Umpolung reactivity of difluoroenol silyl ethers with amines and amino alcohols. Application to the synthesis of enantiopure α-difluoromethyl amines and amino acids

Article abstract of DOI:10.1021/jo702328v

(Chemical Equation Presented) Difluoroenol silyl ethers, produced in situ from acylsilanes and CF₃TMS, react as electrophiles with amines to give difluoroimines, via the corresponding hemiaminal adduct, as evidenced by ¹⁹F NMR spectr

Full text of DOI:10.1021/jo702328v

Umpolung Reactivity of Difluoroenol Silyl Ethers with Amines and
Amino Alcohols. Application to the Synthesis of Enantiopure
r-Difluoromethyl Amines and Amino Acids
Florent Huguenot,† Anne Billac,† Thierry Brigaud,‡ and Charles Portella*,†
Institut de Chimie Mole´culaire de Reims, CNRS - UniVersite´ de Reims Champagne-Ardenne (UMR 6229),
Faculte´ des Sciences, B.P. 1039, 51687 Reims Cedex 2, France, and Laboratoire “ Synthe`se Organique
Se´lectiVe et Chimie Organome´tallique ” (SOSCO), UMR CNRS 8123, UniVersite´ de Cergy-Pontoise,
5 Mail Gay-Lussac, NeuVille sur Oise, 95031 Cergy-Pontoise Cedex, France
charles.portella@uniV-reims.fr
ReceiVed October 28, 2007
Difluoroenol silyl ethers, produced in situ from acylsilanes and CF3TMS, react as electrophiles with
amines to give difluoroimines, via the corresponding hemiaminal adduct, as evidenced by 19F NMR
spectroscopy. Reaction with (R)-phenylglycinol led to 2-difluoromethyloxazolidines. After separation of
the diastereomers, reduction with LAH and Strecker-type synthesis gave enantiopure R-difluoromethy-
lamines and R-difluoromethyl-R-amino acids, respectively.
Introduction
applicable to the preparation of DFSE and higher perfluoroenoxy
silane analogues. Most of the methods proposed for the
preparation of DFSE start from fluorinated substrates.4 We have
proposed another approach with final introduction of fluorine
via reaction of fluoroorganometallic reagents on acylsilanes,
using either trifluoromethyl(trimethyl)silane or perfluoroorga-
nolithium for the preparation of DFSE5 or higher homologues,6
Enol silyl ethers are important intermediates in organic
synthesis. They are used as enolate equivalents, in reactions
involving either a nucleophilic activation or the electrophilic
activation of the counter reactant (Mukayiama type reactions).1
Thus, except for particular situations such as single electron
oxidation giving the corresponding radical cation,2 enol silyl
ethers are essentially nucleophilic intermediates.
Difluoroenol silyl ethers (DFSE) are also building blocks of
great interest for the synthesis of a variety of functionalized
difluoromethylene compounds. Owing to its small size and its
high electronegativity, the presence of fluorine atoms in organic
molecules induces strong modifications of their properties.3 This
effect operates both in the preparation methodologies and in
the properties of the final product. Polyfluorinated enol silyl
ethers offer a good illustration. The usual methods are not
(3) (a) Kirsch, P. Modern Fluorine Chemistry: Synthesis, ReactiVity,
Applications; Wiley-VCH Verlag GmbH and co. KGaA: Weinheim, 2004.
(b) Hiyama, T. Organofluorine Compounds: Chemistry and Applications;
Springer: New York, 2000. (c) Ojima, I.; McCarthy, J. R.; Welch, J. T.
Biomedical Frontiers of Fluorine Chemistry; ACS Publications: Washing-
ton, DC, 1996. (d) Banks, R. E.; Smart, B. E.; Tatlow, J. C. Organofluorine
Chemistry; Principles and Commercial Applications; Plenum Press: New
York, 1994. (e) Filler, R.; Kobayashi, Y.; Yagupolskii, L. N. Organofluorine
Compounds in Medicinal and Biochemical Applications; Elsevier: Am-
sterdam, 1993.
(4) (a) From chlorodifluoromethyl ketones: Yamana, M.; Ishihara, T.;
Ando, T. Tetrahedron Lett. 1983, 24, 507-510. (b) From trifluoroacetyl-
(triphenyl)silane: Jin, F.; Jiang, B.; Xu, Y. Tetrahedron Lett. 1992, 33,
1221-1224. (c) From trifluoromethyl ketones (via reduction with magne-
sium): Uneyama, K.; Mizutani, G.; Maeda, K.; Kato, T. J. Org. Chem.
1999, 64, 6717-6723. Amii, H.; Kobayashi, T.; Hatamoto, Y.; Uneyama,
K. Chem. Commun. 1999, 1323-1324. (d) From trifluoromethylketones
(via nucleophilic silylation): Fleming, I.; Roberts, R.S.; Smith, S.C. J. Chem.
Soc., Perkin Trans. 1 1998, 1215-1228.
† CNRS - Universite´ de Reims Champagne-Ardenne.
‡ Universite´ de Cergy-Pontoise.
(1) (a) Brownbridge, P. Synthesis 1983, 1-28. (b) Kobayashi, S.;
Manabe, K.; Ishitani, H.; Matsuo, J.-I. Sci. Synth. 2002, 4, 317-369.
(2) (a) Sperry, J. B.; Whitehead, C. R.; Ghiviriga, I.; Walczak, R. M.;
Wright, D. L. J. Org. Chem. 2004, 69, 3726-3734 and references therein.
(b) Bunte, J. O.; Heilmann, E. K.; Hein, B.; Mattay, J. Eur. J. Org. Chem.
2004, 3535-3550, and ref. therein.
(5) Brigaud, T.; Doussot, P.; Portella, C. Chem. Commun. 1994, 2117-
2118.
10.1021/jo702328v CCC: $40.75 © 2008 American Chemical Society
Published on Web 03/11/2008
2564
J. Org. Chem. 2008, 73, 2564-2569

Umpolung ReactiVity of Difluoroenol Silyl Ethers
SCHEME 1. SN′-Type Reaction of Perfluoroenoxysilanes
SCHEME 3. Reaction of DFSE 2a and 2b with Primary
Amines
SCHEME 2. Self-Condensation Reaction of Difluoroenol
Silyl Ethers
respectively. DFSE exhibit the classical nucleophilic reactivity
of non-fluorinated analogues. Acid hydrolysis,5 halogenation,7
and Lewis acid-promoted reactions with various electrophiles8
afforded a wide variety of applications in the synthesis of gem-
difluoromethylene compounds. We had mentionned the Mukay-
iama-type aldol reaction of higher homologues,6 but these enol
silyl ethers were essentially used as key intermediates in the
synthesis of polyfluorinated â-enaminoketones and hetero-
cycles,9 via an hemifluorinated enone.10 In these transformations,
perfluoroenol silyl ethers behave as powerful electrophilic
substrates, in an SN′-type displacement of the â-fluorine induced
by the attack of the silyloxy substituted carbon by the amine
(Scheme 1).
SCHEME 4. 19F NMR Monitoring of Addition of
Benzylamine on 2b
Results and Discussion
We reported in our initial paper the formation of a self-
condensation product of DFSE (Scheme 2).5 According to our
preparation methodology, DFSE is the result of a chain reaction
involving the domino sequence: nucleophilic trifluoromethy-
lation of an acylsilane-Brook rearrangement-fluoride elimina-
tion. Depending on the nucleophilicity of the fluoride initiator,
the DFSE is the final product of this chain process or its fluoride
activation leads to a difluoroenolate which adds to another
molecule of DFSE (Scheme 2). That was the very first
observation of the electrophilic behavior of nonoxidized DFSE.
Very recently, it was shown that, under single electron oxidative
conditions, the polarity of DFSE can also be reversed.11 We
report in this paper on our investigation on the umpolung
reactivity of unmodified DFSE with amines and amino alcohols
and its application to the synthesis of R-difluoromethyl amino
derivatives.
The reaction of DFSE 2a (generated in situ from acylsilane
1a (Scheme 3)) with amines depends on the nature of the amine.
Triethylamine led to the self-condensation product and thus acts
similarly to TBAF as a nucleophilic activator. The sole product
observed with secondary amines was the difluoromethylketone,
the formal result of the hydrolysis of 2a, even if a direct
decomposition of an intermediate aminal (vide infra) cannot be
excluded. Much more interestingly, primary amines react slowly
with 2a in a formal addition-elimination process to give the
corresponding difluoromethyl imines. Similar results were
observed from 2b and/or with other amines, giving the imines
3 and 4 (Scheme 3). These imines are of limited stability and
were difficult to isolate and characterize. Authentic samples were
prepared conventionally, in high yield, from the difluoromethyl
ketone obtained by direct hydrolysis of the intermediate DFSE.
To discriminate between an actual addition-elimination se-
quence and a possible in situ hydrolysis of the DFSE followed
by a classical amination of the resulting difluoromethyl ketone,
we have carefully monitored the reaction by 19F NMR spec-
trometry. When 2b, generated in situ from acetyl(trimethyl)-
silane 1b, is treated with benzylamine, we were unable to detect
any trace of difluoromethylketone, but the NMR monitoring
clearly shows the intermediate formation of the hemiaminal
adduct 5, and its slow conversion into the ketimine 3b (Scheme
4). Thus, DFSE acts definitely as an electrophilic species.
To diversify the difluoromethyl intermediates, especially
toward applications in asymmetric synthesis, we have extended
the reaction to chiral amino alcohols, in order to have access to
chiral difluoromethyl oxazolidines. Oxazolidines proved indeed
to be interesting building blocks in the trifluoromethyl series
(vide infra). The reaction of 2a with (R)-phenylglycinol gave
oxazolidine 6a with a high yield and a poor diastereoselectivity
(Scheme 5).
(6) Doussot, P.; Portella, C. J. Org. Chem. 1993, 58, 6675-6680.
(7) (a) Qiu, Z.-M.; Burton, D. J. J. Org. Chem. 1995, 60, 5570-5578.
(b) Prakash, G. K. S.; Hu, J.; M. Alauddin, M.; Conti, P. S.; Olah, G. A.
J. Fluorine Chem. 2003, 121, 239-243.
(8) (a) Reference 4a. (b) Jin, F.; Xu, Y.; Huang, W. J. Chem. Soc., Perkin
Trans. 1 1993, 795-799. (c) Saleur, D.; Brigaud, T.; Bouillon, J.-P.; Portella,
C. Synlett 1999, 432-434. (d) Lefebvre, O.; Brigaud, T.; Portella, C. J.
Org. Chem. 2001, 66, 1941-1946. (e) Kobayashi, S.; Tanaka, H.; Amii,
H.; Uneyama, K. Tetrahedron 2003, 59, 1547-1552. (f) Lefebvre, O.;
Brigaud, T.; Portella, C. Tetrahedron 1998, 54, 5939-5948. (g) Lefebvre
O.; Brigaud T.; Portella, C. Tetrahedron 1999, 55, 7233-7242. (h) Lefebvre
O.; Brigaud T.; Portella, C. J. Org. Chem. 2001, 66, 4348-4351. (i) Jin F.;
Xu Y.; Huang W. Chem. Commun. 1993, 814-816. (j) Berber, H.; Brigaud,
T.; Lefebvre, O.; Plantier-Royon, R.; Portella, C. Chem. Eur. J. 2001, 7,
903-909. (k) Jiang, B.; Zhang, X.; Shi, G. Tetrahedron Lett. 2002, 43,
6819-6821. (l) Jonet, S.; Cherouvrier, F.; Brigaud, T.; Portella, C. Eur. J.
Org. Chem. 2005, 4304-4312. (m) Whitten, J. P.; Barney, C. L.; Huber,
E. W.; Bey, P.; McCarthy, J. R. Tetrahedron Lett. 1989, 30, 3649-3652.
(9) (a) Bouillon, J.-P.; Didier, B.; Dondy, B.; Doussot, P.; Plantier-Royon,
R.; Portella, C. Eur. J. Org. Chem. 2001, 187-192. (b) Chanteau, F.;
Plantier-Royon, R.; Portella, C. Synlett 2004, 512-516. (c) Chanteau, F.;
Didier, B.; Dondy, B.; Doussot, P.; Plantier-Royon, R.; Portella, C. Eur. J.
Org. Chem. 2004, 1444-1454. (d) Plantier-Royon, R.; Portella, C. Targets
Heterocycl. Syst. 2006, 10, 114-131.
(11) Uneyama, K.; Tanaka, H.; Kobayashi, S.; Shioyama, M.; Amii, H.
Org. Lett. 2004, 6, 2733-2736.
(10) Dondy, B.; Portella, C. J. Org. Chem. 1993, 58, 6671-6674.
J. Org. Chem, Vol. 73, No. 7, 2008 2565

Huguenot et al.
SCHEME 5. Synthesis of 2-Difluoromethyl Oxazolidines
from 2a
reoselective organometallics addition and reduction of trifluo-
romethyl imines and 2-trifluoromethyl oxazolidines derived from
(R)-phenylglycinol.14 The iminum-type reactivity of the (R)-
phenylglycinol based oxazolidines and its application to the
synthesis of enantiopure trifluoromethylated amines, R- and
â-amino acids, â-amino ketones, and â- and γ-amino alcohols
was more recently reported.15 The difluoromethyl series was
approached recently, via organometallic arylation of oxazolidine-
derived chiral imines,16 or via diastereoselective reduction of
R-difluoromethylimine derived from (S)-R-phenylethylamine
followed by a regioselective hydrogenolysis.17
Our attempts to prepare optically active R-difluoroamines via
a base induced proton shift from the imine 4a failed. The strong
base (DBU) required for this reaction induced a fluoride
elimination.
SCHEME 6. NOE Data for Oxazolidine 6a
To assess the usefulness of this DFES methodology for the
synthesis of enantiopure R-difluoromethylamines, the difluo-
romethyl imino and oxazolidino intermediates described above
were submitted to LiAlH4 reduction. Poor to fair yields and/or
diastereoselectivity were observed from the difluoroimines 4.
In contrast, reduction of diastereomerically pure oxazolidines
(S,R)-6a and (R,R)-6a afforded the corresponding amino alcohols
(R,R)-10a and (S,R)-10a with a total stereoselectivity (Scheme
8). According to the previous observations of Mikami in the
trifluoromethyl series,14 we reasonably consider here too a
retention of the configuration of the functional carbon due to
the coordination of oxygen to the metal.
Oxidative cleavage of the intermediate amino alcohols (R,R)-
10a and (S,R)-10a led to the corresponding imines 11a, the acid
hydrolysis of which afforded the two enantiomers of 2,2-
difluoro-1-phenylethylamine (R)-12a and (S)-12a. The enan-
tiomeric relationship is confirmed by their opposite optical
rotation. The stereoselectivity of the reduction and the resulting
configuration of the final amine is corroborated by a recent
report on the synthesis of similar amines by a different
methodology.18
Racemic difluoroisopropylamine has been known for a long
time.19 The synthesis of its enantiopure hydrochloride (R)-12b
was achieved by palladium catalyzed hydrogenolysis of the bis-
(benzylic) intermediates (R,R)-13b derived from the LAH
reduction of (S,R)-9b (Scheme 9). This LAH reduction pro-
ceeded in two steps with a faster reduction of the benzoyl
moiety. The intermediate N-benzyloxazolidine 14 has been
isolated during the partial reduction of (R,R)-9b with shorter
reaction time. The enantiomer (S)-12bcould of course be
prepared similarly from the parent diastereomer (S,R)-13b
obtained in 72% yield from (R,R)-9b.
This transformation requires heating in toluene, a solvent not
adapted to the previous step. Thus, the DFSE 2a was prepared
in ether, which was removed under vacuum and replaced by
toluene. Addition of phenylglycinol and a catalytic amount of
pyridinium p-toluenesulfonate, and heating to reflux afforded
the product in high yield. The two diastereomers were easily
separated over silica gel, giving two diastereopure intermediates
(S,R)-6a and (R,R)-6a of high potential for further transforma-
tions (see below). The configuration of the diastereomers were
determined by NOE experiments (Scheme 6).
The similar treatment of 2b, prepared in situ from 1b, afforded
quantitatively the corresponding imine 7 as its O-silyl ether
(Scheme 7). It is worth noting that this imine formation is more
effective and faster than with simple amines. The fast shift of
the equilibrium toward the product is probably due to an irre-
versible silylation of the hydroxyl group by competitive trapping
of TMSOH or intramolecular TMS transfer. This process con-
stitutes an effective one-pot preparation of the imine 7 from
three commercially available starting compounds: acetyltrimeth-
ylsilane, trifluoromethyltrimethylsilane, and phenylglycinol. The
silylated iminoether 7 was easily converted to the corresponding
oxazolidine 6b by desilylation-cyclization (Scheme 7). The
oxazolidine 6b was obtained with a remarkable overal yield of
92% from acetyltrimethylsilane, as an 85/15 mixture of non-
separable diasteromers (S,R)-6b and (R,R)-6b, the configura-
tion of which has been determined by NOE experiments.
Benzoylation of 6b afforded the easily separated N-benzoyl
derivatives (S,R)-9b and (R,R)-9b.
(13) Pirkle, W. H.; Hauske, J. R. J.Org. Chem. 1977, 42, 2436-2439.
(14) (a) Ishii, A.; Higashiyama, K.; Mikami, K. Synlett 1997, 1381-
1382. (b) Ishii, A.; Miyamoto, F.; Higashiyama, K.; Mikami, K. Tetrahedron
Lett. 1998, 39, 1199-1202. (c) Ishii, A.; Miyamoto, F.; Higashiyama, K.;
Mikami, K. Chem. Lett. 1998, 119-120.
The interest of imine and oxazolidine as intermediates in
asymmetric organofluorine synthesis has been disclosed by
several reports. A chirality transfer via a base-induced 1,3-proton
shift on chiral imine was achieved by Soloshonok.12 Asymmetric
preparation of R-perfluoroalkylamines was first achieved by
Pirkle by reduction of the corresponding imines derived from
(S)-R-methylbenzylamine.13 Mikami reported the highly ste-
(15) (a) Lebouvier, N.; Laroche, C.; Huguenot, F.; Brigaud, T. Tetra-
hedron Lett. 2002, 43, 2827-2830. (b) Huguenot, F.; Brigaud, T. J. Org.
Chem. 2006, 71, 2159-2162. (c) Huguenot, F.; Brigaud, T. J. Org. Chem.
2006, 71, 7075-7078. (d) Chaume, G.; Van Severen, M.-C.; Marinkovic,
S.; Brigaud, T. Org. Lett. 2006, 8, 6123-6126.
(16) Gosselin, F.; Roy, A.; O’Shea, P. D.; Chen, C.-Y.; Volante, R. P.
Org. Lett. 2004, 6, 641-644.
(17) Kanai, M.; Ueda, K.; Yasumoto, M.; Kuriyama, Y.; Inomiya, K.;
Ootsuka, T.; Katsuhara, Y.; Higashiyama, K.; Ishii, A. J. Fluorine Chem.
2005, 126, 385-391.
(12) (a) Soloshonok, V. A.; Ono, T.; Soloshonok, I.V. J. Org. Chem.
1997, 62, 7538-7539. (b) Soloshonok, V. A.; Ohkura, H.; Yasumoto, M.
J. Fluorine Chem. 2006, 127, 924-929 and 930-935 and references therein.
(18) Li, Y.; Hu, J. Angew. Chem., Int. Ed. 2005, 44, 5882-5886.
(19) Dickey, J. B.; Towne, E. B. US 2539406 19510130, CAN 45:34277
AN 1951, 1951, 34277.
2566 J. Org. Chem., Vol. 73, No. 7, 2008

Umpolung ReactiVity of Difluoroenol Silyl Ethers
SCHEME 7. Synthesis of 2-Difluoromethyloxazolidines from 1b
SCHEME 8. Synthesis of Enantiopure 2-Difluoromethyl(ethyl)amine
SCHEME 9. Synthesis of Enantiopure
2-Difluoromethyl(ethyl)amine 12b
SCHEME 10. Synthesis of Difluoro Amino Nitriles 15a,b
trifluoroalanine and trifluoromethylalanine from the 2-trifluro-
methyl oxazolidines derived from phenylglycinol and fluoral
and trifluoroacetone was reported recently.15a,c Thus, we have
investigated a second important application of the electrophilic
behavior of DFSE: the synthesis of enantiopure R-difluoro-
methyl-R-amino acids, via a Strecker-type reaction using the
difluoromethyl imines and/or oxazolidines. The cyanosilylation
of the imines was successful, but suffers from the difficulty to
separate the aminonitriles diastereomers. Here again, the starting
material of choice proved to be the difluoromethyl oxazolidines.
Under Lewis acid activation (BF3‚OEt2), cyanosilylation of
compounds 6a,b proceeded with good yield and poor diaste-
reoselectivity, yielding the cyano amino alcohols 15a,b, respec-
tively (Scheme 10). In particular, the different diastereomeric
ratio for compounds 6b and 15b is in accordance with the
addition of the cyanide on an intermediate iminium salt. The
diastereomers were easily separated by chromatography, opening
a way for the preparation of both enantiomers of the corre-
sponding amino acid from a unique amino alcohol auxiliary.
The conversion of the aromatic derivative 15a into the
corresponding amino acid failed. Its acid hydrolysis led to the
difluoromethyl ketone via a sequence dehydrocyanation-hy-
drolysis. In contrast, the two diastereomers (R,R)-15b and (S,R)-
15b derived from acetyltrimethylsilane were converted, via the
hydrochlorides 17, into the two enantiomers of 2-difluoromethyl
alanine (R)-18 and (S)-18 (Scheme 11). The configuration of
each enantiomer was easily ascribed according to the reported
enantiomer (R)-18,23 allowing the determination of the config-
The Strecker reaction (hydrocyanation of imines)20 and its
asymmetric variant21 is a well-known process for the conversion
of aldehydes and ketones into R-amino acids. Hydro- or
silylcyanation of chiral amino alcohol derived imines/oxazo-
lidines was already described.22 The asymmetric synthesis of
(20) Strecker, A. Liebigs. Ann. Chem., 1850, 75, 27.
(21) (a) Williams, R. M. Synthesis of Optically actiVe R-Amino Acids;
Pergamon Press: Oxford, 1989; Chapter 5, p 208. (b) Duthaler, O. R.
Tetrahedron 1994, 50, 1539-1650. (c) Groˆger, H. Chem. ReV. 2003, 103,
2795-2828. (d) Connon, S. J. Angew. Chem. Int. Ed. 2008, 47, 1176-
1178.
(22) (a) Chakraborty, T. K.; Hussain, K. A.; Reddy, G. V. Tetrahedron
1995, 51, 9179-9190. (b) Warmuth, R.; Munsch, T. E.; Stelker, R. A.; Li,
B.; Beatty, A. Tetrahedron 2001, 57, 6383-6397.
J. Org. Chem, Vol. 73, No. 7, 2008 2567

Huguenot et al.
3
3
2
SCHEME 11. Synthesis of Enantiopure
2-Difluoromethylalanine 18
1H, JHH ) 8.0), 3.78 (dd, 1H, JHH ) 8.7, JHH ) 7.9), 4.56 (dd,
1H, 2JHH ) 8.7, 3JHH ) 6.7), 4.71 (ddd, 1H, 3JHH ) 8.0, 7.9, 6.7),
5.87 (t, 1H, 2JHF ) 55.6), 7.2-7.5 (m, 8H), 7.68 (m, 2H); 13C NMR
(CDCl3) δ 62.4, 72.9, 96.5 (t, 2JCF ) 22.5), 115.1 (t, JCF ) 250.9),
125.9, 126.7, 128.0, 128.4, 128.7, 128.9, 137.9, 138.0; 19F NMR
(CDCl3) δ -128.6 (dd,1F, 2JFF ) 275.5, 2JHF ) 55.6), -130.9 (dd,
2
2
1F, JFF ) 275.5, JHF ) 55.6).
(2R,4R)-2-Difluoromehyl-2,4-diphenyl-1,3-oxazolidine (R,R)-
1
6a: [R]20 -86.8 (c 0.84, CHCl3); H NMR (CDCl3) δ 2.94 (br,
D
1H), 3.94 (m, 1H), 4.5 (m, 2H), 5.85 (t, 1H, 2JHF ) 55.6), 7.2-7.5
(m, 8H), 7.70 (m, 2H); 13C NMR (CDCl3) δ 60.7, 72.9, 96.0 (t,
2JCF ) 22.5), 114.6 (t, JCF ) 250.5), 126.6, 126.7, 127.8, 128.2,
128.6, 128.7, 137.9, 138.8; 19F NMR (CDCl3) δ -129.0 (dd, 1F,
2JFF ) 277.4, JHF ) 55.6), -131.5 (dd, 1F, JFF ) 277.4, JHF
)
2
2
2
55.6); IR (neat) ν 3354, 3061, 2972, 1450, 1435, 1074; MS (EI 70
eV) m/z 276 (M + 1), 245, 224 (100), 193, 165, 104. Anal. Calcd
for C16H15F2NO: C, 69.81; H, 5.49; N, 5.09. Found: C, 69.46; H,
5.61; N, 4.80.
Synthesis of 2-Difluoromethyloxazolidine 6b and Their N-
Benzoyl Derivatives 9b. Difluoroenol silyl ether 2b was prepared
similarly from acetyl(trimethyl)silane 1b and treated in situ at
0 °C with (R)-phenylglycinol to give quantitatively, in 3h, (E)-
2,2-difluoro-1-methylethylidene((1R)-2-trimethylsilyloxy-1-phenyl-
ethyl)amine 7 as a yellowish oil. To a stirred solution of ketimine
7 (2.85 g, 10.0 mmol, 1.0 equiv) in 10 mL of THF under argon at
0 °C was added TBAF (3.2 g, 10.0 mmol, 1.0 equiv). After
consumption of starting material, the mixture was poured into a
saturated NaHCO3 solution. After extraction with Et2O (4 × 20
mL), the combined organic layers were dried over Na2SO4 and
concentrated under reduced pressure to afford a mixture of the
desilylated ketimine 8 and oxazolidine 6b (7.3:1 mixture of
diastereomers).
A stirred solution of the mixture 8 + 6b in 60 mL of toluene
was heated to reflux overnight. After the solution was cooled to 0
°C with an ice bath, the resulting mixture was concentrated under
reduced pressure. Purification by flash chromatography (9:1
petroleum ether /ethyl acetate) gave 1.96 g (92% from 2b) of a
5.7:1 mixture of diasteromers 6b as a yellow oil. To a stirred
solution of 6b (0.64 g, 3.0 mmol, 1.0 equiv) in dichloromethane
(10 mL) cooled to 0 °C were added triethylamine (0.63 mL 4.5
mmol, 1.5 equiv), DMAP (0.55 g, 4.5 mmol, 1.5 equiv), and
benzoyl chloride (0.53 mL, 4.5 mmol, 1.5 equiv). After complete
consumption of starting material, the mixture was filtered on Celite
and washed with Et2O. The organic layer was extracted once with
brine, dried over Na2SO4, filtered, and concentrated under reduced
pressure. Separation by flash chromatography (9:1 petroleum ether
/ethyl acetate) and recrystallization in hexane gave 0.67 g (70%)
of major diastereomer (S,R)-9b, and 0.14 g (15%) of minor
diastereomer (R,R)-9b.
uration of the diastereomeric precursors (R,R)-15b and (S,R)-
15b. This correlation indicates that the course of the cyanosi-
lylation is similar to the one described by Chakraborty et al. in
the nonfluorinated series.22a
Conclusion
In summary, difluoroenol silyl ethers can behave as electro-
philic reactant with amines and amino alcohols, giving rise to
difluoromethyl imines and oxazolidines, respectively. The use
of (R)-phenylglycinol allowed to prepare diastereomerically pure
2-difluoromethyl oxazolidines which proved to be good precur-
sors toward enantiopure R-difluoromethyl amines (by LAH
reduction), or R-difluoromethyl alanine (via a Strecker reaction).
The key 2-difluoromethyl oxazolidine intermediates are prepared
in high yield from acylsilanes, successively treated with
trifluoromethyltrimethylsilane and the amino alcohol reagent.
This methodology is of great interest, in particular in the
aliphatic series, where the preparation of DFSE by Mg reduction/
silylation of trifluoromethyl ketones4c is much less effective than
in aromatic series.
After their numerous applications as enolate equivalents, the
possibility of DFSE to react with nucleophilic amines consider-
ably extends their potential as gem-difluoro building blocks.
Experimental Section
Synthesis of 2-Difluoromethyloxazolidine 6a. To a stirred
solution of benzoyl(trimethyl)silane 1a (1.07 g, 6.0 mmol, 1.0 equiv)
in diethyl ether (15 mL) at 0 °C were added CF3SiMe3 (1.4 mL,
(2S,4R)-N-Benzoyl-2-difluoromethyl-2-methyl-4-phenyl-1,3-
oxazolidine (S,R)-9b: white solid; mp 75-76 °C; [R]20 -211.0
D
1
-
7.4 mmol, 1.23 equiv) and nBu4N+Ph3SnF2 (34 mg, 0.23 mmol,
(c 1.0, CHCl3); H NMR (CDCl3) δ 2.03 (s, 3H), 3.93 (dd, 1H,
2JHH ) 8.5, JHH ) 1.2), 4.53 (dd, 1H, JHH ) 8.5, JHH ) 7.0),
3
2
3
0.01 equiv). After complete conversion (GC), the resulting mixture
was filtered and concentrated to afford difluoroenol silyl ether 2a
(1.37 g), which was dissolved in toluene (40 mL). (R)-Phenylgly-
cinol (6.0 mmol, 0.90 g, 1.0 equiv) and pyridinium p-toluene-
sulfonate (0.60 mmol, 0.91 g, 0.1 equiv) were added, and the
mixture was heated to reflux with a Dean-Stark apparatus for
24 h under argon and then cooled to 0 °C with an ice bath. The
resulting mixture was filtered on Celite, and toluene was evaporated.
Separation by flash chromatography (19:1 petroleum ether/ethyl
acetate) afforded (S,R)-6a (0.87 g, 50%) and (R,R)-6a (0.70 g, 45%)
as yellow oils.
3
2
4.87 (dd, 1H, JHH ) 7.0, 1.2), 6.48 (t, 1H, JHF ) 56.5), 6.7-7.6
(m, 8H), 8.03 (m, 2H); 13C NMR (CDCl3) δ 19.8, 62.9, 74.1, 94.6
(dd, 2JCF ) 22.0, 19.3), 113.7 (t, JCF ) 248.0), 125.8, 126.4, 128.1,
128.4, 128.6, 130.1, 136.6, 140.5, 170.3; 19F NMR (CDCl3) δ
2
2
2
-134.2 (dd, 1F, JFF ) 280.9, JHF ) 56.5), -137.1 (dd, 1F, JFF
) 280.9, 2JHF ) 56.5); IR (KBr) ν 3087, 3007, 2912, 1635, 1577,
1394, 1252, 1062; HRMS calcd for C18H17F2NO2 (M + 1)
318.1309, found 318.1306.
(2R,4R)-N-Benzoyl-2-difluoromethyl-2-methyl-4-phenyl-1,3-
oxazolidine (R,R)-9b: white solid; mp 105-107 °C; [R]20D -187.1
(c 1.1, CHCl3); 1H NMR (CDCl3) δ 1.86 (s, 3H), 4.19 (t, 1H, 2JHH
(2S,4R)-2-Difluoromethyl-2,4-diphenyl-1,3-oxazolidine (S,R)-
1
6a: [R]20 +14.7 (c 0.74, CHCl3); H NMR (CDCl3) δ 2.63 (d,
3
2
3
3
) JHH ) 8.3), 4.42 (t, 1H, JHH ) JHH ) 8.3), 5.01 (t, 1H, JHH
) 8.3), 6.78 (t, 1H, 2JHF ) 55.6), 6.9-7.6 (m, 8H), 8.15 (m, 2H);
D
13C NMR (CDCl3) δ 19.4, 63.1, 74.9, 95.1 (t, JCF ) 2.7), 114.7
(t, JCF ) 248.7), 126.0, 127.2, 127.9, 128.3, 128.4, 130.1, 136.7,
2
(23) Bravo, P.; Capelli, S.; Meille, S. V.; Seresini, P.; Volontario, A.;
Zanda, M. Tetrahedron: Asymmetry 1996, 7, 2321-2332.
2568 J. Org. Chem., Vol. 73, No. 7, 2008

Umpolung ReactiVity of Difluoroenol Silyl Ethers
137.9, 170.2; 19F NMR (CDCl3) δ -131.8 (dd, 1F, JFF ) 281.8,
2
Preparation of Enantiopure R-Difluoromethyl-R-amino Ac-
ids. To a solution of oxazolidines 6b (0.54 g, 2.5 mmol) in CH2-
Cl2 (20 mL) under argon at 0 °C were successively added TMSCN
(2.76 mL, 3.75 mmol, 1.5 equiv) and BF3‚OEt2 (2.6 mL, 3.75 mmol,
1.5 equiv). The temperature was slowly raised to room temperature,
and after conversion of the starting material (TLC), the reaction
mixture was poured into a saturated aq NaHCO3 solution. The
aqueous layer was extracted with CH2Cl2 (4 × 20 mL). The
combined organic extracts were dried over Na2SO4, filtered, and
concentrated under reduced pressure. The two diastereomers were
separated by flash chromatography (4:1 petroleum ether/ ethyl
acetate), giving (R,R)-15b (yellow oil, 0.24 g, 40%) and (S,R)-15b
(solid, 0.18 g, 30%). The same procedure was applied to 6a (0.28
g, 1.0 mmol) to give a major (145 mg, 48%) and a minor (115 mg,
38%) diastereomer of propionitrile 15a (SI) as yellow oils.
2JHF ) 55.6), -132.1 (dd, 1F, JFF ) 281.8, JHF ) 55.6).
General Procedure for the Reduction of 1,3-Oxazolidines with
LAH. To a solution of oxazolidine (1.0 mmol) in 40 mL of diethyl
Et2O at room temperature under argon was added LAH (1.2 mmol,
1.2 equiv). After being stirred for 24 h, the reaction mixture was
successively treated with water (0.2 mL), 15% aq KOH (0.2 mL),
and water (4 mL). The resulting mixture was filtered on Celite,
dried over Na2SO4, filtered, and concentrated under reduced
pressure. This procedure afforded the corresponding amines 10a
and 13b (see the Supporting Information). A shorter reaction time
allowed us to isolate the N-benzyloxazolidine (R,R)-14.
2
2
Preparation of Enantiopure R-Difluoromethylamine. To a
solution of compound (R,R)-10a (0.27 g, 0.96 mmol) in MeOH/
CH2Cl2 2:1 (10 mL) was added at 0 °C Pb(OAc)4 (620 mg, 1.4
mmol, 1.4 equiv). After 20 min of stirring at 0 °C, the reaction
mixture was poured into a phosphate buffer aqueous solution pH
) 7 (10 mL) at room temperature and then filtered over Celite.
The aqueous phase was extracted with dichloromethane (4 × 10
mL), and the combined organic extracts were dried over Na2SO4,
filtered, and concentrated under reduced pressure to afford quan-
titatively (R)-11a as a yellow oil. A similar procedure applied to
(S,R)-10a gave (S)-11a. The imine (R)-11a was stirred for 24 h in
a 1:1 mixture of 3 M HCl/ Et2O (5 mL). The aqueous phase was
extracted with Et2O and concentrated under reduced pressure to
afford (R)-(-)-12a (0.15 g, 80%, two steps from (R,R)-10a) as a
white powder which decomposed on heating. Similarly, (S)-(+)-
12a (0.14 g, 73%, two steps) was prepared from (S)-11a.
(R,R)-15b (0.24 g, 1.0 mmol) was treated with Pb(OAc)4 as
described for 10a to afford (R)-16 as a pale yellow oil. A solution
of (R)-16 (0.21 g, 1.0 mmol) in 6 M aq HCl (5 mL) was heated at
reflux for 14 h. After cooling to rt and treatment with Et2O (5 mL),
concentration of the aqueous phase afforded the amino acid
hydrochloride (R)-(+)-17 (147 mg, 84%) as a white powder. This
solid was dissolved in propylene oxide (10 mL) and stirred for 24
h at room temperature. The crude mixture was concentrated under
reduced pressure. Pure (R)-(+)-18 (72 mg, 62%) was obtained after
crystallization in methanol.
(R)-(+)-2-Difluoromethylalanine (R)-18:23 white solid; mp )
194 °C dec (lit.23 196 °C); [R]20D +14.70 (c 0.60, H2O) (lit.23 [R]20
D
+15.35 (c 0.85, H2O)); 1H NMR (CD3OD) δ 1.51 (s, 3H), 6.19 (t,
1H, 2JHF ) 53.1); 13C NMR (CD3OD) δ 20.0 (t, 3JCF ) 43.8, 64.4
(t, 2JCF ) 19.7), 118.4 (t, JCF ) 246.5), 175.0; 19F NMR (CD3OD)
(R)-(-)-2,2-Difluoro-1-phenylethylamine hydrochloride (R)-
1
(-)-12a: [R]20 -17.0 (c 0.2, H2O); H NMR (D2O) δ 4.8 (m,
D
1H), 6.22 (ddd, 1H, 2JHF ) 53.9, 52.9, 3JHH ) 2.8), 7.37 (m, 5H);
2
2
δ -126.2 (dd, 1F, JFF ) 275.6, JHF ) 53.1), -132.0 (dd, 1F,
13C NMR (D2O) δ 56.2 (dd, JCF ) 23.8, 21.2), 114.2 (t, JCF
)
2
2
2JFF ) 275.6, JHF ) 53.1).
245.7), 128.5, 129.9, 130.9, 138.1; 19F NMR (D2O) δ -123.3 (ddd,
Similar successive treatments were applied to (S,R)-15b (0.24
g, 1.0 mmol) to afford (S)-16 (pale yellow oil), then (S)-(-)-17
(136 mg, 78%) (white powder), and finally (S)-18.
(S)-(-)-2-Difluoromethylalanine (S)-18: [R]20D -15.0 (c 0.40,
H2O).
2
2
3
2
1F, JFF ) 285.4, JHF ) 52.9, JHF ) 9.0), -130.5 (ddd, 1F, JFF
2
3
) 285.4, JHF ) 53.9, JHF ) 8.0).
(S)-(+)-2,2-Difluoro-1-phenylethylamine hydrochloride (S)-
(+)-12a: [R]20 +18.0 (c 2.3, H2O).
D
(R)-(+)-1-Difluoromethylethylamine Hydrochloride (R)-(+)-
12b. To a stirred solution of diastereomer (R,R)-13b (0.31 g, 1.0
mmol) in 5 mL of methanol was added in one portion 0.50 g of
Perlman catalyst (0.5 mmol, 0.02 equiv). The reaction mixture was
stirred under H2 atmosphere until complete consumption of starting
material (TLC). After filtration on Celite, the filtrate was diluted
with a 1:1 mixture of HCl (3 N)/Et2O. After 2 h of stirring, the
aqueous phase was extracted with Et2O and concentrated under
reduced pressure to afford 57 mg of (R)-(+)-12b (35%) as a white
powder which decomposed on heating: [R]20D +5.4 (c 0.4, H2O);
Acknowledgment. We thank the French Ministry of Re-
search for a doctoral fellowship (F.H.) and the CNRS and
University of Reims Champagne-Ardenne for supporting this
research.
Supporting Information Available: Complementary proce-
dures and data of the compounds 3a,b, 4a,b, 7, 8, 6b, (R,R)-14,
(R,R)-10a, (S,R)-10a, 12b, (S,R)-13b, (R,R)-13b, (R)-11a, (S)-11a,
3
3
1H NMR (D2O) δ 1.36 (d, 3H, JHH ) 6.9), 3.77 (dddq, 1H, JHF
1
15a, (R,R)-15b, (S,R)-15b, (R)-16, (S)-16, (R)-17, (S)-17. H, 19F,
3
2
3
) 18.8, 8.1, JHH ) 6.9, 2.0), 6.10 (td, 1H, JHF ) 53.9, JHH
2.0); 13C NMR (D2O) δ 11.9 (dd, 3JCF ) 5.5, 2.8), 48.9 (t, 2JCF
)
)
and 13C NMR spectra of new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
22.1), 114.7 (t, JCF ) 243.1); 19F NMR (D2O) δ -125.7 (ddd, 1F,
2JFF ) 286.3, JHF ) 53.9, JHF ) 8.1), -133.8 (ddd, 1F, JFF
)
2
3
2
2
3
286.3, JHF ) 53.9, JHF ) 18.8).
JO702328V
J. Org. Chem, Vol. 73, No. 7, 2008 2569