Synthesis of α-trifluoromethyl-β-lactams and esters of β-amino acids via 1,3-dipolar cycloaddition of nitrones to fluoroalkenes

Article abstract of DOI:10.1021/jo800721w

(Chemical Equation Presented) Nitrones derived from aromatic or aliphatic aldehydes or ketones react with hexafluoropropene (HFP) or 2H-pentafluoropropene (PFP) to give the respective fluorinated isoxazolidine derivatives in good yields with complete regi

Full text of DOI:10.1021/jo800721w

Synthesis of r-Trifluoromethyl-ꢀ-lactams and Esters of ꢀ-Amino
Acids via 1,3-Dipolar Cycloaddition of Nitrones to Fluoroalkenes†
Jakub Jakowiecki, Rafał Loska, and Mieczysław Makosza*
Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224, Warsaw, Poland
icho-s@icho.edu.pl
ReceiVed April 1, 2008
Nitrones derived from aromatic or aliphatic aldehydes or ketones react with hexafluoropropene (HFP) or
2H-pentafluoropropene (PFP) to give the respective fluorinated isoxazolidine derivatives in good yields
with complete regioselectivity and moderate diastereoselectivity. Catalytic hydrogenolysis of the N-O
bond under ambient pressure and temperature leads to fluorides of ꢀ-amino acids that undergo cyclization
to R-trifluoromethylated ꢀ-lactams or, under acidic conditions, form esters of R-trifluoromethylated ꢀ-amino
acids.
Introduction
In this paper we wish to report a novel approach to
R-trifluoromethylated ꢀ-lactams and ꢀ-amino acids. In spite of
very wide application of pharmaceuticals containing a ꢀ-lactam
moiety7 only a few examples of the synthesis of their trifluo-
romethylated derivatives have been reported so far.6,8 Such
compounds can be obtained via [2 + 2] cycloaddition of
fluoroalkylketenes to imines and diimides.9,10 Formation of
R-trifluoromethylated ꢀ-lactams as side products of the diaste-
reoselective synthesis of R-trifluoromethyl-ꢀ-amino acids from
imines and benzyl 2-bromoperfluoropropionate was reported by
Ishihara and co-workers.11 [2 + 2] cycloaddition of perfluor-
oisobutene to benzanilide and hydrolysis of the CF2-N ring
fragment to amide group provided an R,R-bis(trifluoromethy-
lated) ꢀ-lactam.12 A multistep synthesis of R-methyl-R-triflu-
oromethyl ꢀ-lactam was described.13 4-Trifluoromethyl-2-
azetidin-2-one was used in the synthesis of derivatives of
4-trifluoromethylazetidine.6
Fluorinated analogues of biologically relevant compounds are
increasingly important as modern pharmaceutical and plant
protection agents.1,2 In particular, there is a growing interest in
new methods of selective introduction of a trifluoromethyl group
into the desired position in the molecule.1,3 While a similar size
of fluorine and hydrogen allows the biological activity to be
retained,4 the special properties of perfluoroalkyl groups, like
the high energy of C-F bonds, low polarizability, and high
lipophilicity,1,5 often provide an increased metabolic stability
and improved bioavailability to the resulting modified molecule.
High electronegativity of fluorine also has a significant influence
on the electronic character of the neighboring functional groups,
for example, it can strongly decrease basicity of amine func-
tions.6
* To whom correspondence should be addressed. Fax: +48 226326681.
† This paper is dedicated to Professor Dieter Seebach on the occasion of his
70th birthday.
(1) (a) Chambers, R. D. Fluorine in Organic Chemistry; Blackwell Publishing:
Oxford, UK, 2004. (b) Kirsch, P. Modern Fluoroorganic Chemistry; Wiley-
VCH: Weinheim, Germany, 2004. (c) Hiyama, T.; Kanie, K.; Kusumoto, T.;
Morizawa, Y.; Shimizu, M. Organofluorine Compounds: Chemistry and Ap-
plications; Springer-Verlag: Berlin, Germany, 2000.
(6) See, for example: Jiang, J.; Shah, H.; DeVita, R. J. Org. Lett. 2003, 5,
4101.
(7) Chemistry and Biology of ꢀ-Lactam Antibiotics; Morin, R. B., Gorman,
M., Eds.; Academic Press: New York, 1982.
(8) Danelon, G. O.; Mascaretti, O. A. J. Fluorine Chem. 1992, 56, 109.
(9) (a) England, D. C.; Krespan, C. G. J. Fluorine Chem. 1973/1974, 3, 91.
(b) England, D. C. J. Org. Chem. 1981, 46, 147.
(2) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. ReV.
2008, 37, 320.
(3) (a) Langlois, B. R.; Billard, T. Synthesis 2003, 185. (b) Lin, P.; Jiang, J.
Tetrahedron 2000, 56, 3635.
(10) (a) Bełz´ecki, C.; Krawczyk, Z. J. Chem. Soc., Chem. Commun. 1977,
302. (b) Krawczyk, Z.; Bełz´ecki, C. Pol. J. Chem. 1979, 53, 643.
(11) (a) Ishihara, T.; Ichihara, K.; Yamanaka, H. Tetrahedron 1996, 52, 255.
(b) Sekiguchi, T.; Sato, K.; Ishihara, T.; Konno, T.; Yamanaka, H. Chem. Lett.
2004, 33, 666.
(4) (a) Schlosser, M. In Enantiocontrolled Synthesis of Fluoro-Organic
Compounds: Stereochemical Challenges and Biomedical Targets; Soloshonok,
V. A. , Ed.; Wiley: Chichester, UK, 1999. (b) Schlosser, M.; Michel, D.; Guo,
Z.; Sih, C. J. Tetrahedron 1996, 52, 8257.
(12) Samoilova, Z. E.; Zeifman, J. V.; Kostianovskyi, R. G. IzV. Akad. Nauk
SSSR Ser. Khim. 1968, 11, 2621.
(5) Arnone, A.; Bernardi, R.; Blasco, F.; Cardillo, R.; Resnati, G.; Gerus,
I. I.; Kukhar, V. P. Tetrahedron 1998, 54, 2809.
(13) Haddad, M.; Wakselman, C. J. Fluorine Chem. 1995, 73, 57.
5436 J. Org. Chem. 2008, 73, 5436–5441
10.1021/jo800721w CCC: $40.75 2008 American Chemical Society
Published on Web 06/18/2008

Synthesis of R-Trifluoromethyl-ꢀ-lactams
TABLE 1. Cycloaddition of Nitrones to HFP and PFP
SCHEME 1. 1,3-Dipolar Cycloaddition of Azines N-Oxides
and Nitrones to HFP
alkene
nitrone (R1, R2, R3)
producta
HFP (X ) F) 1a (p-MeC6H4, H, Me)
1b (Ph, H, Me)
2a (85%; 2.8:1)
2b (60%; 3.5:1)
2c (87%; 2.1:1)
2d (63%; 4.0:1)
2e (73%; 1.2:1)b
2f (68%)
1c (p-MeOC6H4, H, Me)
1d (2-thienyl, H, Me)
1e (3-Py, H, Me)
1f (Ph, Ph, Me)
1g (Ph, H, -(CH2)3OH)
1h, 3,4-dihydro-6,7-
2g (63%; 1.4:1)
2h (75%; 1:3.7)
dimethoxyisoquinoline N-oxide
1i, 2-methoxycarbonyl-
pyrroline N-oxide
1j, 3,4,5,6-tetrahydropyridine
N-oxide
2i (31%; 1:4.5)
2j (86%; 1:3.4)c
In the course of our research focused on new methods of
selective introduction of fluoroalkyl groups into organic com-
pounds we investigated a reaction of aromatic N-oxides with
hexa- or 2H-pentafluoropropene (HFP or PFP). Isoxazolidines,
the initial products of 1,3-dipolar cycloaddition, are unstable
and undergo spontaneous ring opening leading to a wide range
of derivatives of 2-heteroarylperfluoropropionic acids.14 Herein
we report our results concerning an analogous reaction of 1,3-
dipolar cycloaddition of nitrones to fluorinated alkenes (Scheme
1).15 The obtained isoxazolidines are stable but can be further
transformed under reductive conditions into R-trifluoromethyl-
ꢀ-lactams and esters of ꢀ-amino acids.
The synthesis of ꢀ-lactams via ring contraction of adducts
of nitrones to alkenes and alkynes containing peculiar substit-
uents has several precedents. The Kinugasa reaction is a well-
established way of accessing azetidinone rings from nitrones
and copper acetylides.16 Syntheses of ꢀ-lactams from adducts
of nitrones and 2-nitroacrylonitrile17 or trimethylsilylacetylene
were described.18 Cordero and co-workers reported the forma-
tion of ꢀ-lactams by ethylene extrusion from spirocyclopropane
isoxazolidines, prepared from nitrones and methylenecyclopro-
panes.19 Another example, more closely related with our work,
is formation of a trifluoromethylated ꢀ-lactam by ring contrac-
tion of an isoxazolidine obtained from a nitrone and 1-nitro-
3,3,3-trifluoropropene.20
PFP (X ) H) 1a (p-MeC6H4, H, Me)
1c (p-MeOC6H4, H, Me)
1d (2-thienyl, H, Me)
3a (68%; 2.0:1)
3c (88%; 2.0:1)
3d (65%; >9:1)d
a Yields and diastereoisomers ratios given in parentheses. b Reaction
at rt for 7 days; c Reaction at rt. d 4 days.
are expected to be stable compounds. This reaction pathway
was only scarcely investigated and only a few examples of
adducts of HFP and perfluoroisobutene to nitrones prepared
under harsh conditions (autoclave) were described in a single
report by Knunyants and co-workers.22
Results and Discussion
In the preliminary experiments of dipolar cycloaddition
between nitrones and fluoroalkenes we found that this reaction
is rather slow at room temperature and under moderate pressure
(glass pressure tube). However, after a short search for optimal
reaction conditions for the reaction of C-p-methylphenyl-N-
methyl nitrone 1a with HFP we found that at elevated
temperature (80 °C) in MeCN the respective isoxazolidine 2a
is formed in good 85% yield.
The outcome of the reaction of HFP with compounds of the
general structure 1 containing a XsCdN+(Y)sO- moiety
depends on whether this fragment is or is not a part of an
aromatic ring. For aromatic azine N-oxides, rearomatization of
the heterocyclic ring provides the driving force for the N-O
bond scission in the transient 4,5,5-trifluoro-4-trifluoromethyl-
isoxazolidines 2 which usually cannot be isolated.21 Instead,
they are spontaneously transformed into acyl fluorides of
2-heteroarylperfluoropropionic acids with elimination of HF as
described by us before.14 In the case of nitrones the adducts
We then performed a series of reactions of HFP and PFP
with nitrones (Table 1), obtained from condensation of aliphatic
and aromatic aldehydes and ketones with N-substituted hy-
droxylamines or by oxidation of the respective secondary
amines. In the cases where the nitrone double bond was
conjugated with an aromatic ring or an ester group, the
conditions similar to that established for 1a allowed the expected
adducts 2 and 3 to be obtained in good to high yields. In the
case of aliphatic nitrone 1j, owing to its higher nucleophilicity
and its nature of a cyclic nitrone, which blocks the E config-
uration, the reaction proceeded satisfactorily already at room
temperature.
In all cases the fluorinated isoxazolidines were obtained with
complete regioselectivity. Dipolar cycloaddition of nitrones to
electron-deficient alkenes like HFP or PFP is probably a type I
cycloaddition and is controlled by the interaction of HOMO of
the dipole and LUMO of the alkene.23 The CF2 end of
(14) Loska, R.; Makosza, M. Chem. Eur. J. 2008, 14, 2577.
(15) For previous examples of dipolar cycloaddition of nitrones to fluoro-
alkenes, see: (a) Bigdeli, M. A.; Tipping, A. E. J. Fluorine Chem. 1992, 58,
101. (b) Liu, J.-T.; Lu, H.-J. Chin. J. Chem. 2002, 20, 1330.
(16) (a) Kinugasa, M.; Hashimoto, S. J. Chem. Soc., Chem. Commun. 1972,
466. (b) Marco-Contelles, J. Angew. Chem., Int. Ed. 2004, 43, 2198.
(17) Padwa, A.; Koehler, K.; Rodriguez, A. J. Am. Chem. Soc. 1981, 103,
4974.
(18) Ahn, C.; Kennington, J. W., Jr.; DeShong, P. J. Org. Chem. 1994, 59,
6282.
(19) Cordero, F. M.; Pisaneschi, F.; Goti, A.; Ollivier, J.; Salau¨n, J.; Brandi,
A. J. Am. Chem. Soc. 2000, 122, 8075.
(22) Knunyants, I. L.; Bykhovskaya, E. G.; Frosin, V. N.; Galakhov, I. V.;
Regulin, L. I. Zh. Vsesouz. Khim. Obshch. im. D. I. MendeleeVa 1972, 17, 356.
(23) (a) The Chemistry of Heterocyclic Compounds; Vol. 59, Synthetic
Applications of 1,3-Dipolar Cycloaddition Chemistry; Padwa, A., Pearson, W. H.,
Eds.; Wiley: New York, 2002. (b) Gothelf, K. V.; Jørgensen, K. A. Chem. ReV.
1998, 98, 863. (c) Sustmann, R. Pure Appl. Chem. 1974, 40, 569.
(20) Tanaka, K.; Mori, T.; Mitsuhashi, K. Chem. Lett. 1989, 1115.
(21) (a) Loska, R.; Makosza, M. MendeleeV Commun. 2006, 161. (b) Mailey,
E. A.; Ocone, L. R. J. Org. Chem. 1968, 33, 3343. (c) Banks, R. E.; Haszeldine,
R. N.; Robinson, J. M. J. Chem. Soc., Perkin Trans. 1976, 1, 1226.
J. Org. Chem. Vol. 73, No. 14, 2008 5437

Jakowiecki et al.
SCHEME 2. Reactions of Chiral Nitrones with HFPa
SCHEME 3. Reductive Cleavage of the N-O Bond in
4,5,5-Trifluoro-4-trifluoromethylisoxazolines
TABLE 2. Synthesis of r-Trifluoromethyl-ꢀ-lactams via Reductive
Cleavage of Isoxazolidines 2 and 3
a Reagents and conditions: (i) HFP, MeCN, rt, 25 h; (ii) MeCN, 80 °C,
72 h.
fluoroalkenes is particularly prone to undergo nucleophilic
adddition1 and it preferentially reacts with the negative end of
the dipole.
X
F
isoxazolidine
producta
2a
2c
2d
2e
2f
2g
2h
2i
4a (90%; 3.1:1)
4c (70%; 1.5:1)
4d (62%; 7.3:1)
4e (66%; 1.1:1)b
4f (95%)
The formation of 2 and 3 proceeded with only modest cis/
trans diastereoselectivity. In the case of 2 the two diastereoi-
somers could not be separated and their ratio was determined
by using 1H and 19F NMR spectra, whereas isomers of
compounds 3 were readily separable by chromatography.
However, assignment of the relative stereochemistry was
impossible on the basis of the 1H and 19F NMR spectra. In each
4g (55%; 2.0:1)b c
4h (77%; 1:3.2)
4i (50%; 1:10)
4j (51%; 1:7.3)
4m (64%; 16.7:7.2:6.0:1)
5a (85%)
,
2j
2m
3a
3c
3d
3
case the vicinal JHF coupling constant for the major product
H
5c (76%)
5d (97%)
was in the range 22-23 Hz, and for the minor one 28-30 Hz
(except for 2h and 2j). For the only example of isoxazolidine
described by Knunyants for which stereochemical assignment
was made, the coupling constant value was 26 Hz for the trans
isomer.22
a Yields and diastereoisomers ratios given in parentheses; the first
diasteroisomer is the one with the 3-X, 4-H trans configuration.
b Reaction performed for 20 h. c 11% of the ethyl ester of the respective
ꢀ-amino acid 6g (single diastereoisomer) was isolated.
In the reactions of chiral cyclic nitrones 1k,l with HFP only
two of the four possible diastereoisomers were obtained. The
3
3
values of JHH and JHF coupling constants of the bridgehead
protons and their NOE interactions with O-tBu groups indicate
that the configuration of the products 2k,l is the one shown in
Scheme 2 and is in agreement with the outcome of cycloaddition
of 1l to dimethyl maleate reported by Goti, Brandi, and co-
workers.24 Acyclic nitrone 1m gave a 15.7:4.2:2.8:1 mixture
of diastereoisomers, the first and third of which exhibited a
ducts would eliminate HF to provide acyl fluorides (Scheme
3). This reaction pathway seemed very attractive as such
fluorides could react with nucleophiles similarly to the ones
generated in the reactions of N-oxides with fluoroalkenes (see
Scheme 1).14 In particular, an intramolecular reaction with the
amine group would provide fluorinated ꢀ-lactams. A literature
precedent supporting this assumption was reported by Tada and
Toda, who obtained small amounts of 3-fluoro-3-trifluorometh-
yl-1,4-diphenylazetidin-2-one after heating C,N-diphenylnitrone
with HFP (without isolating the intermediate cycloadduct).26,15a
Two examples of a reaction similar to the one envisaged by us,
but with isoxazolidines derived from (PhS)2CdCF2 as the
dipolarophile, were also described.27
Reductive cleavage of isoxazolidines 2 and 3 proved to be a
very facile process. Under atmospheric pressure of hydrogen
and in the presence of Pd/C catalyst they underwent smooth
transformation into the R-trifluoromethyl ꢀ-lactam derivatives
4 and 5 (Table 2). Compounds 4 were obtained from diastere-
oisomeric mixtures of 2 as mixtures of cis/trans diastereoisomers
which could be separated only in the case of 4a. The isoxazo-
3
smaller JHF value.
We then investigated the possibility of N-O bond scission
in adducts 2 and 3. First we attempted to cleave the heterocyclic
ring in the process analogous to the one shown in Scheme 1
for aromatic N-oxides. Although in the case of 2 and 3 there is
no driving force like rearomatization, we expected that the
elimination reaction and formation of the CdN double bond
could be induced by a sufficiently strong base. Unfortunately,
upon the action of bases of varied strength (pyridine, DBU,
LDA, n-BuLi) and at various temperatures isoxazolidines 2
remained unchanged or underwent decomposition.
We thus turned to the possibility of reductive cleavage of
the N-O bond. It is a widely applied strategy for the synthesis
of γ-amino alcohols etc. from the primary adducts of nitrones
to alkenes.25 We expected that the primary reduction pro-
(25) Aschwanden, P.; Kværnø, L.; Geisser, R. W.; Kleinbeck, F.; Carreira,
E. M. Org. Lett. 2005, 7, 5741, and references cited therein.
(26) Tada, K.; Toda, F. Tetrahedron Lett. 1978, 6, 563.
(24) Goti, A.; Cicchi, S.; Cacciarini, M.; Cardona, F.; Fedi, V.; Brandi, A.
Eur. J. Org. Chem. 2000, 3633.
(27) Purrington, S. T.; Sheu, K. W. Tetrahedron Lett. 1992, 33, 3289.
5438 J. Org. Chem. Vol. 73, No. 14, 2008

Synthesis of R-Trifluoromethyl-ꢀ-lactams
SCHEME 4. Endo Transition State Leading to the Major
Diastereoisomers of 2 and 3
the starting isoxazolidine is consumed but the ethyl ester of the
type 6 is formed only in trace amounts. Instead we observed
formation of a white, very poorly soluble residue that we believe
contains free R-trifluoromethyl-ꢀ-amino acid formed by hy-
drolysis (instead of alcoholysis) of the intermediate acyl fluoride.
Formation of side product ester 6g from reduction of 2g (see
Table 2) may result from intramolecular hydrogen bonding of
the nitrogen atom by the free hydroxy group.
SCHEME 5. Preparation of Esters of r-Trifluoromethyl-ꢀ-
amino Acids by Reduction of Isoxazolidines under Acidic
Conditionsa
Conclusions
In conclusion, we established that 1,3-dipolar cycloaddition
of nitrones to fluorinated alkenes yields the respective fluorinated
isoxazolidine derivatives in preparatively useful yields and with
complete regioselectivity. Under very mild conditions these
products undergo a reductive N-O bond cleavage. This two-
step process provides a novel and general entry to ꢀ-lactams
and esters of ꢀ-amino acids containing a trifluoromethyl group.
a Reagents and conditions: (i) H2, Pd/C, H2SO4, EtOH, then Na2CO3
for 6a; H2, Pd/C, 2.5 M HCl/Et2O, MeOH, then Na2CO3 for 6c; H2, Pd/C,
37% HCl(aq), EtOH, then Na2CO3 for 6d.
Experimental Section
General Procedure for Reactions of Nitrones with Fluoro-
alkenes: Synthesis of Fluorinated Isoxazolidines 2 and 3.
Fluoroalkene (ca. 0.5 mL, 4 mmol) was condensed in a glass
pressure tube at -78 °C under argon atmosphere. MeCN (2.8 mL)
and nitrone (0.95 mmol) were introduced and the pressure tube
was closed with a Teflon valve. The contents of the tube were stirred
vigorously at 80 °C for 24 h (or in some cases at room temperature
and/or for a different period of timessee main text, Table 1 and
Scheme 2). After opening the tube the reaction mixture was poured
into water (10 mL) and the products were extracted with CH2Cl2
(3 × 5 mL). Combined organic layers were washed with water (5
× 10 mL), dried over anhydrous Na2SO4, and concentrated. The
products were purified by column chromatography on silica gel,
using 10:1 or 5:1 mixtures of hexanes/AcOEt or hexanes/Et2O as
eluent. All products were obtained as colorless or pale yellow oils.
2-Methyl-3-p-methylphenyl-4,5,5-trifluoro-4-trifluoromethyl-
isoxazolidine (2a). IR (film, νmax/cm-1) 2929, 2887, 1517, 1309,
1284, 1238, 1211, 1164, 1128, 1035, 1006, 787, 738. Major
lidines 3 were subjected to hydrogenation as pure major
diastereoisomers and thus lactams 5 were obtained as single
diastereoisomers as well.
Owing to the rigid nature of the four-membered ring of 4
the coupling constants 3JHF differ significantly for cis and trans
diastereoisomers. In the cis diastereoisomers (the ones having
the 3-F atom and the R1 substituent in relative cis configuration)
the dihedral angle between the C-F and C-H bonds is close
to 90°. This configuration should then be assigned to the
ꢀ-lactam isomers which were formed as the major ones for
3
4a,c-g,m and as minor ones for 4h,i,j; they all exhibit JHF
values around 3 Hz. For the other isomer in each case the
coupling constant was in the range 11-13 Hz, a value expected
for the cis arrangement of C-F and C-H bonds, which refers
to trans configuration of the molecule. Since no bonds at the
stereogenic centers are broken during the reduction step, the
same stereochemical assignment holds for the isoxazolidines
1
5
diasteroisomer: H NMR δ 2.37 (3H, s), 2.78 (3H, d, JHF ) 1.4
3
3
4
2. A similar analysis of the JHH values in the ꢀ-lactams 5
Hz), 4.12 (1H, dd, JHF ) 23.4 Hz, JHF ) 3.0 Hz), 7.18 - 7.23
(2H, m); 13C NMR δ 21.2, 43.8, 75.2 (d, JCF ) 19.0 Hz), 96.1
2
indicates that trans-isoxazolidines (with CF3 and R1 groups
trans) are major products of the cycloaddition of acyclic nitrones
to PFP. The cycloaddition of nitrones to fluoroalkenes is thus pre-
ferentially an endo additionsin all cases of isoxazolidines
derived from acyclic nitrones the CF3 group and the substituent
at the C terminus of the nitrone are in a trans relationship in
the predominating diastereoisomers of the resulting cycloadducts
(Scheme 4). The cyclic nitrones are locked in the opposite E
configuration and thus give opposite diastereoselectivity.
According to Scheme 3, protonation of the amino group prior
to its intramolecular acylation should prevent formation of the
ꢀ-lactam and provide a simple access to another group of
biologically interesting building blocks, that is ꢀ-amino acids
derivatives.28 Indeed, hydrogenation of 2a in dry EtOH acidified
with concentrated H2SO4 gave ethyl ester 6a in good yield
(Scheme 5). Similar reactions were observed for 2c and 2d in
MeOH or EtOH containing concentrated aqueous HCl or better
dry ∼1 M HCl/Et2O. The presence of water in the reaction
mixture has a strongly deteriorating effect on the yield of the
ester. When the hydrogenolysis reaction is performed, for
example, in a solvent containing diluted aqueous HCl and EtOH,
(dm, 1JCF ) 220.7 Hz, 2JCF ) 31.9 Hz), 120.3 (qdm, 1JCF ) 283.6
2
1
2
Hz, JCF ) 30.2 Hz), 122.8 (ddd, JCF ) 280.2, 260.4 Hz, JCF
)
3
4
23.3 Hz), 125.3 (d, JCF ) 2.6 Hz), 129.5, 129.7 (d, JCF ) 1.7
Hz), 140.4; 19F NMR δ -183.55 (1F, m), -85.13 (1F, dm, 2JFF
)
145.0 Hz, 4JFF ) 13.7 Hz), -82.12 (1F, d, 2JFF ) 145.0 Hz), -76.75
(3F, m). Minor diastereoisomer: 1H NMR δ 2.37 (3H, s), 2.84 (3H,
5
3
4
d, JHF ) 1.4 Hz), 4.21 (1H, dd, JHF ) 30.0 Hz, JHF ) 1.4 Hz),
7.18-7.23 (2H, m); 13C NMR δ 21.2, 44.0, 79.2 (d, JCF ) 26.7
2
Hz), 96.1 (dm, 1JCF ) 220.7, 2JCF ) 31.9 Hz), 120.0 (qdm, 1JCF
)
284.5 Hz, 2JCF ) ca. 30 Hz), 122.8 (ddd, JCF ) 279.3, 264.7 Hz,
1
2JCF ) 22.4 Hz), 126.1 (d, 3JCF ) 1.7 Hz), 128.5, 129.6, 140.0; 19
F
NMR δ -165.83 (1F, dm, 3JFH ) 29.0 Hz, 3JFF ) 7.6 H), -86.90
2
2
4
(1F, d, JFF ) 145.0 Hz), -81.64 (1F, d, JFF ) 145.0 Hz, JFF
)
4
3
16.8 Hz), -74.31 (3F, dm, JFF ) 16.9 Hz, JFF ) 7.6 Hz); MS
(EI 70 eV, m/z, %) 299 (M+, 96), 280 (10), 148 (66), 132 (100);
HRMS (EI) calcd for C12H11NOF6 (M+) 299.0745, found 299.0738.
Anal. Calcd for C12H11NOF6: C, 48.17; H, 3.71; N, 4.68; F, 38.10.
Found: C, 47.98; H, 3.70; N, 4.77; F, 38.02.
2-Methyl-3,3-diphenyl-4,5,5-trifluoro-4-trifluoromethylisox-
azolidine (2f). IR (film, νmax/cm-1) 3064, 2949, 1449, 1309, 1275,
1220, 1151, 1114, 1050, 999, 870, 737, 701; 1H NMR δ 2.60 (3H,
5
4
d, JHF ) 0.9 Hz), 7.10-7.70 (10H, m); 13C NMR δ 41.2 (d, JCF
) 2.6 Hz), 80.8 (d, 2JCF ) 19.0 Hz), 101.4 (dtq, 1JCF ) 224.2 Hz,
2JCF ) 31.0, 22.4 Hz), 120.4 (qd, JCF ) 285.4 Hz, JCF ) 31.0
1
2
(28) (a) Seebach, D.; Matthews, J. L. Chem. Commun. 1997, 2015. (b)
Seebach, D.; Beck, A. K.; Bierbaum, D. J. Chem. BiodiVersity 2004, 1, 1111.
1
2
Hz), 125.5 (td, JCF ) 273.3 Hz, JCF ) 21.6 Hz), 127.5, 127.9,
J. Org. Chem. Vol. 73, No. 14, 2008 5439

Jakowiecki et al.
128.7, 128.7, 130.7, 130.7, 135.0, 135.9; 19F NMR δ -166.22 (1F,
cis-2-Methyl-3-p-methylphenyl-5,5-difluoro-4-trifluorometh-
ylisoxazolidine (cis-3a). IR (film, νmax/cm-1) 3010, 2978, 2928,
2885, 1516, 1392, 1299, 1195, 1162, 1132, 1071, 1039, 851, 813,
756, 667, 504; 1H NMR δ 2.36 (3H, s), 2.79 (3H, s), 3.66 (1H, m),
2
m), -80.15 (1F, JFF ) 146.2 Hz), -76.20 (1F, m), -71.18 (3F,
dd, JFF ) 19.1 Hz, 5.1 Hz); MS (EI 70 eV, m/z, %) 361 (M+, 39),
284 (33), 210 (87), 194 (100), 165 (23), 127 (23), 118 (78); HRMS
(EI) calcd for C17H13NOF6 (M+) 361.0901, found 361.0908. Anal.
Calcd for C17H13NOF6: C, 56.51; H, 3.63; N, 3.88; F, 31.55. Found:
C, 56.51; H, 3.61; N, 3.85; F, 31.51.
3
4.30 (1H, d, JHH ) 8.2 Hz), 7.15-7.21 (2H, m), 7.25-7.30 (2H,
m); 13C NMR δ 21.2, 44.1, 56.8 (m, 2JCF ) 27.6 Hz), 72.7, 122.6
1
2
1
(qd, JCF ) 279.8 Hz, JCF ) 3.0 Hz), 125.7 (ddm, JCF ) 276.7,
Izoxazolidine 2i. IR (film, νmax/cm-1) 2964, 1756, 1440, 1318,
1254, 1215, 1169, 1122, 1076, 1044, 966, 916, 866, 745, 706. Major
diasteroisomer: 1H NMR (500 MHz, CDCl3) δ 1.94 (1H, m), 2.24
255.2 Hz), 128.2, 128.4, 129.4, 139.2; 19F NMR δ -76.29 (1F,
2
2
dm, JFF ) 145.4 Hz), -68.30 (1F, d, JFF ) 146.3 Hz), -63.06
4
3
(3F, dd, JFF ) 14.4 Hz, JFH ) 9.4 Hz); MS (EI 70 eV, m/z, %)
281 (M+, 68), 262 (4), 235 (11), 215 (19), 190 (23), 148 (100),
132 (36), 91 (21); HRMS (EI) calcd for C12H12NOF5 (M+)
281.0839, found 281.0843. Anal. Calcd for C12H12NOF5: C, 51.25;
H, 4.30; N, 4.98; F, 33.78. Found: C, 50.93; H, 4.15; N, 4.92; F,
33.52.
(1H, m, 3JHH ) 8.4, 4.4 Hz, 4JHF ) 1.1 Hz), 2.46 (1H, ddd, 2JHH
13.5 Hz, JHH ) 8.4, 4.3 Hz), 2.58 (1H, m), 3.45 (1H, m), 3.61
(1H, m), 3.85 (3H, s); 13C NMR (100 MHz, CDCl3) δ 24.1, 29.4
(q, 4JCF ) 3.0 Hz), 53.7, 56.2, 82.8 (d, 2JCF ) 19.4 Hz), 97.5 (dm,
)
3
1
2
1JCF ) 217.5 Hz), 119.8 (qd, JCF ) 284.7 Hz, JCF ) 30.6 Hz),
1
2
123.1 (ddd, JCF ) 280.0, 263.4 Hz, JCF ) 23.3 Hz), 165.6 (d,
3JCF ) 4.3 Hz); 19F NMR (376 MHz, CDCl3) δ -168.64 (1F, m,
Hydrogenolysis of Isoxazolidines 2 and 3: Preparation of
r-Trifluoromethyl-ꢀ-lactams 4 and 5. Under Ar atmosphere,
palladium on charcoal (10%, 400 mg) was added to a solution of
substrate (1.0 mmol) in EtOH (10 mL) in a round-bottomed flask.
Argon was then replaced by hydrogen and the reaction mixture
was stirred vigorously at room temperature at 1 atm of H2 for 1 h
(or longer, see Table 2 in the main text). The flask was again filled
with argon and the reaction mixture was filtered through a pad of
celite under reduced pressure (Caution: the dry catalyst on the celite
may start burning). After evaporation of EtOH the products were
purified by using column chromatography on silica gel with
hexanes/AcOEt or hexanes/Et2O 2:1 or 1:1 mixtures as eluents.
All products with the exception of 4f were colorless or pale yellow
oils.
3JFF ) 6.5 Hz), -82.86 (1F, d, JFF ) 145.8 Hz), -79.26 (1F,
2
dqd, 2JFF ) 145.8 Hz, 4JFF ) 14.3 Hz, 3JFF ) 3.4 Hz), -73.14 (3F,
4
3
ddd, JFF ) 13.6, 2.7 Hz, JFF ) 6.8 Hz). Minor diasteroisomer:
1H NMR (500 MHz, CDCl3) δ 1.94 (1H, m), 2.14 (1H, m, 3JHH
7.7 Hz), 2.39 (1H, m), 2.68 (1H, dddd, 2JHH ) 15.7 Hz, 3JHH ) 9.5
Hz, 6.1 Hz, 4JHF ) 2.3 Hz), 3.38 (1H, dd, 2JHH ) 13.4 Hz, 3JHH
7.7 Hz, 3.4 Hz), 3.61 (1H, m), 3.84 (3H, s); 13C NMR (100 MHz,
)
)
3
2
CDCl3) δ 23.5, 30.2 (d, JCF ) 12.5 Hz), 53.7, 57.5, 80.8 (d, JCF
1
) 21.5 Hz), 97.5 (dm, JCF ) 217.5 Hz), 113-128 (m), 167.0 (d,
3JCF ) 4.7 Hz); 19F NMR (376 MHz, CDCl3) δ -170.51 (1F, m),
2
3
4
-85.32 (1F, ddm, JFF ) 145.1 Hz, JFF ) 10.2 Hz, JFF ) 2.7
2
4
Hz), -79.80 (1F, dq, JFF ) 145.1 Hz, JFF ) 16.3 Hz), -75.17
(3F, ddd, 4JFF ) 16.3, 2.7 Hz, 3JFF ) 8.2 Hz); MS (EI 70 eV, m/z,
%) 293 (M+, <1), 234 (100); HRMS (EI) calcd for C9H9NO3F6
(M+) 293.0487, found 293.0499. Anal. Calcd for C9H9NO3F6: C,
36.87; H, 3.09; N, 4.78; F, 38.88. Found: C, 36.88; H, 3.12; N,
4.88; F, 38.01.
cis-1-Methyl-4-p-methylphenyl-3-fluoro-3-trifluoromethyl-2-
azetidinone (cis-4a). IR (CH2Cl2, νmax/cm-1) 2926, 1794, 1333,
1
1274, 1183, 1055, 993, 879, 812; H NMR δ 2.40 (3H, s), 2.92
(3H, d, 5JHF ) 1.6 Hz), 4.86 (1H, d, 3JHF ) 3.3 Hz), 7.23 (4H, AB,
J ) 8.1 Hz). 13C NMR δ 21.3, 27.0, 63.1 (d, 2JCF ) 24.1 Hz), 97.5
Izoxazolidine 2k. IR (film, νmax/cm-1) 2982, 1476, 1445, 1394,
1368, 1347, 1328, 1271, 1210, 1163, 1131, 1109, 1080, 1064, 1026,
1
2
(m), 120.8 (qd, JCF ) 281.9 Hz, JCF ) 31.0 Hz), 126.6, 127.9,
129.9, 140.2, 158.8 (dm, JCF ) 23.5 Hz); 19F NMR δ -187.24
2
1
913, 837, 781, 714. Major diasteroisomer: H NMR δ 1.20 (9H,
3
(1F, m), -79.33 (3F, d, JFF ) 10.5 Hz); MS (EI 70 eV, m/z, %)
s), 1.80-1.95 (1H, m), 2.20-2.38 (1H, m), 3.32-3.50 (1H, m),
261 (M+, 17), 246 (49), 204 (100), 177 (13), 135 (34); HRMS
(EI) calcd for C12H11NOF4 (M+) 261.0777, found 261.0781. Anal.
Calcd for C12H11NOF4: C, 55.18; H, 4.24; N, 5.36; F, 29.09. Found:
C, 55.08; H, 4.25; N, 5.46; F, 28.31.
3
3.55-3.70 (1H, m), 3.97 (1H, dm, JHF ) 21.3 Hz), 4.60 (1H, s);
13C NMR δ 28.4, 34.4, 56.5, 71.1 (m), 75.0, 80.7 (d, JCF ) 19.8
2
Hz), ∼98 (dm, JCF ) 208.6 Hz), 115-127 (m); 19F NMR δ
1
-163.50 (1F, m), -87.40 (1F, dm, 2JFF ) 146.1 Hz), -80.87 (1F,
2
4
4
trans-1-Methyl-4-p-methylphenyl-3-fluoro-3-trifluoromethyl-
dq, JFF ) 146.1 Hz, JFF ) 15.0 Hz), -74.16 (3F, ddd, JFF
)
2-azetidinone (trans-4a). IR (KBr, νmax/cm-1) 2929, 1770, 1430,
3
1
14.4, 2.0 Hz, JFF ) 7.8 Hz). Minor diasteroisomer: H NMR δ
1
1331, 1192, 1062, 1003, 821; H NMR δ 2.38 (3H, s), 3.00 (3H,
1.20 (9H, s), 1.80-1.95 (1H, m), 2.20-2.38 (1H, m), 3.32-3.50
5
3
3
d, JHF ) 0.9 Hz), 4.93 (1H, d, JHF ) 12.6 Hz), 7.22 (4H, AB, J
(1H, m, NCH2), 3.55-3.70 (1H, m, NCH2), 4.11 (1H, dd, JHF
)
) 8.1 Hz); 13C NMR δ 21.2, 27.8, 66.6 (d, JCF ) 24.9 Hz), 97.5
2
16.1 Hz, JHH ) 2.1 Hz, CHCF), 4.55 (1H, m); 13C NMR δ 28.0,
3
1
2
1
34.4, 56.8, 71.1 (m), 75.1, 77.0 (d, 2JCF ) 37.1), ∼98 (dm, 1JCF
)
(dq, JCF ) 231.0 Hz, JCF ) 34.5 Hz), 119.9 (qd, JCF ) 281.9
Hz, 2JCF ) 31.0 Hz), 126.3, 127.4, 129.6, 139.8, 158.9 (dq, 2JCF
)
)
210.0 Hz), 115-127 (m); 19F NMR δ -177.20 (1F, m), -93.00
(1F, ddm, 2JFF ) 146.7 Hz, 3JFF ) 11.1 Hz), -82.45 (1F, dq, 2JFF
23.3 Hz, JCF ) 1.7 Hz); 19F NMR δ -174.12 (1F, dq, JFH
3
3
3
3
4
4
12.6 Hz, JFF ) 9.8 Hz), -74.95 (3F, d, JFF ) 9.8 Hz); MS (EI
70 eV, m/z, %) 261 (M+, 31), 246 (68), 204 (100), 177 (18), 135
(42); HRMS (EI) calcd for C12H11NOF4 (M+) 261.0777, found
261.0770. Anal. Calcd for C12H11NOF4: C, 55.18; H, 4.24; N, 5.36;
F, 29.09. Found: C, 55.12; H, 4.20; N, 5.24; F, 29.06.
) 146.7 Hz, JFF ) 14.4 Hz), -78.33 (3F, ddd, JFF ) 15.0, 2.6
Hz, 3JFF ) 8.5 Hz); MS (EI 70 eV, m/z, %) 292 (2), 234 (10), 185
(10), 57 (100). Anal. Calcd for C11H15NO2F6: C, 43.00; H, 4.92;
N, 4.56; F, 37.10. Found: C, 42.83; H, 4.97; N, 4.35; F, 37.15.
trans-2-Methyl-3-p-methylphenyl-5,5-difluoro-4-trifluoro-
methylisoxazolidine (trans-3a). IR (film, νmax/cm-1) 3008, 2977,
2928, 2884, 1516, 1391, 1301, 1247, 1218, 1149, 1133, 1086, 1052,
1-Methyl-3-fluoro-3-trifluoromethyl-4,4-diphenyl-2-azetidi-
none (4f). Colorless needles, mp 79-80 °C. IR (KBr, νmax/cm-1
)
1
5
3063, 2938, 1781, 1451, 1312, 1201, 1172, 1064, 729, 704, 696;
840, 811, 709, 509; H NMR δ 2.37 (3H, s), 2.71 (3H, d, JHF
)
5
1H NMR δ 3.05 (3H, d, JHF ) 1.0 Hz), 7.28-7.33 (2H, m),
3
3
1.1 Hz), 3.63 (1H, m, JHH ) 10.1 Hz, JHF ) 7.7 Hz), 4.01 (1H,
7.33-7.37 (2H, m), 7.40-7.46 (6H, m); 13C NMR δ 27.9, 75.1 (d,
d, JHH ) 10.6 Hz), 7.19-7.24 (2H, m), 7.26-7.30 (2H, m); 13C
3
1
2
2JCF ) 20.7 Hz), 101.2 (dq, JCF ) 240.5 Hz, JCF ) 32.8 Hz),
120.3 (qd, 1JCF ) 282.8 Hz, 2JCF ) 31.9 Hz), 128.3, 128.5, 129.0,
129.0, 129.1, 129.1, 133.2, 134.7, 160.3 (dq, 2JCF ) 22.4 Hz, 3JCF
1
NMR δ 21.2, 43.2, 59.9 (m), 73.6, 122.8 (qd, JCF ) 278.0 Hz,
2JCF ) 3.0 Hz), 125.1 (ddm, JCF ) 268.1 Hz, 259.1 Hz), 127.8,
1
129.9, 130.1, 139.8; 19F NMR δ -81.70 (1F, dm, JFF ) 145.2
2
) 2.6 Hz); 19F NMR δ -171.30 (1F, q, JFF ) 10.1 Hz), -73.30
3
Hz), -66.83 (3F, ddd, 4JFF ) 11.9, 3.3 Hz, 3JFH ) 7.7 Hz), -62.85
(3F, d, JFF ) 10.1 Hz); MS (EI 70 eV, m/z, %) 323 (M+, 100),
3
(1F, d, JFF ) 145.2 Hz); MS (EI 70 eV, m/z, %) 281 (M+, 48),
2
266 (9), 253 (25), 246 (82), 197 (58), 118 (89), 77 (26); HRMS
(EI) calcd for C17H13NOF4 (M+) 323.0933, found 323.0924. Anal.
Calcd for C17H13NOF4: C, 63.16; H, 4.09; N, 4.33; F, 23.51. Found:
C, 63.19; H, 4.07; N, 4.26; F, 23.56.
262(4), 235 (8), 215 (14), 190 (18), 148 (100), 132 (35), 91 (25);
HRMS (EI) calcd for C12H12NOF5 (M+) 281.0839, found 281.0851.
Anal. Calcd for C12H12NOF5: C, 51.25; H, 4.30; N, 4.98; F, 33.78.
Found: C, 51.01; H, 4.26; N, 5.00; F, 33.77.
5440 J. Org. Chem. Vol. 73, No. 14, 2008

Synthesis of R-Trifluoromethyl-ꢀ-lactams
1
ꢀ-Lactam 4i (Major Diastereoisomer). H NMR δ 2.13 (2H,
m), 2.20-2.31 (1H, m), 2.40-2.51 (1H, m), 3.14 (1H, m), 3.87
(3H, s), 3.87-3.93 (1H, m); 13C NMR δ 28.3 (d, 3JCF ) 12.1 Hz),
erythro-6a (Minor). IR (CH2Cl2, νmax/cm-1) 2940, 1794, 1751,
1
1516, 1449, 1297, 1259, 1185, 1160, 1100, 1052, 878, 662; H
3
NMR δ 1.37 (3H, t, JHH ) 7.2 Hz), 2.20 (3H, s), 2.36 (3H, s),
2
1
29.7, 46.4, 53.4, 71.2 (d, JCF ) 23.3 Hz), 97.6 (dq, JCF ) 244.8
Hz, 2JCF ) 36.2 Hz), 120.0 (dq, 1JCF ) 282.8 Hz, 2JCF ) 30.2 Hz),
161.7 (d,3JCF ) 19.8 Hz), 168.1; 19F NMR δ -172.94 (1F, qd,
3JFF ) 8.7 Hz, 4JFH ) 4.7 Hz), -75.20 (d,3JFF ) 8.7 Hz); MS (EI
70 eV, m/z, %) 255 (M+, <1), 227 (100), 212 (15), 196 (52), 168
(79), 148 (80); HRMS (ESI) calcd for C9H9NO3F4Na (M + Na+)
278.0411, found 278.0406. Anal. Calcd for C9H9NO3F4: C, 42.36;
H, 3.56; N, 5.49; F, 29.78. Found: C, 42.57; H, 3.60; N, 5.42; F,
29.63.
4.11 (d, 3JHF ) 29.3 Hz), 4.42 (2H, m), 7.19 (4H, m); 19F NMR δ
3
-189.45 (1F, m), -74.08 (3F, d, JFF ) 7.8 Hz); MS (EI 70 eV,
m/z, %) 246 (6), 204 (16), 134 (100); HRMS (ESI) calcd for
C14H17NO2F4Na (M + Na+) 330.1088, found 330.1103. Anal. Calcd
for C14H17NO2F4: C, 54.72; H, 5.58; N, 4.56; F, 24.73. Found: C,
54.86; H, 5.45; N, 4.72; F, 24.93.
Ester threo-6c. IR (film, νmax/cm-1) 3354, 2959, 2805, 1779,
1755, 1612, 1514, 1442, 1297, 1267, 1209, 1180, 1153, 1101, 1057,
1
1034, 851,784, 743; H NMR δ 2.25 (3H, s), 3.61 (3H, s), 3.80
3
3
(3H, s), 4.19 (1H, d, JHF ) 27.2 Hz), 6.87 (2H, dm, JHH ) 8.8
trans-1-Methyl-4-p-methylphenyl-3-trifluoromethyl-2-azetidi-
Hz), 7.19 (2H, m); 13C NMR δ 33.9, 53.2, 55.2, 64.2 (d, JCF
)
2
none (trans-5a). IR (CH2Cl2, νmax/cm-1) 2925, 1778, 1372, 1261,
18.1 Hz), 96.2 (dq, 1JCF ) 207.8 Hz, 2JCF ) 30.2 Hz), 114.0, 121.4
(qd, 1JCF ) 286.2 Hz, 2JCF ) 29.3 Hz), 126.8, 129.7, 159.8, 164.0
(d, 2JCF ) 25.9 Hz); 19F NMR δ -188.92 (1F, dq, 3JFH ) 27.1 Hz,
1
4
1200, 1170, 1121; H NMR δ 2.38 (3H, s), 2.82 (3H, d, JHH
)
3
3
0.8 Hz), 3.63 (1H, qm, JHH ) 9.0 Hz), 4.58 (d, JHH ) 2.4 Hz),
7.19 (2H, m), 7.25 (2H, m); 13C NMR δ 21.1, 27.3, 56.8 (q, JCF
3
3JFF ) 5.7 Hz), -72.81 (3F, d, JFF ) 5.7 Hz). Anal. Calcd for
3
2
1
) 3.0 Hz), 61.9 (q, JCF ) 29.7 Hz), 123.4 (q, JCF ) 277.2 Hz),
126.2, 130.1, 131.9, 139.5, 160.1 (q, JCF ) 4.8 Hz); 19F NMR δ
3
C13H15NO3F4: C, 50.49; H, 4.89; N, 4.53; F, 24.57. Found: C, 50.57;
H, 4.63; N, 4.52; F, 24.52.
-68.53 (d, JFH ) 9.2 Hz); MS (EI 70 eV, m/z, %) 255 (M+, 6),
3
Ester threo-6d (major). IR (CH2Cl2, νmax/cm-1) 2924, 1790,
228 (8), 186 (100), 132 (32), 117 (44), 105 (40); HRMS (EI) calcd
for C12H12NOF3 (M+) 243.0871, found 243.0877. Anal. Calcd for
C12H12NOF3: C, 59.26; H, 4.97; N, 5.76; F, 23.43. Found: C, 59.08;
H, 5.10; N, 5.56; F, 22.14.
1
3
1324, 1193, 1175, 1063, 880; H NMR δ 1.14 (3H, t, JHH ) 7.2
3
Hz), 2.34 (3H, s), 4.06-4.23 (2H, m), 4.57 (d, JHF ) 27.2 Hz),
6.98 (1H, dd, 3JHH ) 5.0 Hz, 3.5 Hz), 7.02 (1H, m), 7.32 (1H, dm,
3JHH ) 5.0 Hz); 13C NMR δ 13.7, 33.9, 60.5 (d, JCF ) 18.5 Hz),
2
Preparation of Ethyl and Methyl Esters of r-Fluoro-r-
trifluoromethyl-ꢀ-amino Acids (6a, 6c, 6d). Isoxazolidine (1
mmol) was dissolved in dry EtOH or MeOH (10 mL). Freshly dried
3 Å molecular sieves and concentrated H2SO4 (0.25 mL; 6a) or
concentrated HCl(aq) (0.25 mL; 6d) or 1 M HCl/Et2O (1 mL; 6c)
were added and then, under argon atmosphere, 10% Pd/C catalyst
(about 100 mg) was introduced. Argon was exchanged for hydrogen
and the reaction mixture was vigorously stirred for 1 h at room
temperature and ambient pressure of H2. Hydrogen was then
removed and aqueous Na2CO3 (6 mL of 1 M solution) was added.
After filtration through a pad of celite the mixture was diluted with
water and most of the alcohol was removed with a rotary evaporator.
The resulting residue was extracted with CHCl3 (3 × 10 mL), the
organic phase was dried (Na2SO4) and concentrated, and the two
diastereoisomers of the product were separatedby using column
chromatography (SiO2, hexanes/AcOEt 5:1).
63.0, 95.7 (m), 121.2 (qd, 1JCF ) 286.6 Hz, 2JCF ) 29.3 Hz), 126.4,
126.6, 127.9, 163.2 (d, 2JCF ) 23.6 Hz); 19F NMR δ -187.93 (1F,
m), -72.65 (3F, d, 3JFF ) 5.4 Hz). Anal. Calcd for C11H13NO2SF4:
C, 44.14; H, 4.38; N, 4.68; F, 25.39. Found: C, 44.22; H, 4.59; N,
4.24; F, 25.40.
Ester erythro-6d (minor). IR (CH2Cl2, νmax/cm-1) 3343, 2985,
1
1775, 1752, 1372, 1269, 1202, 1098, 1054, 780, 709; H NMR δ
1.37 (3H, t, 3JHH ) 7.2 Hz), 2.29 (3H, s), 4.35-4.47 (2H, m), 4.48
3
3
(d, JHF ) ∼29 Hz), 6.98 (1H, dd, JHH ) 5.0 Hz, 3.5 Hz), 7.14
(1H, m), 7.35 (1H, dm, 3JHH ) 5.1 Hz), 7.54 (1H, m); 19F NMR δ
3
-167.24 (1F, m), -73.84 (3F, d, JFF ) 8.8 Hz). Anal. Calcd for
C11H13NO2SF4: C, 44.14; H, 4.38; N, 4.68. Found: C, 43.97; H,
4.24; N, 4.38.
Acknowledgment. We thank Prof. Henryk Koroniak (Adam
Mickiewicz Uniwersity, Poznan) for the generous gift of
pentafluoropropene and Prof. Marek Chmielewski (Institute of
Organic Chemistry, Warsaw) for the samples of nitrones 1k
and 1l. This work was supported by the Polish Ministry of
Science and Higher Education (grant no. 3 T09 A 043 27).
threo-6a (Major). IR (film, νmax/cm-1) 2985, 2878, 2805, 1776,
1751, 1515, 1450, 1372, 1291, 1270, 1207, 1183, 1154, 1101, 853,
1
3
783, 665; H NMR δ 1.08 (3H, t, JHH ) 7.2 Hz), 2.26 (3H, s),
2.33 (3H, s), 4.06 (2H, m), 4.21 (1H, d, 3JHF ) 27.4 Hz), 7.12-7.21
(4H, m); 13C NMR δ 13.6, 21.1, 33.9, 62.8, 64.4 (d, JCF ) 18.1
2
1
2
1
Hz), 95.9 (dq, JCF ) 208.6 Hz, JCF ) 29.3 Hz), 121.5 (qd, JCF
2
4
Supporting Information Available: Characterization data
for 2b, 2c, 2d, 2e, 2g, 2h, 2j, 2l, 2m, 3c, 3d, 4c, 4d, 4e, 4g, 6g,
4h, 4j, 4m, 5c, and 5d and copies of the NMR spectra of all
new compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
) 286.6 Hz, JCF ) 29.8 Hz), 128.6 (d, JCF ) 2.8 Hz), 129.3,
131.7, 138.6, 163.4 (d, 2JCF ) 24.6 Hz); 19F NMR δ -188.79 (1F,
3
m), -72.78 (3F, JFF ) 5.5 Hz); MS (EI 70 eV, m/z, %) 204 (1),
134 (100); HRMS (ESI) calcd for C14H18NO2F4 (M + H+)
308.1268, found 308.1263. Anal. Calcd for C14H17NO2F4: C, 54.72;
H, 5.58; N, 4.56; F, 24.73. Found: C, 54.70; H, 5.56; N, 4.52; F,
24.85.
JO800721W
J. Org. Chem. Vol. 73, No. 14, 2008 5441