Application of PhSCF2CF2SiMe3 as a tandem anion and radical tetrafluoroethylene equivalent: Fluoride-catalyzed addition to N-substituted cyclic imides followed by radical cyclization

Article abstract of DOI:10.1055/s-0031-1290917

PhSCF₂CF₂SiMe₃ undergoes a fluoride-catalyzed nucleophilic addition to N-substituted cyclic amides affording adducts in moderate to good yields. Reductive cleavage of the phenylsulfanyl group of N-methylated adducts under radical conditions yields the corresponding tetrafluoroethyl-containing adducts in excellent yields. Under the same reduction conditions, N-allylated adducts undergo 6-exo radical cyclization to afford the corresponding tetrafluorinated 1-azabicyclic compounds in moderate to good yields and cis selectivities. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1290917

LETTER
▌1187
lAettper plication of PhSCF2CF2SiMe3 as a Tandem Anion and Radical Tetra-
fluoroethylene Equivalent: Fluoride-Catalyzed Addition to N-Substituted
Cyclic Imides Followed by Radical Cyclization
Fluoride-Catalyzed Addition to N-Substituted Cyclic Imides
Yana Chernykh, Stanislav Opekar, Blanka Klepetářová, Petr Beier*
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Flemingovo nám. 2, 166 10 Prague, Czech
Republic
Fax +420(220)183578; E-mail: beier@uochb.cas.cz
Received: 19.01.2012; Accepted after revision: 02.03.2012
less aggressive Deoxofluor the reaction is limited to sim-
Abstract: PhSCF2CF2SiMe3 undergoes a fluoride-catalyzed nu-
ple aromatic benzil derivatives.8
cleophilic addition to N-substituted cyclic amides affording adducts
in moderate to good yields. Reductive cleavage of the phenylsulfa-
nyl group of N-methylated adducts under radical conditions yields
the corresponding tetrafluoroethyl-containing adducts in excellent
yields. Under the same reduction conditions, N-allylated adducts
undergo 6-exo radical cyclization to afford the corresponding tetra-
fluorinated 1-azabicyclic compounds in moderate to good yields
and cis selectivities.
Recently, we have reported the development of tri-
methyl(1,1,2,2-tetrafluoro-2-phenylsulfanylethyl)silane
(PhSCF2CF2SiMe3) as a tandem anion and radical tetra-
–
fluoroethylene synthon (·CF2CF2 ) and used it to convert
aldehydes and ketones into tetrafluoroethyl-substituted al-
cohols and tetrafluoro-tetrahydropyrans.9 As an extension
of the scope of this methodology we now wish to report
our findings on application of PhSCF2CF2SiMe3 in the re-
action with cyclic imides to give either the corresponding
tetrafluoroethyl-containing adducts (after reductive phe-
nyl sulfanyl group removal) or the corresponding tetraflu-
orinated 1-azabicyclic compounds (after radical 6-exo
cyclization). These cyclizations should be relatively fast
judging from Dolbier’s observation of a remarkable rate-
enhancement effect in 5-exo, 6-exo, and 6-endo cycliza-
tions when using fluorinated radicals compared to their
hydrocarbon analogues.10 Both compound types have not
been previously reported. 1-Azabicyclic ring systems
having angular substituents adjacent to nitrogen are struc-
tural motifs found in a variety of alkaloid natural products
and biologically active agents.11
Key words: nucleophilic addition, radical reaction, fluorine, het-
erocycles, imides
Many advances in modern medicinal, synthetic, and ma-
terial chemistries are connected with compounds of the
most electronegative atom – fluorine. For example, in
drug design, incorporation of fluorine atom(s) or fluorine-
containing moieties into organic molecules modulates
their biological properties. As a result, selective introduc-
tion of fluorinated moieties (fluoroalkylation) into organ-
ic molecules has become an important and fast-growing
research field. While the introduction of perfluoroalkyl
(including trifluoromethyl),1 difluoromethyl, difluoro-
methylene,2 and –(CF2)n– groups,3 where n > 2 by nucleo-
philic, radical, or electrophilic alkylations is well
established, reports of the introduction of tetrafluoroethyl
(–CF2CF2H) and tetrafluoroethylene (–CF2CF2–) moieties
are relatively rare. This is due to unavailability or high
price of halotetrafluoroethanes for the generation of tetra-
fluoroethyl radical or carbanion, or facile β-halogen elim-
ination of organometallic species derived from 1,2-
dihalotetrafluoroethanes.4 However, radical chain reac-
tions of 1,2-dihalotetrafluoroethanes with alkenes or al-
kynes are known.5 This chemistry has been applied, for
example, by Linclau and co-workers6 in their enantiose-
lective synthesis of tetrafluorinated glucose and galactose
derivatives starting with radical addition of bromoiodotet-
rafluoroethane to an alkene. Other approaches towards
tetrafluoroethylene-containing compounds such as the re-
action of 1,2-dicarbonyls with SF4/HF use highly toxic re-
agents and high-pressure reaction conditions,7 while with
PhSCF2CF2SiMe3 was prepared in excellent yield accord-
ing to literature procedure by a two-step reaction starting
from thiophenol and 1,2-dibromotetrafluoroethane.12 Nu-
cleophilic additions of twofold excess of this silane to
N-methyl- or N-allyl-substituted succinimides or
phthalimides (1a–d) proceeded smoothly in the presence
of catalytic tetrabutylammonium triphenyldifluorosilicate
(TBAT) in THF at ambient temperature giving the ad-
ducts as TMS ethers, which after silyl-group removal us-
ing excess of aqueous hydrofluoric acid gave compounds
2 in moderate to good yields (Scheme 1).13 Cyclic imides
were found to be less reactive than aldehydes presumably
due to their lower electrophilicity and higher steric hin-
drance. Using 10 mol% of TBAT or TMAF initiator was
found to be satisfactory, while with TBAF no desired ad-
duct was formed and the silyl reagent transferred to
PhSCF2CF2H. Reducing the amount of TBAT to 1 mol%,
which is the amount of initiator sufficient for reactions
with aldehydes, did not provide good conversions of cy-
clic imides. The hydrolysis of TMS ether adduct to com-
pounds 2 with HCl works only in the case of 2d, for other
examples HF with slight heating had to be used.
SYNLETT 2012, 23, 1187–1190
Advanced online publication: 17.04.2012
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DOI: 10.1055/s-0031-1290917; Art ID: ST-2012-B0045-L
© Georg Thieme Verlag Stuttgart · New York

1188
Y. Chernykh et al.
LETTER
CF2CF2SPh
Me
O
HO
O
HO
CF2CF2SPh
CF2CF2SPh
N R
or
CF2CF2SPh Et3SiH (5 equiv)
1. PhSCF2CF2SiMe3 (2 equiv)
TBAT (10 mol%), THF, r.t., 1 h
BF3⋅OEt2 (3 equiv)
N
R
or
N
N
R
N
R
or
N Me
CH2Cl2
R = Me
2. aq HF (excess), 35 °C, 1 h
O
O
O
O
O
O
2a, R = Me, 54%
2b, R = allyl, 58%
4c, 96%
(r.t., 1 h)
1c, R = Me
1d, R = allyl
4a, 92%
(reflux, 2.5 h)
2c, R = Me, 72%
2d, R = allyl, 69%
1a, R = Me
1b, R = allyl
n-Bu3SnH (1.75 equiv)
AIBN (15 mol%)
toluene
R = Me
n-Bu3SnH (1.75 equiv)
AIBN (15 mol%)
toluene, reflux, 4 h
R = allyl
reflux, overnight
F
F
F
F
F
F
F
F
CF2CF2H
Me
CF2CF2H
Me
HO
HO
HO
CF2CF2H
Me
HO
CF2CF2H
Et3SiH (5 equiv),
BF3⋅OEt2 (3 equiv)
N
or
N
N
or
N Me
N
N
or
CH2Cl2, reflux
O
O
O
O
O
O
5a, 90%
(2.5 h)
5c, 93%
(1 h)
3a, 94%
3c, 92%
3b, 78%
cis/trans 76:24
3d, 55%
cis/trans 90:10
Scheme 1 Fluoride-initiated nucleophilic tetrafluoro(phenylsulfanyl)ethylenation of cyclic imides 1, radical-mediated cleavage of the phenyl-
sulfanyl group or cyclization, and hydroxy reduction
Reductive cleavage of the phenylsulfanyl group in ad- The stereochemistry assumed by compound 3b can be ra-
ducts 2 was investigated. In adducts 2a and 2c (R = Me) tionalized as shown in Scheme 2, where radical-mediated
the PhS group was readily substituted with hydrogen by cyclization proceeds through a 6-exo-trig cyclization
using an excess amount of n-Bu3SnH and a catalytic mode. The forming fused bicyclic structure adopts a con-
amount of AIBN [2,2′-azobis(2-methylpropionitrile)] in formation with pseudoaxial hydroxy group. Transition
refluxing toluene, giving the corresponding tetrafluoro- state A, which leads to cis-3b, should be energetically
ethyl-containing hydroxy lactams 3a and 3c, respectively, more favorable than transition state B because it does not
in excellent yields.14 For adducts 2b and 2d (R = allyl) involve unfavorable 1,3-diaxial interactions between the
similar free-radical conditions gave products of 6-exo cy- fluorine atom and the methyl group. Conceptually, similar
clization 3b and 3d, respectively, in good yields.15 Forma- models were used to explain the stereochemistry of 5-exo
tion of the product of phenylsulfanyl group reduction was and 6-exo cyclization to gem-difluoromethylenated 1-aza-
minimized to less than 10% conversion by slow addition bicyclic compounds in an analogous reaction sequence
of n-Bu3SnH and AIBN. The major compound 3b was starting from cyclic imides and PhSCF2SiMe3.17
formed as a mixture of cis and trans isomers in an 76:24
‡
ratio (determined by GC–MS analysis of the crude reac-
F
F
OH
OH
F
F
tion mixture). A single cis-3b was obtained by crystalliza-
tion from methanol, and its relative stereochemistry was
determined by X-ray crystallography (Figure 1).16 The
phthalimide derived cyclized product 3d was also formed
as a mixture of cis and trans isomers in a ratio of 90:10.
The major isomer of 3d was assigned as cis by compari-
son of 1H NMR and 19F NMR data with cis-3b.
F
F
N
N
F
F
HO
O
O
CF2CF2SPh
n-Bu3SnH
cis-3b (major)
A (favored)
AIBN (cat.)
N
toluene
reflux
‡
F
F
OH
OH
F
F
O
F
F
N
N
F
F
O
O
B
trans-3b
Scheme 2 Proposed transition states for 6-exo radical cyclization of
2b to 3b
We expected that the presence of hydroxy group in ad-
ducts 2 and 3 will provide convenient access to an imini-
um intermediated, which can be reacted with various
nucleophiles. However, the compounds 2a or 2c could not
be efficiently allylated with allyltrimethylsilane (Scheme
3), and the cyclized compounds 3b and 3d did not under-
go reduction with Et3SiH in the presence of BF3·OEt2
(Scheme 4). This lack of reactivity is probably due to the
Figure 1 X-ray crystal structure of the major isomer of 3b crystal-
lizing in centrosymmetric space group. Hydrogen atoms are omitted
for clarity, and thermal ellipsoids are set as 50% probability.
Synlett 2012, 23, 1187–1190
© Georg Thieme Verlag Stuttgart · New York

LETTER
Fluoride-Catalyzed Addition to N-Substituted Cyclic Imides
1189
757. (b) Prakash, G. K. S.; Mandal, M. J. Fluorine Chem.
2001, 112, 123. Radical perfluoroalkylation: (c) Dolbier,
W. R. Chem. Rev. 1996, 96, 1557. (d) Nagib, D. A.; Scott,
M. E.; MacMillan, D. W. C. J. Am. Chem. Soc. 2009, 131,
10875. (e) Nagib, D. A.; MacMillan, D. W. C. Nature
(London) 2011, 480, 224. Electrophilic perfluoroalkylation:
(f) Umemoto, T. Chem. Rev. 1996, 96, 1757. (g) Kieltsch, I.;
Eisenberger, P.; Stanek, K.; Togni, A. Chimia 2008, 62, 260.
Transition-metal-catalyzed trifluoromethylation: (h) Cho,
E. J.; Senecal, T. D.; Kinzel, T.; Zhang, Y.; Watson, D. A.;
Buchwald, S. L. Science 2010, 328, 1679. (i) Furuya, T.;
Kamlet, A. S.; Ritter, T. Nature (London) 2011, 473, 470.
(j) Tomashenko, O. A.; Grushin, V. V. Chem. Rev. 2011,
111, 4475.
presence of the electron-withdrawing tetrafluoroethyl
group, which destabilize the iminium intermediates.
SiMe3 (5 equiv)
HO
CF2CF2SPh
Me
CF2CF2SPh
Me
BF3⋅OEt2 (1.5 equiv)
N
N
CH2Cl2 or MeCN
–78 °C to reflux
O
O
2a or 2c
traces
Scheme 3 Attempted allylation of 2a and 2c
F
F
F
F
(2) Hu, J.; Zhang, W.; Wang, F. Chem. Commun. 2009, 7465.
(3) (a) Metzger, J. O.; Mahler, R.; Schmidt, A. Liebigs Ann.
1996, 693. (b) Huang, X.-T.; Chen, Q.-Y. J. Org. Chem.
2001, 66, 4651.
(4) (a) Locke, E. G.; Brode, W. R.; Henne, A. L. J. Am. Chem.
Soc. 1934, 56, 1726. (b) Chen, Q.-Y.; Qiu, Z.-M. J. Fluorine
Chem. 1987, 35, 343. (c) Haszeldine, R. N. J. Chem. Soc.
1952, 4423.
F
F
F
F
HO
Et3SiH (5 equiv)
BF3⋅OEt2 (2 equiv)
N
N
CH2Cl2, reflux
O
O
3b or 3d
traces
(5) (a) Hu, C.-M.; Qiu, Y.-L. J. Fluorine Chem. 1991, 55, 109.
(b) Hu, C.-M.; Qiu, Y.-L.; Qing, F.-L. J. Fluorine Chem.
1991, 51, 295. (c) Hu, C.-M.; Qiu, Y.-L. J. Chem. Soc.,
Perkin Trans. 1 1992, 1569. (d) Hu, C.-M.; Qiu, Y.-L.
J. Chem. Soc., Perkin Trans. 1 1993, 331. (e) Long, Z.-Y.;
Chen, Q.-Y. J. Org. Chem. 1999, 64, 4775.
(6) (a) Timofte, R. S.; Linclau, B. Org. Lett. 2008, 10, 3673.
(b) Boydell, A. J.; Vinader, V.; Linclau, B. Angew. Chem.
Int. Ed. 2004, 43, 5677.
(7) (a) Christy, M. E.; Colton, C. D.; Mackay, M.; Staas, W. H.;
Wong, J. B.; Engelhardt, E. L. J. Med. Chem. 1977, 20, 421.
(b) Kirsch, P.; Bremer, M.; Huber, F.; Lannert, H.; Ruhl, A.;
Lieb, M.; Wallmichrath, T. J. Am. Chem. Soc. 2001, 123,
5414.
(8) Chang, Y.; Tewari, A.; Adi, A.; Bae, C. Tetrahedron 2008,
64, 9837.
(9) Chernykh, Y.; Hlat-Glembová, K.; Klepetářová, B.; Beier,
P. Eur. J. Org. Chem. 2011, 4528.
(10) (a) Dolbier, W. R.; Rong, X. X.; Bartgerger, M. D.;
Koroniak, H.; Smart, B. E.; Yang, Z.-Y. J. Chem. Soc.,
Perkin Trans. 2 1998, 219. (b) Li, A.; Shtarev, A. B.; Smart,
B. E.; Yang, Z.-Y.; Lusztyk, J.; Ingold, K. U.; Bravo, A.;
Dolbier, W. R. J. Org. Chem. 1999, 64, 5993.
(11) Chen, C.; Kozikowski, A. P.; Wood, P. L.; Reynolds, I. J.;
Ball, R. G.; Pang, Y. P. J. Med. Chem. 1992, 35, 1634.
(12) Toulgoat, F.; Langlois, B. R.; Médebielle, M.; Sanchez,
J.-Y. J. Org. Chem. 2007, 72, 9046.
Scheme 4 Attempted reduction of 3b and 3d
In contrast, reduction of adducts 2a,c and 3a,c with
Et3SiH in the presence of BF3·OEt2 to the corresponding
N-methyl pyrrolidinones and isoindolinones 4 and 5 pro-
ceeded in excellent yields (Scheme 1).18
In summary, PhSCF2CF2SiMe3 was successfully used as
a tandem anion and radical tetrafluoroethylene equivalent
for introduction of –CF2CF2H and –CF2CF2– moieties to
cyclic N-methyl- and N-allyl-substituted succinimides
and phthalimides. Fluoride-mediated nucleophilic addi-
tion of the reagent to cyclic imides provided (after hydro-
lysis of the intermediate TMS ether) N-substituted 5-
hydroxy-5-[1,1,2,2-tetrafluoro-2-(phenylthio)ethyl]pyrro-
lidin-2-ones and 3-hydroxy-3-[1,1,2,2-tetrafluoro-2-
(phenylthio)ethyl]isoindolin-1-ones 2 in moderate to
good yields. Under free-radical conditions, compounds 2
underwent either substitution of the phenylsulfanyl group
for hydrogen to 3a and 3c in high yields or 6-exo radical
cyclization to the corresponding tetrafluorinated 1-azabi-
cyclic compounds 3b and 3d in moderate to good yields
and cis selectivities. Substitution of the hydroxy group for
hydrogen in adducts 2a,c, and 3a,c with triethylsilane
gave the corresponding N-methyl pyrrolidinones and
isoindolinones 4 and 5 in high yields.
(13) (a) 5-Hydroxy-1-methyl-5-[1,1,2,2-tetrafluoro-2-
(phenylthio)ethyl]pyrrolidin-2-one (2a′)
A solution of TBAT (108 mg, 10 mol%) in dry THF (2 mL)
was added dropwise to a solution of PhSCF2CF2SiMe3 (1.13
g, 4 mmol) and 1a (226 mg, 2 mmol) in dry THF (10 mL).
The mixture was stirred at r.t. under argon for 1 h, followed
by the addition of aq HF (4 mL, 1 M), and stirred at 35 °C
for another hour. The reaction product was extracted in Et2O
(3 × 25 mL), the combined organic phase was washed with
brine (15 mL), dried (MgSO4), and concentrated under
reduced pressure. The resulting residue was purified by flash
column chromatography (SiO2, PE–EtOAc) to give the
desired product 2a (349 mg, 54% yield); white solid; mp
116–118 °C; Rf = 0.26 (PE–EtOAc, 50:50). 1H NMR (400
MHz, CDCl3): δ = 2.10–2.18 (m, 1 H), 2.39–2.45 (m, 2 H),
2.67–2.74 (m, 1 H), 2.87 (s, 3 H), 5.34 (br s, 1 H), 7.38–7.43
(m, 2 H), 7.46–7.50 (m, 1 H), 7.62–7.65 (m, 2 H). 13C NMR
(100 MHz, CDCl3): δ = 26.3, 28.8, 29.5, 90.7–91.2 (m),
Acknowledgment
Financial support from the Academy of Sciences of the Czech Re-
public (Research Plan AVZ40550506) and the Grant Agency of the
Czech Republic (207/11/0421) is gratefully acknowledged.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.onmorinftIangoimnuSpinorttfoIangiStupor
References
(1) Key references for nucleophilic perfluoroalkylation:
(a) Prakash, G. K. S.; Yudin, A. K. Chem. Rev. 1997, 97,
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1187–1190

1190
Y. Chernykh et al.
LETTER
116.0 (tt, 1JCF = 262.2 Hz, 2JCF = 30.9 Hz), 123.8, 124.8 (tt,
1JCF = 289.0 Hz, 2JCF = 35.1 Hz), 129.2, 130.6, 137.2, 175.7.
19F NMR (376 MHz, CDCl3): δ = –118.7 (dd, 1 F,
2JFF = 273.2 Hz, 3JFF = 8.0 Hz), –117.5 (dd, 1 F, 2JFF = 273.2
Hz, 3JFF = 3.4 Hz), –85.4 (dd, 1 F, 2JFF = 224.5 Hz, 3JFF = 8.0
Hz), –83.6 (d, 1 F, 2JFF = 224.5 Hz, 3JFF = 3.4 Hz). IR (film):
νmax = 3191, 1680, 1578, 1105, 753, 691 cm–1. MS (EI): m/z
(%) = 190 (5), 114 (100), 109 (11), 86 (9), 58 (13). HRMS
(ESI+): m/z calcd for C13H14F4NO2S [MH]+: 324.06759;
found: 324.06760.
3.61–3.69 (m, 1 H, trans), 3.77–3.88 (m, 1 H, cis), 7.08 (s, 1
H, trans), 7.11 (s, 1 H, cis). 13C NMR (100 MHz, CDCl3):
δ (cis) = 8.0 (d, J = 5.6 Hz), 25.9, 28.6, 35.3 (t, 2JCF = 21.4
Hz), 36.1 (d, J = 8.3 Hz), 88.1–88.7 (m), 171.8. 19F NMR
(376 MHz, CDCl3): δ = –140.9 (ddd, 1 F, 2JFF = 252.4 Hz,
3JFF = 16.1, 10.4 Hz, cis), –135.8 (ddd, 1 F, 2JFF = 257.8 Hz,
3JFF = 16.3, 12.1 Hz, trans), –124.7 (ddd, 1 F, 2JFF = 255.1
Hz, 3JFF = 16.1, 14.6 Hz, cis), –121.2 (ddd, 1 F, 2JFF = 255.1
Hz, 3JFF = 18.1, 10.4 Hz, cis), –121.1 (ddd, 1 F, 2JFF = 252.4
Hz, 3JFF = 18.1, 14.6 Hz, cis), –120.4 (ddd, 1 F, 2JFF = 257.4
Hz, 3JFF = 17.9, 12.1 Hz, trans), –117.2 (ddd, 1 F,
(14) (a) 5-Hydroxy-1-methyl-5-(1,1,2,2-tetrafluoroethyl)-
pyrrolidin-2-one (3a)
2JFF = 257.8 Hz, 3JFF = 17.9, 12.4 Hz, trans), –106.1 (ddd, 1
F, 2JFF = 257.4 Hz, 3JFF = 16.3, 12.4 Hz, trans). IR (film):
A solution of n-Bu3SnH (470 μL, 1.75 mmol) and AIBN (25
mg, 0.15 mmol) in dry toluene (3 mL) was added over 1 h
using a syringe pump to a refluxing solution of 2a (323 mg,
1 mmol) in dry toluene (5 mL). The resulting mixture was
refluxed under argon for 3 h, followed by concentration
under reduced pressure and purification by flash column
chromatography (SiO2, PE–EtOAc) to give product 3a (202
mg, 94% yield); colorless oil; Rf = 0.23 (PE–EtOAc, 60:40).
1H NMR (400 MHz, CDCl3): δ = 1.90–2.00 (m, 1 H), 2.26–
2.38 (m, 2 H), 2.41–2.50 (m, 1 H), 2.73 (d, 3 H, J = 2.5 Hz),
6.59 (tdd, 1 H, 2JHF = 51.5 Hz, 3JHF = 9.6, 3.5 Hz), 7.36 (br
d, 1 H, J = 2.8 Hz). 13C NMR (100 MHz, CDCl3): δ = 25.8,
28.4, 28.8, 88.7–90.2 (m), 173.8. 19F NMR (376 MHz,
CDCl3): δ = –138.3 (ddd, 1 F, 2JFF = 301.0 Hz, 3JFF = 10.7,
7.1 Hz), –134.3 (ddd, 1 F, 2JFF = 301.0 Hz, 3JFF = 12.5, 1.3
Hz), –130.6 (ddd, 1 F, 2JFF = 265.8 Hz, 3JFF = 12.5, 7.1 Hz),
–126.8 (ddd, 1 F, 2JFF = 265.8 Hz, 3JFF = 10.7, 1.3 Hz). IR
(film): νmax = 3204, 1687, 1110 cm–1. MS (EI): m/z (%) = 198
(6), 114 (100), 101 (8), 86 (20), 58 (45). HRMS (ESI+): m/z
calcd for C7H10F4NO2 [MH]+: 216.06422; found:
ν
max = 3252, 1699, 116 cm–1. MS (EI): m/z (%) = 241 (2)
[M]+, 221 (58), 201 (22), 173 (12), 112 (100), 84 (77), 55
(35). HRMS (EI+): m/z calcd for C9H11F4NO2 [M]+:
241.0726; found: 241.0731.
(16) CCDC-860878 (for cis-3b) contains the supplementary
crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge
Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
(17) Bootwicha, T.; Panichakul, D.; Kuhakarn, C.; Prabpai, S.;
Kongsaeree, P.; Tuchinda, P.; Reutrakul, V.; Pohmakotr, M.
J. Org. Chem. 2009, 74, 3798.
(18) (a) 1-Methyl-5-[1,1,2,2-tetrafluoro-2-(phenylthio)-
ethyl]pyrrolidin-2-one (4a)
To a solution of 2a (323 mg, 1 mmol) in CH2Cl2 (5 mL) was
added dropwise triethylsilane (0.8 mL, 5 mmol) and
BF3·OEt2 (377 μL, 3 mmol) under argon atmosphere. The
mixture was refluxed for 2.5 h, followed by the addition of
sat. NaHCO3 solution (10 mL), and extracted with CH2Cl2 (3
× 25 mL). The combined extracts were washed with brine
and dried over anhyd MgSO4. Filtration followed by
evaporation gave a crude product, which was purified by
flash column chromatography (SiO2, PE–EtOAc) to give the
desired product 4a (282 mg, 92% yield); colorless oil; Rf =
0.26 (PE–EtOAc, 80:20). 1H NMR (400 MHz, CDCl3): δ =
2.15–2.34 (m, 3 H), 2.44–2.59 (m, 1 H), 2.95 (d, 3 H, J = 2.0
Hz), 4.04–4.13 (m, 1 H), 7.37–7.43 (m, 2 H), 7.44–7.51 (m,
1 H), 7.56–7.68 (m, 2 H). 13C NMR (100 MHz, CDCl3): δ =
19.6–19.8 (m), 29.0, 30.9–31.0 (m), 60.8–61.4 (m), 129.3,
130.7, 137.2. 19F NMR (376 MHz, CDCl3): δ = –120.7 (dd,
1 F, 2JFF = 270.9 Hz, 3JFF = 20.1 Hz), –111.0 (d, 1 F,
2JFF = 270.9 Hz), –86.3 (s, 2 F). IR (film): νmax = 3063, 1707,
1577, 1108 cm–1. MS (EI): m/z (%) = 109 (6), 98 (100), 42
(5). HRMS (ESI+): m/z calcd for C13H13F4NNaOS [MNa]+:
330.05453; found: 330.05462.
216.06417.
(15) (a) 7,7,8,8-Tetrafluoro-8a-hydroxy-6-methylhexa-
hydroindolizin-3(2H)-one (3b)
A solution of n-Bu3SnH (470 μL, 1.75 mmol) and AIBN (25
mg, 0.15 mmol) in dry toluene (3 mL) was added over 3 h
using a syringe pump to a refluxing solution of 2b (349 mg,
1 mmol) in dry toluene (5 mL). The resulting mixture was
refluxed under argon overnight, followed by concentration
under reduced pressure and purification by flash column
chromatography (SiO2, PE–EtOAc) to give product 3b (188
mg, 78% yield); white solid; cis/trans = 76:24; mp (cis) 160–
162 °C; Rf = 0.42 (PE–EtOAc, 25:75). 1H NMR (400 MHz,
CDCl3): δ = 0.91 (dd, 3 H, 3JHH = 7.3 Hz, 4JHH = 3.8 Hz,
trans), 1.02 (d, 3 H, 3JHH = 6.7 Hz, cis), 1.88–1.97 (m, 2 H,
cis + trans), 2.10–2.25 (m, 2 H, cis + trans), 2.28–2.35 (m, 1
H, cis), 2.37–2.40 (m, 1 H, trans), 2.42–2.53 (m, 2 H, cis +
trans), 2.69–2.79 (m, 1 H, cis), 3.16–3.23 (m, 1 H, trans),
Synlett 2012, 23, 1187–1190
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