Mild synthesis of β-amino-α,α-difluoro ketones from acylsilanes and trifluoromethyltrimethylsilane in a one-pot imino aldol reaction

Article abstract of DOI:10.1002/ejoc.200500106

β-Amino-α,α-difluoro ketones have been very conveniently prepared in a one-pot procedure from acylsilanes, trifluoromethyltrimethylsilane and imines. The key intermediate in this reaction is a difluoroenoxysilane. The Lewis acid promoted imino aldol react

Full text of DOI:10.1002/ejoc.200500106

FULL PAPER
Mild Synthesis of β-Amino-α,α-difluoro Ketones from Acylsilanes and
Trifluoromethyltrimethylsilane in a One-Pot Imino Aldol Reaction[‡]
Sylvain Jonet,[a] Franck Cherouvrier,[a] Thierry Brigaud,*[b] and Charles Portella[a]
Keywords: Imino aldol reaction / Amino ketones / Fluorine / Silicon / Silyl enol ether
β-Amino-α,α-difluoro ketones have been very conveniently
prepared in a one-pot procedure from acylsilanes, trifluoro-
methyltrimethylsilane and imines. The key intermediate in
this reaction is a difluoroenoxysilane. The Lewis acid pro-
moted imino aldol reaction was performed with BF3·OEt2 or
under very mild conditions using a catalytic amount of
Yb(OTf)3. The reaction with chiral benzylimines occurred in
good yield with 52–78% de. Palladium-catalyzed hydro-
genolysis furnished an unprotected β-amino-α,α-difluoro
ketone or a β-amino-α,α-difluoro alcohol.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2005)
In recent years we have demonstrated the utility of a
three-component system involving an acylsilane, trifluoro-
Introduction
The introduction of fluorine atoms into a molecule often methyltrimethylsilane (TFMTMS) and an electrophile in
produces significant changes in its physical, chemical and the synthesis of various α,α-difluorocarbonyl compounds.[9]
biological properties.[1] For example, the insertion of the β- The major advantage of this one-pot method is that the
amino-α,α-difluoro ketone unit into a peptide proved to be intermediate difluoroenol silyl ether does not need to be
successful in the design of enzyme inhibitors such as prote- isolated and the α,α-difluorocarbonyl compounds are ob-
ase inhibitors. The mechanism postulated for their bio- tained in high yield from a wide variety of acylsilanes. We
logical activity involves the hydration of or hemiketal for- report herein a new application of this strategy to the one-
mation from the carbonyl group to provide a stable tetrahe- pot synthesis of β-amino-α,α-difluoro ketones.
dral analogue of the transition state formed in peptide-
bond cleavage reactions.[2] In spite of the interest in β-amin-
odifluoro ketones, only a few methods have been reported
Results and Discussion
for their synthesis. They have been prepared by Reformat-
sky addition[3] or reductive coupling reactions[4] of α-halod-
According to our procedure, the difluoroenoxysilanes
ifluoro ketones to imines, by intramolecular [3,3] rearrange- were generated in situ from acylsilanes 1 and 2 and trifluor-
ment of difluoroallylic alcohols[5] and by the reaction of omethyltrimethylsilane (TFMTMS) in dichloromethane by
difluoroenol methyl ethers[6] or difluoroenol silyl ethers[7,8] fluoride initiation (Table 1). Various substituted aldimines
with N-acyliminiums or imines under Lewis acid activation. 3 were then added to the solution and, under Lewis acid
However, in the latter method, difluoroenol silyl ethers have activation the corresponding β-amino-α,α-difluoro ketones
to be isolated, but these compounds are not easily prepared 4 and 5 were produced. Unlike non-fluorinated enoxysil-
from aliphatic compounds.
anes,[10] difluoroenoxysilanes proved to be unreactive with
N-arylbenzaldimine 3a in the presence of a catalytic
amount of Yb(OTf)3 or TMSOTf or with a stoichiometric
amount of triflic acid (Table 1, entries 1–3). Only trace
amounts of β-amino ketone 4b were obtained from the N-
benzylbenzaldimine 3b under catalytic Yb(OTf)3 or
[‡] Mixed Organofluorine-Organosilicone Chemistry, 14. – Part 13:
F. Chanteau, B. Didier, B. Dondy, P. Doussot, R. Plantier-
Royon, C. Portella, Eur. J. Org. Chem. 2004, 1444–1454.
[a] Laboratoire “Réactions Sélectives et Applications”, UMR
CNRS 6519,
Université de Reims-Champagne-Ardenne, Faculté des Sci- TMSOTf activation demonstrating the poor regeneration of
ences,
the catalytic activating species (Table 1, entry 4). The β-
BP 1039, 51687 Reims Cedex 2, France
amino ketone 4b was obtained in a better yield by using
2 equiv. of BF3·OEt2 as the Lewis acid (Table 1, entry 5). In
a similar manner, the aliphatic imine 3c afforded the corre-
sponding β-amino ketone 4c in 46% yield. The N-ethoxy-
carbonylimine 3d proved to be much more reactive, giving
the β-amino ketones 4d and 5d in 82 and 70% yields,
respectively, from reactions with the aromatic acylsilane 1
Fax: +33-3-26913166
E-mail: charles.portella@univ-reims.fr
[b] Laboratoire “Synthèse Organique Sélective et Chimie Organom-
étallique” (SOSCO), UMR CNRS 8123, Université de Cergy-
Pontoise,
5, Mail Gay-Lussac, Neuville sur Oise, 95031 Cergy-Pontoise
Cedex, France
Fax: +33-1-34257071
E-mail: thierry.brigaud@chim.u-cergy.fr
4304
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/ejoc.200500106
Eur. J. Org. Chem. 2005, 4304–4312

Synthesis of β-Amino-α,α-difluoro Ketones in a One-Pot Imino Aldol Reaction
FULL PAPER
Table 1. One-pot imino aldol reaction of acylsilanes 1 and 2, trifluoromethyltrimethylsilane and imine 3.
Entry
Acylsilane
Imine[a]
R2
R3
Lewis acid (equiv.)
Product
Yield [%][b]
1
2
3
4
5
6
7
8
1
1
1
1
1
1
1
2
1
1
1
2
3a
3a
3a
3b
3b
3c
3d
3d
3d
3d
3e
3e
pMeOPh
pMeOPh
pMeOPh
Ph
pMeOPh
pMeOPh
pMeOPh
Bn
Bn
Bn
CO2Et
CO2Et
CO2Et
CO2Et
t-Boc
Yb(OTf)3 (0.2)
TMSOTf (0.15)
CF3SO3H (1.1)[c]
Yb(OTf)3 (0.2)
BF3·OEt2 (2)
no reaction
no reaction
no reaction
4b
4b
4c
4d
5d
4d
4d
4e
5e
traces[d]
36
Ph
Et
Ph
Ph
Ph
Ph
Ph
Ph
BF3·OEt2 (2)
46
82
70
58
72
44
70
CF3SO3H (1.1)[c]
CF3SO3H (1.1)[c]
Yb(OTf)3 (0.2)
TMSOTf (0.1)
Yb(OTf)3 (0.2)
Yb(OTf)3 (0.2)
9
10
11
12
t-Boc
[a] 1.2 equiv. [b] Isolated yields of pure compound based on 1 or 2. [c] Triflic acid was added to the imine in order to form the iminium
salt before addition of the difluoroenoxysilane. [d] Trace amounts of 4b were also obtained with TMSOTf (0.2 equiv.) as the Lewis acid.
and the aliphatic acylsilane 2 in the presence of a stoichio- atom occurs as a side-reaction. Note that these fluorinated
metric amount of triflic acid (Table 1, entries 7 and 8). The β-ketosulfoxides are rarely reported in the literature.[12] The
one-pot imino aldol reaction of this activated imine 3d was reaction promoted by BF3·OEt2 did not produce better re-
also efficiently performed under very mild conditions by sults; the sulfoxide 6 was isolated in a low yield (14%) and
using a catalytic amount of Yb(OTf)3 or TMSOTf as the the expected β-amino ketone was not formed.
Lewis acid at room temperature (Table 1, entries 9 and 10).
Chiral aldimines prepared from (R)- or (S)-α-methylben-
In order to anticipate a convenient removal of the imine zylamine and aldehydes are frequently used as precursors
activating group, the reactivity of the N-Boc-benzaldimine in the stereoselective synthesis of chiral amino compounds.
3e was studied. The one-pot imino aldol reactions of the Some examples of the reactions of these imines with silyl
difluoroenoxysilanes prepared from the acylsilanes 1 and 2 ketene acetals to give β-amino esters have been reported in
with the imine 3e also occurred in very mild conditions at the literature.[13] Nevertheless, to the best of our knowledge,
room temperature with Yb(OTf)3 as the catalyst to give the their imino aldol reactions with a silyl enol ether, resulting
corresponding N-Boc-amino ketones 4e and 5e.
in the corresponding β-amino ketones, have not been de-
The diastereoselective addition of nucleophiles to imines scribed. In the fluorinated series, the reaction of the di-
derived from aldehydes and chiral amines is a useful fluoroenoxysilane derived from the aromatic acylsilane 1
method for the preparation of optically active secondary with the (R)-benzaldimine 3g in the presence of BF3·OEt2
amines. In order to study the stereoselectivity of the reac- gave the corresponding β-amino ketone 4g in 53% yield and
tion of difluoroenoxysilanes with chiral imines, we first ex- with a 76:24 diastereomeric ratio (Table 2). Under the same
amined the reaction of the aliphatic difluoroenoxysilane conditions, the reaction of the aliphatic acylsilane 2 fur-
prepared from
2
with the chiral sulfinylimine 3f[11] nished the β-amino ketone 5g in 83% yield and with a
(Scheme 1). No reaction occurred without activation by a higher stereoselectivity (89:11 diastereomeric ratio). The
Lewis acid. Unfortunately, the Yb(OTf)3-mediated reaction one-pot imino aldol reaction of 2 with the (R)-isopropylim-
furnished the expected β-amino ketone 5f in a very low ine 3h gave 5h in 55% yield as a 87:13 mixture of dia-
yield (5%). The major product of the reaction was the di- stereomers.
fluoromethyl ketone resulting from the hydrolysis of the di-
The absolute configuration of the major diastereomers
fluoroenoxysilane. Furthermore, the formation of the fluo- of 4g and 5g is anticipated to be (R,S) on the basis of the
rinated sulfoxide 6 (13%) suggests that attack at the sulfur 1H NMR chemical-shift measurements. Yamamoto and co-
Eur. J. Org. Chem. 2005, 4304–4312
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4305

S. Jonet, F. Cherouvrier, T. Brigaud, C. Portella
FULL PAPER
Table 3. Literature NMR spectroscopic data for (S)-1-phenylethyl-
amine-based benzaldimine addition products.
R
(H1,H3) relative configu- δ(H1) [ppm]
Ref.
ration
[13d]
tBuOCOCH2
syn
anti
syn
syn
anti
4.14
3.73
4.35
4.37
4.00
[14]
[15]
C3F7
C6F13
Scheme 1. One-pot imino aldol reaction using the enantiopure sul-
finylimine 3f.
1
workers reported detailed H NMR spectroscopic data for
the (R,S) and (S,S) β-amino tert-butyl esters derived from
(S)-benzaldimine.[13d] In the fluorinated series Pirkle et
al.[14] and Uno et al.[15] gave similar data for the perfluoalk-
ylated analogues. As already mentioned by Uno et al., for
all these compounds, the anti relative configuration of the
H1 and H3 atoms was accompanied by a shielding of the
H1 atom due to the phenyl group of the phenethyl moiety
(Table 3).
1
Figure 1. H NMR chemical shift measurements of H1 in 4g and
5g.
lylated imine 3j in order to evaluate the effect of an hetero-
As we started with the (R)-benzaldimine 3g and as we atom in the chiral side-chain on the stereoselectivity of the
observed a 0.5 ppm upfield shift of the H1 proton in the reaction (Scheme 2). Under the standard conditions, the re-
minor diastereomers of 4g and 5g, we assign the (S,R) con- actions of the difluoroenoxysilanes derived from the acylsil-
figuration to these minor diastereomers (Figure 1). The anes 1 and 2 with 3i gave the β-amino ketones 4i (63%
configurations of the 5h diastereomers could not be as- yield, 79:21 diastereomeric ratio) and 5i (73% yield, 65:35
signed by using the same NMR argument. The major dia- diastereomeric ratio), respectively. The diastereoselectivity
stereomers of 5g and 5h were isolated in a pure form after of these reactions was not improved by generating an inter-
column chromatography.
mediate chiral iminium ion. However the stereoselectivity
The one-pot imino aldol reaction was then extended to of the reaction of the aromatic difluoroenoxysilane was in-
the (R)-phenylglycinol-derived oxazolidine 3i and the si- creased by using the silylated imine 3j which gave the amino
Table 2. One-pot imino aldol reactions using chiral aldimines 3g,h.
Entry
Acylsilane
R1
Aldimine[a]
R2
Product
Yield [%][b]
dr[c]
1
2
3
1
2
2
Ph
C8H17
C8H17
3g
3g
3h
Ph
Ph
iPr
4g
5g
5h
53
83
55
76:24
89:11
87:13
[a] 1.2 equiv. [b] Isolated yields of pure compound based on 1 or 2. [c] Determined from the 19F NMR spectrum of the crude mixture.
4306 © 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.eurjoc.org
Eur. J. Org. Chem. 2005, 4304–4312

Synthesis of β-Amino-α,α-difluoro Ketones in a One-Pot Imino Aldol Reaction
FULL PAPER
Scheme 2. One-pot imino aldol reactions with the (R)-phenylglycinol-derived oxazolidine 3i and imine 3j.
ketone 4j in 54% yield and with a 87:13 diastereomeric ra- difluoro-1,3-amino alcohol or the unprotected β-amino-
tio.
α,α-difluoro ketone.
We then investigated the removal of the chiral auxiliary
from the amine by palladium-catalyzed hydro-
genolysis.[16–18]
Experimental Section
The hydrogenolysis of the β-amino ketone 5h was carried
out at room temperature under an atmospheric hydrogen
pressure in the presence of Pd/C in methanol or ethyl ace-
tate (Table 4, entries 1 and 2). Under these conditions, both
debenzylation and reduction of the carbonyl group oc-
curred to give the β-amino alcohol 7 in high yield. The rela-
tive configurations of the two diastereomers of 7 could not
be assigned. A similar total reduction of 5h occurred in
methanol even in the presence of Pd(OH)2 which is known
to favour benzylic hydrogenolysis (Table 4, entry 3). The
high efficiency of the reduction of the α-difluorocarbonyl
group in very mild conditions should be underlined. Usu-
ally, this reaction requires the use of a ruthenium,[19] rho-
dium[20] or platinum[21] catalyst under hydrogen pressure.
The reduction of the carbonyl group could be avoided by
using Pd(OH)2 in a non-protic solvent such as ethyl acetate.
Under these conditions, the expected unprotected β-amino-
α,α-difluoro ketone 8 was obtained in a high yield (Table 4,
entry 4). This amino ketone proved to be unstable to silica
gel chromatography giving the imine 9 in a self-condensa-
tion reaction. Such behaviour can easily be explained by the
high electrophilicity of the α,α-difluorocarbonyl group.
General Remarks: Melting points are uncorrected. Optical rotations
were determined with a Perkin–Elmer Model 241 polarimeter.
FTIR spectra were recorded with a MIDAC corporation apparatus.
1H, 13C and 19F NMR spectra were recorded with a Bruker AC-
250 spectrometer using CDCl3 as the solvent. Tetramethylsilane
was used as the internal standard for 1H and 13C NMR spectra
and CFCl3 for 19F NMR spectra. MS data were obtained with a
JEOL D300 apparatus at 70 eV in the electron-impact mode. Ele-
mental analyses were performed with a Perkin–Elmer CHN 2400
apparatus. All reactions were monitored by TLC (Merck F 254) or
GC. GC analyses were performed with a HP 6890 chromatograph
equipped with a poly(dimethylsiloxane) HP ultra I column and a
flame-ionization detector. Merck 9385 silica gel (40–63 μm) was
used for flash chromatography. Commercially available reagents
were used as supplied. Dichloromethane of puriss quality from
Fluka (over molecular sieves) was used. Tetra-n-butylammonium
difluorotriphenylstannate (DFTPS) was prepared according to the
previously reported procedure.[22] The acylsilanes 1 and 2 were syn-
thesized by the method developed by Corey[23] and Brook[24] and
their co-workers. Imines 3c,[25] 3d,[26] 3e,[27] 3f,[11b,28,29] and oxazoli-
dine 3i[30] were prepared according to literature procedures.
(1R)-N-Isobutylidene-2-tert-butyldimethylsilyloxy-1-phenylethylam-
ine (3j): Isobutyraldehyde (288 mg, 4 mmol) was added to a solu-
tion of (R)-2-tert-butyldimethylsilyloxy-1-phenylethylamine (1 g,
4 mmol) in CH2Cl2 (50 mL). The mixture was stirred for 12 h in
the presence of MgSO4 and then filtered. The solution was concen-
trated under reduced pressure to afford 3j in a quantitative yield as
Conclusions
1
a colourless oil. H NMR (250 MHz, CDCl3, 25 °C): δ = 0.03 (s,
In summary, we have developed a convenient one-pot
procedure for preparing various β-amino-α,α-difluoro
ketones from acylsilanes, trifluoromethyltrimethylsilane and
imines in very mild conditions. In an exploratory study, we
have demonstrated that this strategy can be applied to a
chiral series. Depending on the reaction conditions, palla-
3
6 H, CH3), 0.90 (s, 9 H, CH3), 0.97 (d, JHH = 4.5 Hz, 3 H, 3Ј-H),
3
3
3
1.12 (d, JHH = 4.5 Hz, 3 H, 3Ј-H), 2.51 (dsept, JHH = 5.0, JHH
3
= 4.5 Hz, 3 H, 2Ј-H), 3.78 (m, 2 H, 2-H), 4.15 (dd, JHH = 7.8,
3JHH = 5.2 Hz, 3 H, 1-H), 7.29–7.45 (m, 5 H, Ph), 7.63 (d, JHH
=
3
5.0 Hz, 1 H, 1Ј-H) ppm. 13C NMR (62.89 MHz, CDCl3, 25 °C): δ
= –4.9 (CH3), 18.7 [C(CH3)3], 19.8 (C-3Ј), 19.9 (C-3Ј), 26.3 (CH3),
dium-catalyzed hydrogenation selectively afforded the 2,2- 34.5 (C-2Ј), 68.5 (C-2), 77.1 (C-1), 127.5 (Ph), 127.8 (Ph), 128.7
Eur. J. Org. Chem. 2005, 4304–4312
www.eurjoc.org © 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 4307

S. Jonet, F. Cherouvrier, T. Brigaud, C. Portella
FULL PAPER
MgSO4 and the solvent evaporated under reduced pressure. The
crude product was purified by silica gel column chromatography
(see Table 1).
Table 4. Hydrogenolysis of imino aldol reaction product 5h.
CF3SO3H Activation of the Imine: The difluoroenoxysilane solution
was added to a solution of imine 3 (1.8 mmol, 1.2 equiv.) and triflic
acid (1.65 mmol, 1.1 equiv.) under argon at 0 °C. After stirring for
45 min at room temperature, the reaction was quenched by addition
of a saturated NaHCO3 solution (10 mL). After extraction with
CH2Cl2 (3×15 mL), the organic layer was washed with brine, dried
with MgSO4 and the solvent evaporated under reduced pressure.
The crude product was purified by silica gel column chromatog-
raphy (see Table 1).
Yb(OTf)3 or TMSOTf Activation of the Imine: Imine 3 (1.8 mmol,
1.2 equiv.) and Yb(OTf)3 (0.15 mmol, 0.1 equiv.) at room tempera-
ture or TMSOTf (0.15 mmol, 0.1 equiv.) at 0 °C was added to the
difluoroenoxysilane solution. The reaction mixture was stirred
overnight [Yb(OTf)3] or for 4 h (TMSOTf) at room temperature. A
saturated NaHCO3 solution (10 mL) was then added. After extrac-
tion with CH2Cl2 (3×15 mL), the organic layer was washed with
brine, dried with MgSO4 and the solvent evaporated under reduced
pressure. The crude product was purified by column chromatog-
raphy over silica gel (see Table 1).
3-Benzylamino-2,2-difluoro-1,3-diphenylpropan-1-one (4b): Pro-
cedure with BF3·OEt2. Elution: ethyl acetate/petroleum ether, 2:98.
Pale yellow liquid (190 mg, 36%). 1H NMR (250 MHz, CDCl3,
25 °C): δ = 2.18 (s, 1 H, NH), 3.52 (d, JAB = 13.2 Hz, 1 H, CH2),
3
3
3.79 (d, JAB = 13.2 Hz, 1 H, CH2), 4.44 (dd, JHF = 20.2, JHF
=
7.6 Hz, 1 H, 3-H), 7.05–7.65 (m, 13 H, Ph), 7.99 (d, 3JHH = 7.6 Hz,
2 H, Ph) ppm. 13C NMR (62.89 MHz, CDCl3, 25 °C): δ = 50.8
En- Catalyst
try
Solvent
Yield [%]
2
1
(CH2), 63.6 (t, JCF = 27.4 Hz, C-3), 117.8 (t, JCF = 257.9 Hz, C-
Amino
Amino
2), 127.1, 128.2, 128.3, 128.6, 129.1, 129.7, 133.4, 133.8, 134.6,
alcohol 7
ketone 8
2
138.9 (Ph), 190.4 (t, JCF = 28.6 Hz, C-1) ppm. 19F NMR
1[a]
2[a]
3[a]
Pd/C 0.2 equiv.
MeOH
AcOEt
MeOH
98[b]
92[c]
53[d]
–
–
–
3
(235.36 MHz, CDCl3, 25 °C): δ = –102.4 (dd, JAB = 270.9, JHF
=
Pd/C 0.2 equiv.
Pd(OH)2/C
0.2 equiv.
Pd(OH)2/C
0.2 equiv.
3
7.6 Hz, 1 F), –115.3 (dd, JAB = 270.9, JHF = 20.2 Hz, 1 F) ppm.
IR (film): ν = 3355, 3063, 3021, 2916, 2853, 1705, 1597, 1454,
˜
918 cm–1. MS (EI): m/z (%) = 352 (6) [M + 1]+, 260 (6), 239 (6),
226 (9), 211 (9), 197 (100), 178 (11), 165 (12), 156 (35), 140 (30),
127 (14), 117 (18), 105 (65). C22H19ONF2: calcd. C 75.20, H 5.45,
N 3.99; found C 75.08, H 5.80, N 3.55.
4[e]
AcOEt
–
91[f]
[a] Reaction of a diastereomeric mixture of 5h. [b] 48% de. [c] 50%
de. [d] 62% de. [e] Reaction of the pure major diastereomer 5h. [f]
Yield of the crude product; silica gel chromatography gave isolated
8 (32%) and 9 (15%).
3-Benzylamino-2,2-difluoro-1-phenylpentan-1-one (4c): Procedure
with BF3·OEt2. Elution: ethyl acetate/cyclohexane, 2:98. Pale yel-
1
low liquid (208 mg, 46%). H NMR (250 MHz, CDCl3, 25 °C): δ
3
3
= 1.02 (t, JHH = 7.6 Hz, 3 H, 5-H), 1.63 (quint., JHH = 7.6 Hz, 2
(Ph), 141.9 (Ph), 170.5 (C-1Ј) ppm. IR (film): ν = 2957, 2929, 2857,
˜
3
3
3
1670, 1601, 1105 cm–1.
H, 4-H), 3.35 (ddt, JHF = 21.0, JHF = 8.0, JHH = 7.6 Hz, 1 H,
3-H), 2.10 (s, 1 H, NH), 3.42 (d, JAB = 13.2 Hz, 1 H, 1Ј-H), 3.76
(d, JAB = 13.2 Hz, 1 H, 1Ј-H), 7.25–7.47 (m, 8 H, Ph), 7.96 (d, 3JHH
= 7.3 Hz, 2 H, Ph) ppm. 13C NMR (62.89 MHz, CDCl3, 25 °C): δ
Imino Aldol Reaction – General Procedure
In situ Preparation of the Difluoroenoxysilane: A catalytic amount
of tetra-n-butylammonium difluorotriphenylstannate (54 mg,
0.08 mmol) was added to a solution of acylsilane 1 or 2 (1.5 mmol)
and (trifluoromethyl)trimethylsilane (0.30 mL, 2.0 mmol) in dry
CH2Cl2 (5 mL) at 0 °C under argon and protected from light. After
stirring for 5 min at 0 °C, the reaction mixture was stirred for
25 min at room temperature. The formation of the difluoroenoxysi-
lane was monitored by GC and was used in the next step in a one-
pot procedure.
2
= 13.7 (C-5), 21.5 (C-4), 50.3 (C-1Ј), 66.4 (t, JCF = 25.9 Hz, C-3),
1
118.6 (t, JCF = 258.0 Hz, C-2), 128.4, 128.5, 129.0, 129.5, 129.7,
129.9, 133.6, 135.8 (Ph), 190.3 (t, JCF = 29.0 Hz, C-1) ppm. 19F
2
NMR (235.36 MHz, CDCl3, 25 °C): δ = –104.1 (dd, JAB = 267.0,
3
3JHF = 8.0 Hz, 1 F), –114.4 (dd, JAB = 267.0, JHF = 21.0 Hz, 1
F) ppm. IR (film): ν = 3349, 3063, 3030, 2965, 2933, 1705, 1494,
˜
1125 cm–1.
Ethyl 2,2-Difluoro-3-oxo-1,3-diphenylpropylcarbamate (4d): Pro-
cedure with CF3SO3H. Elution: ethyl acetate/petroleum ether,
10:90. White solid (410 mg, 82%); m.p. 101 °C. 1H NMR
BF3·OEt2 Activation of the Imine: Imine 3 (1.8 mmol, 1.2 equiv.)
and BF3·OEt2 (0.38 mL, 0.38 mmol, 2 equiv.) were added to the
difluoroenoxysilane solution at –78 °C. The temperature was al-
lowed to rise slowly to room temperature. After stirring overnight
at room temperature, the reaction was quenched by addition of a
saturated NaHCO3 solution (10 mL). After extraction with CH2Cl2
(3×15 mL), the organic layer was washed with brine, dried with
3
(250 MHz, CDCl3, 25 °C): δ = 1.22 (t, JHH = 7.1 Hz, 3 H, CH3),
3
4.11 (q, JHH = 7.1 Hz, 2 H, CH2), 5.63 (m, 2 H, NH, 1-H), 7.26–
8.01 (m, 10 H, Ph) ppm. 13C NMR (62.89 MHz, CDCl3, 25 °C): δ
2
= 14.3 (CH3), 57.4 (t, JCF = 24.6 Hz, C-1), 61.5 (CH2), 116.6 (t,
1JCF = 259.9 Hz, C-2), 128.3, 128.5, 128.6, 129.8, 132.2, 133.8,
4308
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2005, 4304–4312

Synthesis of β-Amino-α,α-difluoro Ketones in a One-Pot Imino Aldol Reaction
FULL PAPER
2
134.4, 155.7 (Ph), 188.7 (t, JCF = 28.6 Hz, C-3) ppm. 19F NMR
C-7, C-6, C-5, C-4, C-3), 119.2 (dd, 1JCF = 308.1, 1JCF = 302.2 Hz,
3
2
(235.36 MHz, CDCl3, 25 °C): δ = –106.7 (d, JHF = 11.4 Hz, 2
C-1), 125.9, 130.2, 136.6, 144.1 (Ar), 196.4 (t, JCF = 24.1 Hz, C-
F) ppm. IR (film): ν = 3366, 2990, 1701, 1533, 1450, 1248,
2) ppm. 19F NMR (235.36 MHz, CDCl3, 25 °C): δ = –110.0 (d, JAB
= 228.9 Hz, 1 F), –113.8 (d, JAB = 228.9 Hz, 1 F) ppm. IR (film):
˜
1039 cm–1. MS (EI): m/z (%) = 334 (27) [M + 1]+, 313 (14), 240
(11), 178 (100), 140 (15), 105 (81). C18H17O3NF2: calcd. C 64.86, ν = 2926, 2855, 1744, 1595, 1462, 1146 cm–1.
˜
H 5.14, N 4.20; found C 64.80, H 4.93, N 4.16.
(SS)-2,2-Difluoro-1-phenyl-1-(p-tolylsulfinylamino)undecan-3-one
Ethyl 2,2-Difluoro-3-oxo-1-phenylundecylcarbamate (5d): Procedure
with CF3SO3H. Elution: ethyl acetate/petroleum ether 5:95. Orange
liquid (387 mg, 70%). 1H NMR (250 MHz, CDCl3, 25 °C): δ =
(5f): Procedure with Yb(OTf)3 (0.4 equiv.). Elution: diethyl ether/
petroleum ether, 4:96. Orange oil (33 mg, 5 %). 1H NMR
3
(250 MHz, CDCl3, 25 °C): δ = 0.88 (t, JHH = 6.7 Hz, 3 H, 11-H),
3
3
0.88 (t, JHH = 6.9 Hz, 3 H, CH3), 1.10–1.40 (m, 13 H, 6-H, 7-H,
1.25 (m, 10 H, 6-H, 7-H, 8-H, 9-H, 10-H), 1.55 (quint., JHH
=
8-H, 9-H, 10-H, 11-H), 1.47 (quint., 3JHH = 7.2 Hz, 2 H, 5-H), 2.46
3
6.7 Hz, 2 H, 5-H), 2.43 (s, 3 H, CH3), 2.58 (t, JHH = 6.7 Hz, 2 H,
3
3
3
3
(t, JHH = 7.2 Hz, 2 H, 4-H), 4.11 (q, JHH = 6.9 Hz, 2 H, CH2),
4-H), 5.16 (dd, JHF = 16.4, JHF = 7.4 Hz, 1 H, 1-H), 7.13–7.60
3
(m, 5 H, Ph) ppm. 19F NMR (235.36 MHz, CDCl3, 25 °C): δ =–
5.40 (m, 1 H, 1-H), 5.76 (d, JHH = 9.9 Hz, 1 H, NH), 7.35 (m, 5
H, Ph) ppm. 13C NMR (62.89 MHz, CDCl3, 25 °C): δ = 13.8
3
113.7 (dd, JAB = 270.8, JHF = 7.4 Hz, 1 F), –123.3 (dd, JAB
270.8, JHF = 16.4 Hz, 1 F) ppm. IR (film): ν = 2928, 2857, 1740,
=
3
(CH3), 14.2 (CH3), 22.1, 22.4, 28.5, 28.8, 29.0, 31.4, 31.5 (C-10, C-
˜
2
1597, 1458, 1146, 812 cm–1.
9, C-8, C-7, C-6, C-5, C-4), 56.3 (t, JCF = 25.1 Hz, C-1), 61.4
1
(CH2), 115.2 (t, JCF = 259.9 Hz, C-2), 128.2, 128.5, 128.6, 133.6
2
(Ph), 155.7 (CO), 200.9 (t, JCF = 28.5 Hz, C-3) ppm. 19F NMR
2,2-Difluoro-1,3-diphenyl-3-[(1R)-1-phenylethylamino]propan-1-one
(4g): Procedure with BF3·OEt2. Elution: diethyl ether/petroleum
ether, 3:97 (290 mg, 53%). Major diastereomer (R,R): Yellow li-
3
(235.36 MHz, CDCl3, 25 °C): δ = –113.2 (dd, JAB = 263.2, JHF
=
3
11.4 Hz, 1 F), –115.1 (dd, JAB = 263.2, JHF = 15.2 Hz, 1 F) ppm.
3
quid. 1H NMR (250 MHz, CDCl3, 25 °C): δ = 1.18 (d, JHH
=
IR (film): ν = 3314, 2917, 2853, 1705, 1529, 1462, 1404, 1244,
˜
3
1036 cm–1. MS (EI): m/z (%) = 370 (7) [M + 1]+, 251 (7), 209 (9),
179 (100), 162 (10), 150 (16), 140 (12), 134 (46). C20H29O3NF2:
calcd. C 65.02, H 7.91, N 3.79; found C 64.93, H 7.89, N 3.80.
6.5 Hz, 3 H, 2Ј-H), 2.18 (s, 1 H, NH), 3.78 (q, JHH = 6.5 Hz, 1 H,
3
3
1Ј-H), 4.68 (dd, JHF = 21.4, JHF = 6.9 Hz, 1 H, 3-H), 7.17–7.67
(m, 13 H, Ph), 8.14 (d, JHH = 7.3 Hz, 2 H, Ph) ppm. 13C NMR
3
(62.89 MHz, CDCl3, 25 °C): δ = 21.8 (C-2Ј), 54.9 (C-1Ј), 61.9 (t,
2JCF = 23.6 Hz, C-3), 118.1 (t, 1JCF = 258.9 Hz, C-2), 126.6, 126.8,
127.2, 128.4, 128.7, 129.6, 129.9, 130.5, 131.0, 133.6, 134.9, 145.1
tert-Butyl 2,2-Difluoro-3-oxo-1,3-diphenylpropylcarbamate (4e):
Procedure with Yb(OTf)3. Elution: ethyl acetate/petroleum ether
5:95. White solid (239 mg, 44%), m.p. 141 °C. 1H NMR (250 MHz,
CDCl3, 25 °C): δ = 1.41 (s, 9 H, CH3), 5.45–5.70 (m, 2 H, NH, 1-
2
(Ph), 191.0 (t, JCF = 28.2 Hz, C-2) ppm. 19F NMR (235.36 MHz,
3
CDCl3, 25 °C): δ = –101.4 (dd, JAB = 267.0, JHF = 6.9 Hz, 1 F),
3
H), 7.20–7.68 (m, 8 H, Ph), 8.01 (d, JHH = 8.0 Hz, 2 H, Ph) ppm.
3
–116.8 (dd, JAB = 267.0, JHF = 21.4 Hz, 1 F) ppm. IR (film): ν =
˜
13C NMR (62.89 MHz, CDCl3, 25 °C): δ = 28.2 (CH3), 57.2 (t,
2JCF = 23.6 Hz, C-1), 80.5 [C(CH3)3], 116.8 (t, 1JCF = 259.9 Hz, C-
2), 128.4, 128.6, 128.7, 129.9, 132.4, 134.0, 134.4 (Ph), 154.7 (CO),
3400, 2968, 2926, 1709, 1450, 1132 cm–1. MS (EI): m/z (%) = 366
(7) [M + 1]+, 350 (34), 240 (7), 210 (92), 194 (25), 156 (27), 140
(41), 120 (26). C23H21ONF2: calcd. C 75.60, H 5.79, N 3.83; found
C 75.79, H 5.71, N 3.74. Minor diastereomer (S,R): Yellow liquid.
2
188.9 (t, JCF = 28.5 Hz, C-3) ppm. 19F NMR (235.36 MHz,
CDCl3, 25 °C): δ = –106.1 (dd, JAB = 282.3, 3JHF = 7.6 Hz, 1 F), –
1H NMR (250 MHz, CDCl3, 25 °C): δ = 1.18 (d, JHH = 6.5 Hz, 3
H, 2Ј-H), 2.18 (s, 1 H, NH), 3.55 (q, JHH = 6.5 Hz, 1 H, 1Ј-H),
3
3
108.1 (dd, JAB = 282.3, JHF = 11.5 Hz, 1 F) ppm. IR (film): ν =
˜
3
3375, 2978, 2351, 1705, 1692, 1529, 1253, 1178 cm–1. MS (EI):
m/z (%) = 362 (0.1) [M + 1]+, 306 (7), 240 (16), 206 (100), 194 (10),
156 (25), 150 (35), 105 (13). C20H21O3NF2: calcd. C 66.47, H 5.86,
N 3.88; found C 66.62, H 5.77, N 3.69.
3
3
4.18 (dd, JHF = 22.1, JHF = 6.9 Hz, 1 H, 3-H), 6.91–7.70 (m, 13
H, Ph), 8.01 (d, JHH = 7.2 Hz, 2 H, Ph) ppm. 19F NMR
3
3
(235.36 MHz, CDCl3, 25 °C): δ = –101.7 (dd, JAB = 267.0, JHF
6.9 Hz, 1 F), –116.6 (dd, JAB = 267.0, JHF = 22.1 Hz, 1 F) ppm.
=
3
tert-Butyl 2,2-Difluoro-3-oxo-1-phenylundecylcarbamate (5e): Pro-
cedure with Yb(OTf)3. Elution: ethyl acetate/petroleum ether 2:98.
White solid (417 mg, 70%), m.p. 77 °C. 1H NMR (250 MHz,
2,2-Difluoro-1-phenyl-1-[(1R)-1-phenylethylamino]undecan-3-one
(5g): Procedure with BF3·OEt2. Elution: diethyl ether/petroleum
ether, 2:98 (499 mg, 83%). Major diastereomer (R,R): Yellow li-
3
CDCl3, 25 °C): δ = 0.88 (t, JHH = 6.5 Hz, 3 H, 11-H), 1.22 (m, 10
3
quid. 1H NMR (250 MHz, CDCl3, 25 °C): δ = 0.92 (t, JHH
=
H, 6-H, 7-H, 8-H, 9-H, 10-H), 1.42 (s, 9 H, CH3), 1.56 (m, 2 H, 5-
6.9 Hz, 3 H, 11-H), 1.10–1.45 (m, 13 H, 2Ј-H, 10-H, 9-H, 8-H, 7-
H, 6-H), 1.50–1.80 (m, 2 H, 5-H), 1.97 (s, 1 H, NH), 2.50–2.85 (m,
3
H), 2.49 (t, JHH = 6.9 Hz, 2 H, 4-H), 5.40 (m, 2 H, NH, 1-H),
7.36 (m, 5 H, Ph) ppm. 13C NMR (62.89 MHz, CDCl3, 25 °C): δ
3
3
2 H, 4-H), 3.70 (q, JHH = 6.5 Hz, 1 H, 1Ј-H), 4.40 (dd, JHF
=
= 14.0 (C-11), 22.3, 22.6, 28.2, 28.7, 29.0, 29.1, 31.7, 37.6 (CH3, C-
22.9, JHF = 7.6 Hz, 1 H, 1-H), 7.15–7.50 (m, 10 H, Ph) ppm. 13C
NMR (62.89 MHz, CDCl3, 25 °C): δ = 14.2 (C-11), 21.8 (C-2Ј),
22.6, 22.7, 29.0, 29.2, 31.9, 38.4 (C-10, C-9, C-8, C-7, C-6, C-5),
3
2
10, C-9, C-8, C-7, C-6, C-5, C-4), 56.1 (t, JCF = 31.8 Hz, C-1),
80.6 [C(CH3)3], 115.4 (t, 1JCF = 259.8 Hz, C-2), 128.3, 128.7, 128.8,
2
133.8 (Ph), 154.7 (CO), 200.1 (t, JCF = 29.2 Hz, C-3) ppm. 19F
55.0 (C-1Ј), 61.2 (dd, 2JCF = 27.6, JCF = 21.7 Hz, C-1), 117.0 (dd,
2
NMR (235.36 MHz, CDCl3, 25 °C): δ = –113.0 (dd, JAB = 263.2,
1JCF = 259.9, JCF = 256.0 Hz, C-2), 126.6, 127.4, 128.6, 134.8,
1
3
3JHF = 7.6 Hz, 1 F), –116.1 (dd, JAB = 263.2, JHF = 15.3 Hz, 1
2
2
145.3 (Ph), 202.8 (dd, JCF = 32.5 Hz JCF = 25.6 Hz, C-3) ppm.
F) ppm. C22H33O3NF2: calcd. C 66.47, H 8.37, N 3.52; found C
66.48, H 8.31, N 3.20.
19F NMR (235.36 MHz, CDCl3, 25 °C): δ = –107.6 (dd, JAB
=
=
3
3
255.6, JHF = 7.6 Hz, 1 F), –124.5 (dd, JAB = 255.6, JHF
1,1-Difluoro-1-(p-tolylsulfinyl)decan-2-one (6): Procedure with
22.9 Hz, 1 F) ppm. IR (film): ν = 2928, 2859, 1742, 1455,
˜
Yb(OTf)3 (0.4 equiv.). Elution: diethyl ether/petroleum ether, 4:96.
1130 cm–1. MS (EI): m/z (%) = 402 (7) [M + 1]+, 212 (5), 210 (20),
1
Orange liquid (64 mg, 13%). H NMR (250 MHz, CDCl3, 25 °C): 123 (10), 122 (100), 120 (40), 106 (24). C25H33ONF2: calcd. C
3
δ = 0.86 (t, JHH = 6.5 Hz, 3 H, 11-H), 1.25 (m, 10 H, 6-H, 7-H,
74.78, H 8.28, N 3.49; found C 74.56, H 8.50, N 3.23. Minor dia-
8-H, 9-H, 10-H), 1.52 (m, 2 H, 5-H), 2.44 (s, 3 H, CH3), 2.58 (m, stereomer (S,R): Yellow liquid. 1H NMR (250 MHz, CDCl3,
2 H, 4-H), 7.37 (d, 3JHH = 8.0 Hz, 2 H, Ar), 7.56 (d, 3JHH = 8.0 Hz, 25 °C): δ = 0.92 (t, JHH = 6.9 Hz, 3 H, 11-H), 1.10–1.45 (m, 13
3
2 H, Ar) ppm. 13C NMR (62.89 MHz, CDCl3, 25 °C): δ = 14.1 (C-
H, 2Ј-H, 10-H, 9-H, 8-H, 7-H, 6-H), 1.50–1.80 (m, 2 H, 5-H), 1.97
3
10), 21.7 (CH3), 22.2, 22.7, 28.8, 29.1, 29.3, 31.8, 40.5 (C-9, C-8,
(s, 1 H, NH), 2.50–2.85 (m, 2 H, 4-H), 3.52 (q, JHH = 6.5 Hz, 1
Eur. J. Org. Chem. 2005, 4304–4312
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4309

S. Jonet, F. Cherouvrier, T. Brigaud, C. Portella
FULL PAPER
3
3
3
3
H, 1Ј-H), 3.89 (dd, JHF = 22.9, JHF = 7.6 Hz, 1 H, 1-H), 7.15– JAB = 266, JHF = 12 Hz, 1 F), –114.3 (dd, JAB = 266, JHF
=
7.50 (m, 10 H, Ph) ppm. 19F NMR (235.36 MHz, CDCl3, 25 °C):
17 Hz, 1 F) ppm. IR (film): ν = 3450, 2928, 2854, 1738, 1455, 1111,
˜
3
1
δ = –108.3 (dd, JAB = 255.6, JHF = 7.6 Hz, 1 F), –124.1 (dd, JAB
1038 cm–1. Minor diastereomer (as a cyclic hemiacetal): H NMR
3
= 255.6, JHF = 22.9 Hz, 1 F) ppm.
(250 MHz, CDCl3, 25 °C): δ = 0.83–0.89 (m, 3 H, 13-H), 0.97 (d,
3JHH = 7.3 Hz, 3 H, 1-H), 1.05 (d, 3JHH = 6.6 Hz, 3 H, CH3), 1.06–
1.40 (m, 12 H, 12-H, 11-H, 10-H, 9-H, 8-H, 7-H), 1.42 (s, 2 H,
NH, OH), 1.66 (m, 2 H, 6-H), 1.82 (m, 1 H, 2-H), 3.10 (m, 1 H,
4,4-Difluoro-2-methyl-3-[(1R)-1-phenylethylamino]tridecan-5-one
(5h): Procedure with BF3·OEt2. Elution: diethyl ether/petroleum
ether, 1:99 (303 mg, 55%). Major diastereomer: Yellow liquid. [α]
3
3
3-H), 3.60 (dd, JHH = 11.1, JHH = 4 Hz, 1 H, 2Ј-H), 3.75 (dd,
20
1
= +0.8 (c = 1.0, CHCl3). H NMR (250 MHz, CDCl3, 25 °C): δ
3
3
3JHH = 12.3, JHH = 4 Hz, 1 H, 2Ј-H), 4.12 (dd, 3JHH = 12.3, JHH
= 11.1 Hz, 1 H, 1Ј-H), 7.24–7.37 (m, 5 H, Ph) ppm. 13C NMR
(62.89 MHz, CDCl3, 25 °C): δ = 14.5 (C-13), 28.4 (CH3), 28.5
(CH3), 28.6 (C-2), 29.6 (C-12), 29.7 (C-11), 29.8 (C-10), 29.9 (C-9),
31.7 (C-8), 33.5 (C-7), 37.9 (C-6), 68.0 (C-1Ј), 68.7 (C-2Ј), 71.2 (dd,
D
= 0.80–1.00 (m, 9 H, 1-H, 2Ј-H, CH3), 1.20–1.40 (m, 13 H, 13-H,
12-H, 11-H, 10-H, 9-H, 8-H), 1.47 (s, 1 H, NH), 1.66 (m, 2 H, 7-
3
3
H), 1.88 (dsept, JHH = 6.9, JHH = 3.4 Hz, 1 H, 2-H), 2.5 (m, 2
3
3
3
H, 6-H), 3.06 (ddd, JHF = 19.5, JHF = 11.5, JHH = 3.4 Hz, 1 H,
3
3-H), 3.94 (q, JHH = 6.5 Hz, 1 H, 1Ј-H), 7.20–7.50 (m, 5 H,
2
2
2JCF = 34.0, JCF = 24.5 Hz, C-3), 100.6 (t, JCF = 28.3 Hz, C-5),
Ph) ppm. 13C NMR (62.89 MHz, CDCl3, 25 °C): δ = 14.0 (C-13),
17.3 (CH3), 21.0 (CH3), 22.6 (C-12), 23.4 (C-2Ј), 27.8 (C-11), 29.0
(C-10), 29.1 (C-9), 29.3 (C-8), 31.8 (C-7), 38.3 (C-6), 56.6 (C-1Ј),
1
121.1 (t, JCF = 258.5 Hz, C-4), 127.7, 128.5, 129.0, 138.7
(Ph) ppm. 19F NMR (235.36 MHz, CDCl3, 25 °C): δ = –107.6 (dd,
3
3
JAB = 246, JHF = 10 Hz, 1 F), –122.2 (dd, JAB = 246, JHF
=
2
2
1
60.1 (dd, JCF = 24.6, JCF = 20.7 Hz, C-3), 119.4 (t, JCF
=
=
20 Hz, 1 F) ppm.
2
258.9 Hz, C-4), 127.0, 127.2, 128.4, 137.2 (Ph), 203.4 (dd, JCF
2
31.5, JCF = 26.6 Hz, C-5) ppm. 19F NMR (235.36 MHz, CDCl3,
3-[(1R)-2-tert-Butyldimethylsilyloxy-1-phenylethylamino]-2,2-di-
fluoro-4-methyl-1-phenylpentan-1-one (4j): Procedure with
BF3·OEt2. Elution: ethyl acetate/cyclohexane, 2:98 (372 mg, 54%).
3
25 °C): δ = –108.9 (dd, JAB = 255.6, JHF = 11.5 Hz, 1 F), –117.5
3
(dd, JAB = 255.6, JHF = 19.5 Hz, 1 F) ppm. IR (film): ν = 2930,
˜
2859, 1742, 1468, 1456, 1130, 1049 cm–1. MS (EI): m/z (%) = 368
Major diastereomer: Yellow liquid. 1H NMR (250 MHz, CDCl3,
3
(31) [M + 1]+, 328 (5), 246 (15), 176 (35), 123 (8), 122 (100), 120
25 °C): δ = 0.07 (s, 6 H, CH3), 0.92 (s, 9 H, CH3), 1.11 (d, JHH
=
3
(42). Minor diastereomer: 19F NMR (235.36 MHz, CDCl3, 25 °C):
4.5 Hz, 3 H, 5-H), 1.12 (d, JHH = 4.5 Hz, 3 H, 5-H), 1.70 (dsept,
δ = –107.2 (dd, JAB = 255.6, JHF = 7.6 Hz, 1 F), –122.2 (dd, JAB 3JHH = 4.5, JHH = 2.9 Hz 1 H, 4-H), 2.50 (m, 1 H, NH), 3.23
3
3
3
3
3
3
= 255.6, JHF = 26.7 Hz, 1 F) ppm.
(ddd, JHF = 18.0, JHF = 12.0, JHH = 2.9 Hz 1 H, 3-H), 3.59 (m,
3
3
2 H, 2Ј-H), 4.29 (dd, JHH = 6.5, JHH = 4.5 Hz, 1 H, 1Ј-H), 7.24–
7.47 (m, 8 H, Ph), 8.00 (d, 3JHH = 6.5 Hz, 2 H, Ph) ppm. 13C NMR
(62.89 MHz, CDCl3, 25 °C): δ = –5.40 (CH3), 16.3 (C-3Ј), 19.8 (C-
3Ј), 18.1 [C(CH3)3], 21.8 (CH3), 28.6 (C-4), 60,61 (t, 2JCF = 19.0 Hz,
C-3), 62.9 (C-1Ј), 68.3 (C-2Ј), 121.1 (t, 1JCF = 257.0 Hz, C-2), 128.2
2,2-Difluoro-3-[(1R)-2-hydroxy-1-phenylethylamino]-4-methyl-1-
phenylpentan-1-one (4i): Procedure with BF3·OEt2. Elution: ethyl
acetate/cyclohexane, 20:80 (320 mg, 63 %). Major diastereomer:
Yellow liquid. 1H NMR (250 MHz, CDCl3, 25 °C): δ = 0.78 (d,
3JHH = 6.9 Hz, 3 H, 5-H), 0.91 (d, JHH = 6.9 Hz, 3 H, 5-H), 1.85
3
2
(Ph), 128.5 (Ph), 128.6 (Ph), 141.9 (Ph), 190.4 (t, JCF = 31.9 Hz
3
3
(dsept, JHH = 6.9, JHH = 2.9 Hz 1 H, 4-H), 2.22 (m, 2 H, NH,
2JCF = 29.8 Hz, C-1) ppm. 19F NMR (235.36 MHz, CDCl3, 25 °C):
3
3
OH), 3.28 (td, JHF = 15.0, JHH = 2.9 Hz 1 H, 3-H), 3.53 (m, 2
H, 2Ј-H), 4.01 (m, 1 H, 1Ј-H), 7.24–7.44 (m, 8 H, Ph), 7.98 (d, 3JHH
= 6.5 Hz, 2 H, Ph) ppm. 13C NMR (62.89 MHz, CDCl3, 25 °C): δ
3
δ = –100.1 (dd, JAB = 268, JHF = 12 Hz, 1 F), –109.5 (dd, JAB
=
268, 3JHF = 18 Hz, 1 F) ppm. IR (film): ν = 3066, 2954, 2928, 1703,
˜
1467, 1254 cm1. Minor diastereomer (selected data): 19F NMR
2
= 16.7 (C-5), 20.7 (C-5), 28.3 (C-4), 61.2 (t, JCF = 20.6 Hz, C-3),
63.4 (C-1Ј), 67.1 (C-2Ј), 120.7 (t, JCF = 258.0 Hz, C-2), 126.9,
3
(235.36 MHz, CDCl3, 25 °C): δ = –100.2 (dd, JAB = 261, JHF
=
1
3
6 Hz, 1 F), –115.8 (dd, JAB = 261, JHF = 24 Hz, 1 F) ppm.
2
127.4, 127.8, 128.4, 128.5, 132.8, 134.1, 140.4 (Ph), 190.9 (t, JCF
= 28.5 Hz, C-1) ppm. 19F NMR (235.36 MHz, CDCl3, 25 °C): δ
Hydrogenolysis of 5h: A solution of 5h (368 mg, 1 mmol, dia-
3
= –104.9 (dd, JAB = 270, JHF = 15 Hz, 1 F), –106.5 (dd, JAB
=
stereomeric mixture) in MeOH (10 mL) was stirred under hydrogen
270, 3JHF = 15 Hz, 1 F) ppm. IR (film): ν = 3364, 2966, 2879, 1765, in the presence of Pd(OH)2/C (280 mg, 0.2 mmol) (or Pd/C,
˜
1449, 1107 cm–1. MS (EI): m/z (%) = 316 (47) [M – 31]+, 176 (25), 0.2 equiv.). The reaction was monitored by GC and the reaction
105 (100), 91 (23), 77 (35). Minor diastereomer (as a mixture of two
mixture was filtered through Celite. The solvent was evaporated
under reduced pressure and the crude product was purified by col-
umn chromatography over silica gel (elution: diethyl ether/petro-
leum ether, 50:50) to give the amino alcohol 7 (141 mg, 53%) as a
81:19 mixture of two diastereomers.
cyclic hemiacetals, selected data): 19F NMR (235.36 MHz, CDCl3,
3
25 °C): δ = –101.2 (dd, JAB = 250, JHF = 13 Hz, 1 F), –102.8 (dd,
JAB = 266, 3JHF = 9 Hz, 1 F), –111.9 (dd, JAB = 266, 3JHF = 20 Hz,
3
1 F), –121.1 (dd, JAB = 250, JHF = 20 Hz, 1 F) ppm.
4,4-Difluoro-3-[(1R)-2-hydroxy-1-phenylethylamino]-2-methyltride- 3-Amino-4,4-difluoro-2-methyltridecan-5-ol (7): Major dia-
1
can-5-one (5i): Procedure with BF3·OEt2. Elution: ethyl acetate/cy-
stereomer: Yellow liquid. H NMR (250 MHz, CDCl3, 25 °C): δ =
3
clohexane, 10:90 (420 mg, 73 %). Major diastereomer: Yellow li-
0.86 (t, 3JHH = 6.9 Hz, 3 H, 13-H), 0.96 (d, JHH = 6.9 Hz, 3 H, 1-
H), 0.98 (d, JHH = 6.9 Hz, 3 H, CH3), 1.15-1.45 (m, 13 H, 12-H,
3
3
quid. 1H NMR (250 MHz, CDCl3, 25 °C): δ = 0.81 (d, JHH
=
6.9 Hz, 3 H, 1-H), 0.83–0.89 (m, 6 H, 13-H, CH3), 1.06–1.40 (m, 11-H, 10-H, 9-H, 8-H, 7-H, OH), 1.55-1.70 (m, 2 H, 6-H), 2.09
3
3
12 H, 12-H, 11-H, 10-H, 9-H, 8-H, 7-H), 1.42 (m, 2 H, NH, OH), (dsept, JHH = 6.9, JHH = 2.7 Hz, 1 H, 2-H), 2.50–2.90 (m, 2 H,
3
3
3
1.66 (m, 2 H, 6-H), 1.82 (m, 1 H, 2-H), 2.67 (t, JHH = 7.1 Hz, 1
NH2), 3.04 (dt, JHF = 22.9, JHH = 5.0 Hz, 1 H, 3-H), 3.70–3.95
(m, 1 H, 5-H) ppm. 13C NMR (62.89 MHz, CDCl3, 25 °C): δ =
14.0 (C-13), 16.9 (CH3), 20.8 (CH3), 22.6 (C-12), 25.7 (C-2), 29.2
3
H, 2Ј-H), 3.10 (m, 1 H, 3-H), 3.58 (t, JHH = 7.1 Hz, 1 H, 2Ј-H),
3
3.92 (t, JHH = 7.1 Hz, 1 H, 1Ј-H), 7.24–7.27 (m, 5 H, Ph) ppm.
13C NMR (62.89 MHz, CDCl3, 25 °C): δ = 14.0 (C-13), 28.4 (CH3), (C-11), 29.4 (C-10), 29.5 (C-9), 30.7 (C-8), 30.8 (C-7), 31.8 (C-6),
28.5 (CH3), 29.3 (C-2), 29.5 (C-12), 29.7 (C-11), 29.8 (C-10), 29.9 57.6 (dd, 2JCF = 27.6, 2JCF = 24.6 Hz, C-3), 72.9 (t, 2JCF = 28.5 Hz,
2
(C-9), 31.7 (C-8), 31.8 (C-7), 37.9 (C-6), 60.5 (t, JCF = 22.8 Hz,
C-5), 122.8 (t, 1JCF = 251.0 Hz, C-4) ppm. 19F NMR (235.36 MHz,
CDCl3, 25 °C): δ = –116.4 (dd, JAB = 263.2, JHF = 15.3 Hz, 1
C-3), 64.1 (C-1Ј), 67.6 (C-2Ј), 119.1 (t, 1JCF = 258.5 Hz, C-4), 126.9,
3
127.9, 128.5, 140.6 (Ph), 203.5 (dd, 2JCF = 31.9 Hz 2JCF = 28.1 Hz, F), –118.7 (dd, JAB = 263.2, JHF = 22.9 Hz, 1 F) ppm. IR (film):
3
C-5) ppm. 19F NMR (235.36 MHz, CDCl3, 25 °C): δ = –109.6 (dd,
ν = 3378, 3310, 2924, 2857, 1736, 1595, 1468, 1082 cm–1. MS (EI):
˜
4310
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2005, 4304–4312

Synthesis of β-Amino-α,α-difluoro Ketones in a One-Pot Imino Aldol Reaction
FULL PAPER
m/z (%) = 266 (17) [M + 1]+, 100 (26), 88 (31), 74 (40), 72 (100).
[2]
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The sulfinylimine 3f was prepared according to a literature pro-
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G. H. Posner, Org. Synth. 1986, 64, 196–206; b) G. Solladié, J.
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2785–2792; d) K. Hattori, M. Miyata, H. Yamamoto, J. Am.
Chem. Soc. 1993, 115, 1151–1152.
2
Minor diastereomer (selected data): 13C NMR: δ = 59.6 (dd, JCF
2
2
2
= 23.6, JCF = 28.6 Hz), 74.3 (dd, JCF = 30.5, JCF = 25.6 Hz),
122.8 (t, JCF = 251.0 Hz) ppm. 19F NMR: δ = –131.4 (dt, JAB
255.6, JHF = 22.9 Hz, 1 F), –115.1 (d, JAB = 255.6 Hz, 1 F) ppm.
=
1
3
The same procedure as above but in anhydrous EtOAc and with
pure major diastereomer 5h (368 mg, 1 mmol) in the presence of
Pd(OH)2/C (280 mg, 0.2 mmol) gave 8 (239 mg, 91%). Purification
by column chromatography over silica gel (elution: diethyl ether/
petroleum ether, 15:85) gave pure amino ketone 8 (84 mg, 32%)
and 9 (76 mg, 15%).
[3]
[4]
[5]
[6]
[7]
[8]
[9]
3-Amino-4,4-difluoro-2-methyltridecan-5-one (8): Colorless liquid.
3
1H NMR (250 MHz, CDCl3, 25 °C): δ = 0.87 (t, JHH = 6.5 Hz, 3
H, 13-H), 0.93 (d, 3JHH = 6.9 Hz, 3 H, 1-H), 1.00 (d, 3JHH = 6.9 Hz,
3 H, CH3), 1.13–1.43 (m, 12 H, 12-H, 11-H, 10-H, 9-H, 8-H, NH2),
3
3
1.61 (quint., JHH = 6.9 Hz, 2 H, 7-H), 1.96 (dsept, JHH = 6.9,
3JHH = 3.1 Hz, 1 H, 2-H), 2.67 (t, JHH = 6.9 Hz, 2 H, 6-H), 3.11
3
(ddd, 3JHF = 20.6, 3JHF = 11.4, 3JHH = 3.1 Hz, 1 H, 3-H) ppm. 13
C
NMR (62.89 MHz, CDCl3, 25 °C): δ = 14.0 (C-13), 16.4 (CH3),
20.8 (CH3), 22.6 (C-2), 27.6 (C-12), 28.8 (C-11), 28.9 (C-10), 29.0
(C-9), 29.1 (C-8), 31.7 (C-7), 37.7 (C-6), 57.1 (dd, 2JCF = 24.6, 2JCF
1
2
= 21.7 Hz, C-3), 118.1 (t, JCF = 256.9 Hz, C-4), 202.8 (dd, JCF
=
32.5, JCF = 28.5 Hz, C-5) ppm. 19F NMR (235.36 MHz, CDCl3,
25 °C): δ = –112.7 (dd, JAB = 267.0, JHF = 11.4 Hz, 1 F), –120.4
2
3
[10]
[11]
3
(dd, JAB = 267.0, JHF = 20.6 Hz, 1 F) ppm. IR (film): ν = 3418,
˜
2928, 2859, 1742, 1740, 1373, 1217, 1047 cm–1. MS (EI): m/z (%)
= 264 (11) [M + 1]+, 74 (30), 72 (100).
3-[1-(2-Amino-1,1-difluoro-3-methylbutyl)nonylideneamino]-4,4-di-
fluoro-2-methyltridecan-5-one (9): Colourless liquid. 1H NMR
(250 MHz, CDCl3, 25 °C): δ = 0.87 (t, 3JHH = 6.9 Hz, 6 H, 2 CH3),
3
3
0.94 (d, JHH = 6.9 Hz, 6 H, 2 CH3), 1.01 (d, JHH = 6.9 Hz, 6 H,
2 CH3), 1.15–1.42 (m, 22 H, 10 CH2, NH2), 1.45–1.65 (m, 4 H, 2
CH2), 1.95–2.25 [m, 2 H, 2 CH(CH3)2], 2.25–2.45 (m, 2 H CH2CN),
[12]
[13]
3
3
2.50–2.75 (m, 2 H CH2CO), 3.26 (ddd, JHF = 19.7, JHF = 11.4,
3JHH = 3.1 Hz, 1 H, CHN), 3.85–4.00 (m, 1 H, CHNH2) ppm. 13C
NMR (62.89 MHz, CDCl3, 25 °C): δ = 14.0–38.2 [22 C, 6 CH3, 14
CH2, 2 CH(CH3)2], 59.9 (dd, JCF = 27.6, JCF = 24.6 Hz,
CHNH2), 66.7 (t, JCF = 22.6 Hz, CHNH2),118.1 (t, JCF
2
2
2
1
=
=
F
1
2
256.9 Hz, CF2), 121.0 (t, JCF = 251.0 Hz, CF2), 172.1 (dd, JCF
30.5, 2JCF = 28.5 Hz, CN), 202.2 (t, 2JCF = 29.5 Hz, CO) ppm. 19
[14]
[15]
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NMR (235.36 MHz, CDCl3, 25 °C): δ = –107.8 (dd, JAB = 270.9,
3
3JHF = 11.4 Hz, 1 F), –109.6 (dd, JAB = 263.2, JHF = 11.4 Hz, 1
3
F), –111.5 (dd, JAB = 270.9, JHF = 19.7 Hz, 1 F), –113.4 (dd, JAB
[16]
[17]
[18]
[19]
= 263.2, 3JHF = 15.3 Hz, 1 F) ppm. IR (film): ν = 2928, 2857, 1477,
˜
1672, 1468, 1372, 1039 cm–1.
Acknowledgments
The authors thank Bayer A.G. (Dr A. Marhold) for a gift of (tri-
fluoromethyl)trimethylsilane, and H. Bailla and S. Lanthony for
their technical assistance in the analytical aspects.
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Eur. J. Org. Chem. 2005, 4304–4312
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4311

S. Jonet, F. Cherouvrier, T. Brigaud, C. Portella
FULL PAPER
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Received: February 8, 2005
Published Online: September 1, 2005
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© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2005, 4304–4312