4* (t, J = 257.1 Hz, CF2), 128.8* (2CH), 128.7