Diethylzinc-mediated addition of 2,2-dibromo-2-fluoroacetamides to carbonyl compounds: Synthesis of α-bromo-α-fluoro-β-hydroxy amides and/or (Z)-fluorovinyl amides

Article abstract of DOI:10.1002/ejoc.201300140

We describe straightforward routes either to α-bromo-α-fluoro- β-hydroxy amides or to (Z)-α-fluoroacrylamides starting from aldehydes, ketones or imine and 2,2-dibromo-2-fluoroacetamides. Depending on the nature of the amide, these diethylzinc-mediated additions to aldehydes, ketones or imine afford selective access either to bromofluorohydrins or to (Z)-α-fluoroacrylamides. The corresponding products were obtained in moderate to very good yields and the configurations of both products were confirmed by X-ray analyses. Reactions between aldehydes, ketones or imines and 2,2-dibromo-2-fluoroacetamides, a new class of fluorinated reagent, allow straightforward selective access to α-bromo-α-fluoro-β-hydroxy amides and/or (Z)-α-fluoroacrylamides with moderate to excellent yields. Copyright

Full text of DOI:10.1002/ejoc.201300140

FULL PAPER
DOI: 10.1002/ejoc.201300140
Diethylzinc-Mediated Addition of 2,2-Dibromo-2-fluoroacetamides to Carbonyl
Compounds: Synthesis of α-Bromo-α-fluoro-β-hydroxy Amides and/or
(Z)-Fluorovinyl Amides
Gérald Lemonnier,[a] Thomas Poisson,[a] Samuel Couve-Bonnaire,[a] Philippe Jubault,[a] and
Xavier Pannecoucke*[a]
Keywords: Synthetic methods / Fluorine / Olefination / Aldehydes
We describe straightforward routes either to α-bromo-α-
or imine afford selective access either to bromofluorohydrins
fluoro-β-hydroxy amides or to (Z)-α-fluoroacrylamides start- or to (Z)-α-fluoroacrylamides. The corresponding products
ing from aldehydes, ketones or imine and 2,2-dibromo-2-
fluoroacetamides. Depending on the nature of the amide,
these diethylzinc-mediated additions to aldehydes, ketones
were obtained in moderate to very good yields and the con-
figurations of both products were confirmed by X-ray analy-
ses.
Introduction
allylic alcohols, α,β-unsaturated ketones, aldehydes or
imines.[5] However, the direct olefination of carbonyl com-
pounds to afford highly valuable α-fluorinated α,β-unsatu-
rated amides has been scarcely reported to date.[6] The
methods used have basically involved Pd-catalysed conden-
sation of fluoroiodomethylpiperidino ketone on alde-
hydes,[7] a two-step addition of tetrafluoroethane (HFC-
134a) onto aldehydes,[8] or Julia–Kocienski olefination of
aldehydes and ketones with the aid of a well-designed pre-
synthesized fluorinated reagent.[9] Nevertheless, despite
their synthetic utility, these methodologies can suffer from
several issues such as narrow substrate scope, the presence
of inseparable E/Z isomers, moderate yields and/or the need
for a multistep preparation of the fluorinated reagent. To
overcome these major drawbacks, we turned our attention
to 2,2-dibromo-2-fluoroacetamides as fluorinated precur-
sors. Surprisingly, despite their potential to achieve more
convergent access to α-fluorinated acetamide derivatives,
only a single example of the use of such reagents has, to the
best of our knowledge, been reported in the literature:
Ando and co-workers described the preparation of α-
bromo-α-fluoro-β-hydroxyamides as non-isolated interme-
diates through Et2Zn-mediated addition of N-benzyl-2,2-di-
bromo-2-fluoroacetamide to a few aromatic aldehydes in
the presence of Wilkinson’s catalyst.[10] Inspired by our re-
cent work dealing with the direct conversion of carbonyl
compounds either into α-bromo-α-fluoro-β-hydroxy es-
ters[4g] or into (Z)-acrylates,[4i] here we report the use of
secondary and tertiary 2,2-dibromo-2-fluoroacetamides as
fluorine sources, thus furnishing access to α-bromo-α-
fluoro-β-hydroxy amides and/or fluorinated (Z)-acrylamide
derivatives (Scheme 1).
Physical, chemical and biological properties of a mole-
cule can be modulated by judicious introduction of a fluor-
ine atom.[1] Consequently, for the past decades, fluorine-
containing molecules have received considerable attention
for the development of new technologies and biologically
active compounds.[2] In view of the unique features of fluor-
ine, it is not surprising that about 20% of pharmaceutical
compounds and 40% of agrochemicals contain at least one
fluorine atom.
Although fluorine is quite abundant on earth, fluoroor-
ganic compounds are scarce in nature, and one of the most
efficient means to access such compounds involves the use
of fluorinated building blocks prepared from commercially
available fluorinated precursors.[3] In that context, our
group have developed several methodologies for the synthe-
sis of monofluorinated scaffolds.[4] One of our approaches
was based on Et2Zn- or Zn-mediated addition of commer-
cially available ethyl dibromofluoroacetate, affording
straightforward access to fluoroacrylates,[4j] α-bromo-α-
fluoro-β-hydroxy esters,[4h] fluoroepoxides[4i] and fluorocy-
clopropanes.[4c–4e]
In addition, α,β-unsaturated amides are valuable syn-
thetic intermediates that can lead, through one-step reac-
tions, to various functional groups such as allylic amines,
[a] Normandie Univ., COBRA, UMR 6014 et FR 3038; Univ.
Rouen, INSA Rouen, CNRS,
1 rue Tesnière, 76821 Mont Saint-Aignan Cedex, France
Fax: +33-2-35522959
E-mail: xavier.pannecoucke@insa-rouen.fr
Homepage: http://www.normandie-univ.fr
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300140
3278
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 3278–3289

Synthesis of Fluorinated Amides
Although the addition of the secondary amide 2 occurs
without diastereoselectivity, this methodology can be suc-
cessfully applied to a wide range of carbonyl compounds
with good yields (Table 2). Electron-rich aromatic aldehydes
were suitable partners in this process and the corresponding
α-bromo-α-fluoro-β-hydroxy amides were isolated in excel-
lent yields (Entries 1–3). Pleasingly, chlorinated aldehydes
were compatible and afforded the corresponding adducts in
fairly good yields (Entries 4–5). Aromatic aldehydes bearing
electron-withdrawing groups such as ester or nitrile groups
were also tolerated (Entries 6–7), as was a heteroaromatic
backbone (Entry 8). Interestingly, substituted α,β-unsatu-
rated aldehydes (Entry 9) and aliphatic aldehydes (En-
tries 10–11) afforded the corresponding fluorinated prod-
ucts in moderate to good yields. Finally, ketones were toler-
ated well in this process, thus giving straightforward access
to fluorinated building blocks containing two contiguous
quaternary centres (Entries 12 and 13).
Scheme 1. Synthesis of fluorinated building blocks.
Results and Discussion
Initially, we examined the reactivity of the secondary
amide 2 toward aromatic aldehydes 1a and 1b (Table 1).
From our previous results with ethyl dibromofluoroacetate
as a versatile fluorinated reagent,[4c–4j] we assumed that
Et2Zn-mediated addition of the amide 2 to a carbonyl com-
pound might result in the formation of an alcohol of type
3 and/or an olefin of type 4. With a slight excess of reac-
tants,[11] the electron-rich aldehyde 1a exclusively furnished
the alcohol 3a, albeit in low yield, as an equimolar mixture
of diastereoisomers (Entry 1). An increase in reaction time
was ineffective to improve the yield (Entry 2), whereas the
use of a larger excess of Et2Zn resulted in the partial forma-
tion of olefin 4a (Entry 3). After a survey of the stoichiome-
try of the reaction, we were pleased to observe that the alde-
hyde 1a was fully converted into 3a with the use of 3 equiva-
lents of amide 2 and 6 equiv. of Et2Zn (Entries 4–6). In the
case of a more electrophilic aldehyde such as benzaldehyde
(1b), only 2 equiv. of amide 2 and 4 equiv. of Et2Zn were
required to ensure complete conversion into the alcohol 3b
(Entries 7–8).
Table 2. Synthesis of α-bromo-α-fluoro-β-hydroxy amides 3.[a]
Table 1. Reactivity of N-benzyl-2,2-dibromo-2-fluoroacetamide.
En-
try
Amide Et2Zn
t
3/4
syn-3/anti-
Yield
[%][b]
equiv. equiv. [h] ratio[a] 3 ratio[a]
[a] Reactions performed in CH2Cl2 at room temp. for 2 h;
Method A: 1/2/Et2Zn 1:2:4; Method B: 1/2/Et2Zn 1:3:6. [b] Deter-
mined by 19F NMR examination of the crude mixtures. [c] Only
the syn diastereoisomer was isolated.
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1b
1b
1.1
1.5
2.0
1.5
2.0
3.0
2.0
3.0
2.2
3.0
5.0
3.0
4.0
6.0
4.0
6.0
2
100:0
56:44
58:42
n.d.
56:44
55:45
55:45
57:43
57:43
43
66
40
60
16 100:0
16 72:28
2
2
2
2
2
100:0
100:0
100:0
100:0
100:0
77
99 (92)[c]
99 (85)[c]
99
Moreover, this methodology was also successfully ap-
plied to the N-tosylimine 5 (Scheme 2). Although the ad-
duct 6 was obtained with a modest yield and poor dia-
stereoselectivity, this represents the first example of a one-
step synthesis of an α-bromo-α-fluoro-β-amino amide.
[a] Determined by 19F NMR examination of the crude mixtures.
[b] Determined by 19F NMR with trifluorotoluene as an internal
standard. [c] Isolated yields.
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X. Pannecoucke et al.
FULL PAPER
achieve full consumption of the alcohol anti-9ad,[12] with an
excellent global yield (96% isolated yield, Entry 7).
In order to evaluate the influence of amide substituents
on this process, various dibromofluoroacetamides were syn-
thesized[13] and engaged in reaction with 4-chlorobenzalde-
hyde (1d, Table 3). N-Dibromofluoroacetylpiperidine (7b,
Entry 8) and the corresponding diethylamide 7c (Entry 9)
gave the corresponding olefin (Z)-8d and alcohol syn-9d in
good but somewhat lower yields. Surprisingly, the corre-
sponding N-benzylmethyl amide 7d and Weinreb amide 7e
gave poorer results. Indeed, these two substrates either were
unreactive or fully decomposed under the standard condi-
tions (Entries 10–11). For comparison with fluorinated es-
ters, when 1d was engaged in the olefination reaction with
ethyl dibromofluoroacetate under these optimized condi-
tions, the corresponding (Z)-acrylate and syn-α-bromo-α-
fluoro-β-hydroxy ester were obtained in only 22% and 19%
yields, respectively. In fact, 2 equiv. of ethyl dibromofluoro-
acetate and 4 equiv. of diethylzinc were necessary to achieve
the full conversion of the aldehyde,[4j] thus highlighting the
advantage of using N-dibromofluoroacetylmorpholine to
prepare such α-carbonylated fluorinated olefins.
Furthermore, these optimization results showed that syn
and anti isomers of the α-bromo-α-fluoro-β-hydroxy amides
9 exhibit different reactivities towards excess diethylzinc.
19F NMR monitoring of the reactions showed that the anti
isomers were rapidly converted into the corresponding (Z)-
olefins whereas – as can be seen from Entry 7 (3 h reaction
time, 62% yield of (Z)-olefin, 96% global yield) and Entry 6
(72 h reaction time, 74% yield of (Z)-olefin, 91% global
yield) – the conversion of the syn isomers is slower and
slight degradation occurs.
Scheme 2. Synthesis of α-bromo-α-fluoro-β-amino amide 6.
Despite numerous attempts to optimize the formation of
the (Z)-olefin 4, we were not able to find suitable conditions
to favour the elimination step over the degradation of the
alcohols syn-3 and anti-3. Consequently, we turned our at-
tention to tertiary amides, and in particular to N-dibromo-
fluoroacetylmorpholine (7a, Table 3), to develop conditions
for stereoselective preparation of fluorinated (Z)-acryl-
amide derivatives. Firstly, a screening of solvents was car-
ried out with 4-chlorobenzaldehyde (1d) as a model sub-
strate, 1.1 equiv. of amide 7a and 4.4 equiv. of Et2Zn (En-
tries 1–4). The best result was obtained with CH2Cl2 as a
solvent, with a 74% yield of olefin (Z)-8ad and a 17% yield
of alcohol syn-9ad being obtained. In order to enhance the
degree of conversion of the alcohol syn-9ad into olefin (Z)-
8ad we tested the use of additives. Unfortunately, the ad-
dition of TMEDA only enhanced the degradation of the
alcohol syn-9ad (Entry 5), whereas the addition of molecu-
lar sieves had no effect on the outcome of the reaction (En-
try 6). Finally, the amount of Et2Zn was decreased to
2.5 equiv. A reaction time of 2 hours was then sufficient to
Table 3. Reactivity of fluorinated acetamides.
We thus examined the kinetics of the reaction between
the α-bromo-α-fluoro-β-hydroxy amide syn-9ad and Et2Zn.
In the first 2 h we observed the rapid formation of the (Z)-
olefin 8ad, and the elimination then slowed down to reach
about 50% conversion. This reactivity pattern clearly
showed that a significant amount of syn-α-bromo-α-fluoro-
β-hydroxy amide affords the corresponding α-fluoroacryl-
amide. However, all our attempts to increase the molecular
ratio between (Z)-8ad and syn-9ad were unsuccessful and
the use of more equivalents of diethylzinc resulted in the
degradation of syn-9ad.
Entry
Solv.
Equiv.
t [h] % Yield[b]
7
7
Et2Zn
4.4
4.4
4.4
4.4
4.4
4.4
2.5
2.5
2.5
2.5
2.5
8
(Z)-8
9
syn-9
1
2
3
4
7a THF
7a Et2O
7a C6H12
1.1
1.1
1.1
18
18
18
72
3
72
3
3
8ad 58
8ad 62
8ad 47
8ad 74
8ad 44
8ad 71
8ad 62[d]
8bd 32[d]
8cd 39[d]
9ad 14
9ad
9ad
9ad 17
9ad
9
2
7a CH2Cl2 1.1
7a CH2Cl2 1.1
7a CH2Cl2 1.1
7a CH2Cl2 1.1
7b CH2Cl2 1.1
7c CH2Cl2 1.1
7d CH2Cl2 1.1
7e CH2Cl2 1.1
5[b]
6[c]
7
2
9ad 17
9ad 34[d]
9bd 54[d]
9cd 38[d]
9dd 19[d]
8
9
10
11
3
3
3
8dd
0
8ed trace 9ed
0
[a] Determined by 19F NMR with trifluorotoluene as internal stan-
dard. [b] TMEDA (5 equiv.) was added. [c] MS (4 Å) were added.
[d] Isolated yields.
Scheme 3. Multi-cycle reaction.
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Eur. J. Org. Chem. 2013, 3278–3289

Synthesis of Fluorinated Amides
To obtain the α-fluoroacrylamide in better yield, we next electron-withdrawing or -donating group were nicely con-
sought to perform several cycles of reactions. We hypothe- verted into the corresponding α-fluoroacrylamides (En-
sized that the residual syn-α-bromo-α-fluoro-β-hydroxy tries 1–10). Aliphatic (Entry 12) and α,β-unsaturated alde-
amide might be re-engaged in another elimination reaction hydes (Entry 11) were also converted into the desired fluoro-
to improve the level of conversion into the desired fluoroac- alkenes with excellent global yields. In all cases, the α,β-
rylamide. We were pleased to observe that after three cycles unsaturated amide (Z)-8a and the α-bromo-α-fluoro-β-hy-
the syn-α-bromo-α-fluoro-β-hydroxy amide had been con- droxy amide syn-9a were obtained stereoselectively and
verted into the corresponding α-fluoroacrylamide in good were easily separated by flash chromatography. Addition-
overall yield (83%, Scheme 3).
ally, ketones were successfully tested in this process (En-
Under our optimized conditions, this methodology was tries 13–18). Interestingly, in these cases, the olefins were
successfully applied to a wide variety of carbonyl com- the exclusive reaction products, obtained in excellent yields.
pounds (Table 4). Aromatic aldehydes bearing either an Moreover, unsymmetrical ketones gave the tetrasubstituted
olefins with complete stereoselectivity (Entries 13–15).[14]
Finally, this method showed good chemical tolerance, with
an ester function (Entry 9), an alcohol function (Entry 7)
Table 4. Synthesis of olefins 8 and compounds syn-9.
and an aliphatic chlorinated compound (Entry 15) being
well tolerated in this process.
The configurations of the compounds were confirmed by
X-ray analyses (Figure 1).[15] We were able to obtain crystal
structures of (Z)-8ad and syn-9ac.
Figure 1. X-ray structures of (Z)-8ad and syn-9ac.
Morpholine acrylamides are versatile intermediates, be-
ing transformable into various functional groups such as
acids, aldehydes or ketones.[5a] In this context, to highlight
the synthetic utility of fluorinated morpholine acrylamides,
we prepared the α,β-unsaturated ketone 10 (Scheme 4) in
72% yield by addition of MeLi to acrylamide 8ab.
Scheme 4. Synthesis of fluorinated α,β-unsaturated ketone 10.
Conclusions
In summary, we have described selective and straightfor-
ward routes either to syn-α-bromo-α-fluoro-β-hydroxy
amides or to (Z)-α-fluoroacrylamides. The developed meth-
[a] Determined by 19F NMR examination of the crude mixtures.
odologies, based on Et2Zn-mediated addition of 2,2-di-
Eur. J. Org. Chem. 2013, 3278–3289
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X. Pannecoucke et al.
FULL PAPER
(Method A: 200 mg, 0.6 mmol,
2
equiv; Method B: 300 mg,
bromo-2-fluoroacetamides to aldehydes or ketones, afford
the products in good to excellent yields. It is worth men-
tioning that aromatic and aliphatic substrates bearing either
electron-donating or electron-withdrawing group are suit-
able for these reactions. The stereochemical outcome of the
reaction has been unambiguously determined by X-ray
analysis of the products. Finally, the versatility of our prod-
ucts was highlighted through a useful synthetic transforma-
tion. Deeper mechanistic studies to elucidate the elimi-
nation process are currently underway in our laboratory.
0.9 mmol, 3 equiv.) and the reaction mixture was stirred at room
temperature for 2 h. The reaction was then quenched by the drop-
wise addition of a saturated solution of NH4Cl (50 μL). After the
addition of silica gel, solvents were evaporated, and the crude resi-
due was adsorbed on silica gel and purified by column chromatog-
raphy to afford the desired product 3 as a mixture of diastereoiso-
mers.
N-Benzyl-2-bromo-2-fluoro-3-hydroxy-3-(3,4,5-trimethoxyphenyl)-
propanamide (3a): Yield 122 mg, 92%, Rf (cyclohexane/EtOAc 6:4)
= 0.28, white solid, m.p. 132–135 °C. 1H NMR (300 MHz, CDCl3,
25 °C): δ = 7.29–7.13 (m, 3 H), 7.11–7.03 (m, 1 H), 6.98–6.84 (m,
1.5 H), 6.79–6.66 (m, 0.5 H), 6.59 (s, 1 H), 6.58 (s, 1 H), 5.15 (d,
Experimental Section
3JH,F = 18.4 Hz, 1 H), 4.51–4.28 (m, 1 H), 4.39 (dd, JH,H = 5.6,
2
3JH,H = 12.9 Hz, 0.5 H), 4.20 (dd, JH,H = 5.6, JH,H = 15.0 Hz,
2
3
General Methods: Residual CHCl3 served as internal standard (δ =
7.26 ppm) for 1H NMR, CFCl3 served as internal standard (δ =
0.0 ppm) for 19F NMR, and CDCl3 served as internal standard (δ
= 77.16 ppm) for 13C NMR spectroscopy. Chemical shifts are
quoted in parts per million (ppm) and the following abbreviations
have been used: δ (chemical shift), J (coupling constant), br
(broad), s (singlet), d (doublet), dd (doublet of doublets), ddd
(doublet of doublet of doublets), t (triplet), q (quartet), dq (doublet
of quartets), m (multiplet). Flash chromatography was performed
with silica gel (0.063–0.200 mm). Analytical thin layer chromatog-
raphy (TLC) was performed with silica gel aluminium plates (F-
254 indicator) and visualized by UV fluorescence and/or staining
with KMnO4 or PMA. THF, Et2O and hexane were distilled from
Na/benzophenone prior to use. CH2Cl2 was distilled from CaH2
prior to use. HRMS analyses were performed under ESI conditions
with a micro-TOF detector. IR spectra were recorded with a Per-
kin–Elmer Spectrum 100 instrument. All experiments were con-
ducted under nitrogen in oven-dried glassware with magnetic stir-
ring and use of standard Schlenk techniques. All aldehydes and
ketones were recrystallized, distilled or filtered through basic alu-
mina prior to use.
0.5 H), 3.75 (s, 3 H), 3.71 (s, 3 H), 3.68 (s, 3 H) ppm. 13C NMR
2
(75 MHz, CDCl3, 25 °C): δ = 166.5 (d, JC,F = 23 Hz), 165.9 (d,
2JC,F = 21 Hz), 152.7, 152.6, 138.0 (2 C), 136.4, 136.3, 131.3, 130.3,
128.7 (2 C), 128.6 (2 C), 127.7 (2 C), 127.2 (2 C), 127.1 (2 C), 105.4,
4
1
1
105.2 (d, JC,F = 1 Hz), 103.0 (d, JC,F = 275 Hz), 100.2 (d, JC,F
2
2
= 276 Hz), 77.7 (d, JC,F = 22 Hz), 77.2 (d, JC,F = 19 Hz), 60.7 (2
C), 55.9 (4 C), 43.4, 43.2 ppm. 19F NMR (282 MHz, CDCl3,
3
3
25 °C): δ = –130.8 (d, JF,H = 17 Hz, 0.56 F), –132.5 (d, JF,H
=
16 Hz, 0.44 F) ppm. IR (neat): ν
= 3302, 1674, 1540, 700 cm–1.
˜
max
C19H21BrFNO5 (442.28): calcd. C 51.60, H 4.79, N 3.17; found C
51.64, H 4.64, N 3.56.
N-Benzyl-2-bromo-2-fluoro-3-hydroxy-3-phenylpropanamide (3b):
Yield 90 mg, 85%, Rf (cyclohexane/EtOAc 8:2) = 0.26, white solid,
1
m.p. 129–132 °C. H NMR (300 MHz, MeOD/CDCl3, 25 °C): δ =
7.54–7.43 (m, 1 H), 7.43–7.35 (m, 1 H), 7.35–7.18 (m, 6 H), 7.17–
7.07 (m, 2 H), 6.84–6.73 (m, 1 H), 5.27 (d, 3JH,F = 23.0 Hz, 0.5 H),
3
2
5.26 (d, JH,F = 23.8 Hz, 0.5 H), 4.52 (d, JH,H = 15.0 Hz, 0.5 H),
2
2
4.46 (d, JH,H = 15.0 Hz, 0.5 H), 4.36 (d, JH,H = 15.1 Hz, 0.5 H),
4.08 (d, 2JH,H = 15.1 Hz, 0.5 H) ppm. 13C NMR (75 MHz, MeOD/
2
2
CDCl3, 25 °C): δ = 168.2 (d, JC,F = 23 Hz), 167.5 (d, JC,F
=
4
Product 10 has been described previously and gave satisfactory
spectroscopic and physical data. It was prepared from acrylamide
8ab by known procedure.[5a]
21 Hz), 138.8, 138.3, 138.0, 137.4, 129.8 (d, JC,F = 2 Hz, 2 C),
4
129.5, 129.4, 129.3 (d, JC,F = 2 Hz, 2 C), 129.3 (2 C), 129.1 (2 C),
129.0 (2 C), 128.6 (2 C), 128.1 (2 C), 128.0, 127.81, 127.78 (2 C),
105.6 (d, 1JC,F = 278 Hz), 102.0 (d, 1JC,F = 276 Hz), 77.92 (d, 2JC,F
N-Benzyl-2,2-dibromo-2-fluoroacetamide
(2):
Benzylamine
2
= 20 Hz), 77.86 (d, JC,F = 18 Hz), 44.0, 43.5 ppm. 19F NMR
(9.86 mL, 90 mmol, 2 equiv.) was added to a solution of Me2AlCl
(0.9 n in hexanes, 100 mL, 90 mmol, 2 equiv.) in dry CH2Cl2
(200 mL) and the mixture was stirred at room temperature for
45 min. The reaction mixture was cooled to 0 °C, after which ethyl
dibromofluoroacetate (6.27 mL, 45 mmol, 1 equiv.) was added
slowly. After 16 h stirring at room temperature, the reaction was
quenched by slow addition of HCl (4 n, 25 mL). The organic layer
was separated, the aqueous layer was extracted with Et2O (2ϫ
50 mL), the combined organic layers were concentrated, and the
desired amide 2 was recrystallized from cyclohexane (12.4 g, 85%
yield, 97% purity by 19F NMR): Rf (cyclohexane/EtOAc 8:2) =
0.48, white solid, m.p. 77–80 °C. 1H NMR (300 MHz, CDCl3,
3
(282 MHz, CDCl3, 25 °C): δ = –135.1 (d, JF,H = 23 Hz, 0.56 F),
3
–138.8 (d, JF,H = 16 Hz, 0.44 F) ppm. IR (neat): ν
= 3322,
˜
max
1676, 1537, 696, 672 cm–1. C16H15BrFNO2 (352.20): calcd. C 54.56,
H 4.29, N 3.98; found C 54.48, H 4.59, N 4.20.
3-(Benzo[d][1,3]dioxol-5-yl)-N-benzyl-2-bromo-2-fluoro-3-hydroxy-
propanamide (3c): Yield 108 mg, 91%, Rf (cyclohexane/EtOAc 8:2)
= 0.20, yellow solid, m.p. 136–140 °C. 1H NMR (300 MHz, MeOD,
25 °C): δ = 7.28–7.01 (m, 3.5 H), 6.95–6.63 (m, 4 H), 6.57 (d, 3JH,H
3
= 7.9 Hz, 0.5 H), 5.86–5.77 (m, 2 H), 5.10 (d, JH,F = 23.1 Hz, 0.5
3
2
H), 5.07 (d, JH,F = 23.9 Hz, 0.5 H), 4.42 (d, JH,H = 15.1 Hz, 0.5
2
2
H), 4.36 (d, JH,H = 15.1 Hz, 0.5 H), 4.33 (d, JH,H = 15.0 Hz, 0.5
3
25 °C): δ = 7.41–7.28 (m, 5 H), 6.52 (br. s, 1 H), 4.55 [d, J(H,H)
2
H), 3.97 (d, JH,H = 15.0 Hz, 0.5 H) ppm. 13C NMR (75 MHz,
= 5.8 Hz, 2 H] ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ = 162.5
2
2
MeOD, 25 °C): δ = 168.5 (d, JC,F = 24 Hz), 167.8 (d, JC,F
=
2
(d, JC,F = 18 Hz), 136.3, 128.6 (2 C), 127.7, 127.5 (2 C), 86.9 (d,
21 Hz), 149.32, 149.28, 149.0, 148.7, 139.3, 138.9, 132.3, 131.5,
129.5 (2 C), 129.3 (2 C), 128.3 (2 C), 128.2 (2 C), 128.0 (2 C), 124.2,
123.7, 110.0 (d, 4JC,F = 3 Hz), 109.6 (d, 4JC,F = 3 Hz), 108.8, 108.3,
1JC,F = 328 Hz), 44.1 ppm. 19F NMR (282 MHz, CDCl3, 25 °C): δ
= –66.0 (s) ppm. IR (neat): ν
= 3264, 1678, 1537, 1085,
˜
max
812 cm–1. C9H8Br2FNO (324.97): calcd. C 33.26, H 2.48, N 4.31;
1
1
105.0 (d, JC,F = 277 Hz), 103.5 (d, JC,F = 277 Hz), 102.5, 102.4,
found C 33.51, H 2.61, N 4.53.
78.1 (d, 2JC,F = 17 Hz), 78.0 (d, 2JC,F = 19 Hz), 44.1, 43.6 ppm. 19
F
General Procedure for the Synthesis of α-Bromo-α-fluoro-β-hydroxy
Amides 3: Et2Zn (1.0 n in hexanes. Method A: 1.2 mL, 1.2 mmol,
4 equiv. Method B: 1.8 mL, 1.8 mmol, 6 equiv.) was added to a
solution of an aldehyde 1 (0.3 mmol, 1 equiv.) and an amide 2
NMR (282 MHz, CDCl3, 25 °C): δ = –135.8 (d, 3JF,H = 24 Hz, 0.56
3
F), –139.3 (d, JF,H = 23 Hz, 0.44 F) ppm. IR (neat): ν
= 3328,
˜
max
1670, 1531, 690, 660 cm–1. C17H15BrFNO4 (396.21): calcd. C 51.53,
H 3.82, N 3.54; found C 51.89, H 4.06, N 3.60.
3282
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 3278–3289

Synthesis of Fluorinated Amides
2
2
N-Benzyl-2-bromo-3-(4-chlorophenyl)-2-fluoro-3-hydroxypropan-
amide (3d): Yield 100 mg, 86%, Rf (cyclohexane/EtOAc 8:2) = 0.23,
white solid, m.p. 124–127 °C. 1H NMR (300 MHz, MeOD, 25 °C):
166.8, 166.7, 166.3 (d, JC,F = 23 Hz), 166.2 (d, JC,F = 21 Hz),
140.5, 139.8, 136.3, 136.2, 130.54, 130.51, 129.3 (4 C), 128.8 (2 C),
128.7 (2 C), 128.5 (d, JC,F = 2 Hz, 2 C), 128.4 (d, JC,F = 2 Hz, 2
4
4
3
δ = 7.39 (d, JH,H = 7.5 Hz, 1 H), 7.28–7.04 (m, 8 H), 6.76–6.69
C), 127.90 (2 C), 127.88 (2 C), 127.50 (2 C), 127.46 (2 C), 102.3 (d,
(m, 1 H), 5.18 (d, 3JH,F = 23.2 Hz, 0.5 H), 5.14 (d, 3JH,F = 23.7 Hz,
1JC,F = 274 Hz), 99.8 (d, JC,F = 275 Hz), 77.3 (d, JC,F = 21 Hz),
1
2
0.5 H), 4.42 (d, JH,H = 15.1 Hz, 0.5 H), 4.35 (d, JH,H = 15.1 Hz, 75.9 (d, JC,F = 21 Hz), 52.2 (2 C), 43.5, 43.4 ppm. 19F NMR
2
2
2
2
2
3
0.5 H), 4.30 (d, JH,H = 15.0 Hz, 0.5 H), 3.94 (d, JH,H = 15.0 Hz, (282 MHz, CDCl3, 25 °C): δ = –130.0 (d, JF,H = 14 Hz, 0.53 F),
0.5 H) ppm. 13C NMR (75 MHz, DMSO, 25 °C): δ = 165.4 (d, –133.4 (d, JF,H = 17 Hz, 0.47 F) ppm. IR (neat): ν
= 3473,
3
˜
max
2JC,F = 23 Hz), 164.9 (d, 2JC,F = 22 Hz), 138.7, 138.2, 136.9, 136.2, 3334, 1700, 1670, 1531, 1275, 533 cm–1. C18H17BrFNO4 (410.23):
133.0 (2 C), 130.9 (2 C), 130.2 (2 C), 128.3 (2 C), 128.0 (4 C), 127.7 calcd. C 52.70, H 4.18, N 3.41; found C 52.74, H 4.54, N 3.54.
1
(2 C), 127.0 (2 C), 126.7 (2 C), 103.2 (d, JC,F = 278 Hz), 102.4 (d,
N-Benzyl-2-bromo-2-fluoro-3-hydroxy-3-(thiophen-2-yl)propan-
2
2
1JC,F = 279 Hz), 75.1 (d, JC,F = 18 Hz), 74.9 (d, JC,F = 19 Hz),
amide (3h): Yield 88 mg, 82%, Rf (cyclohexane/EtOAc 8:2) = 0.29,
42.3, 41.8 ppm. 19F NMR (282 MHz, MeOD, 25 °C): δ = –136.1
brown solid, m.p. 101–103 °C. 1H NMR (300 MHz, MeOD, 25 °C):
3
3
(d, JF,H = 24 Hz, 0.59 F), –139.6 (d, JF,H = 23 Hz, 0.41 F) ppm.
IR (neat): ν
= 3425, 3330, 1665, 1537, 696, 530 cm–1
3
3
4
δ = 7.32 (d, JH,H = 5.0 Hz, 0.5 H), 7.28 (dd, JH,H = 5.1, JH,H
=
.
˜
max
0.9 Hz, 0.5 H), 7.25–7.19 (m, 2 H), 7.19–7.06 (m, 3 H), 6.94–6.86
C16H14BrClFNO2 (386.64): calcd. C 49.70, H 3.65, N 3.62; found
C 49.92, H 3.76, N 3.54.
(m, 1 H), 6.86–6.78 (m, 2 H), 5.49 (d, 3JH,F = 23.4 Hz, 0.5 H), 5.47
3
2
(d, JH,F = 23.6 Hz, 0.5 H), 4.42 (d, JH,H = 15.1 Hz, 0.5 H), 4.36
2
2
N-Benzyl-2-bromo-3-(3,4-dichlorophenyl)-2-fluoro-3-hydroxy- (d, JH,H = 15.1 Hz, 0.5 H), 4.30 (d, JH,H = 15.2 Hz, 0.5 H), 4.06
2
propanamide (3e): Yield 82 mg, 71%, Rf (cyclohexane/EtOAc 8:2)
(d, JH,H = 15.2 Hz, 0.5 H) ppm. 13C NMR (75 MHz, MeOD,
= 0.28, white solid, m.p. 116–120 °C. 1H NMR (300 MHz, CDCl3, 25 °C): δ = 168.1 (d, 2JC,F = 23 Hz), 167.7 (d, 2JC,F = 22 Hz), 140.9,
3
3
25 °C): δ = 7.58 (d, JH,H = 8.9 Hz, 1 H), 7.42 (d, JH,H = 8.5 Hz,
140.2, 139.2, 138.8, 129.5 (2 C), 129.4 (2 C), 129.2, 128.6, 128.3 (2
3
0.5 H), 7.38 (d, JH,H = 8.7 Hz, 0.5 H), 7.36–7.25 (m, 4 H), 7.18– C), 128.2, 128.1 (2 C), 128.0, 127.5, 127.43, 127.38, 127.1, 103.7 (d,
7.11 (m, 1 H), 7.11–7.05 (m, 1 H), 6.72 (br. s, 0.5 H), 6.63 (br. s, 1JC,F = 277 Hz), 102.9 (d, JC,F = 277 Hz), 74.6 (d, 2JC,F = 20 Hz),
1
0.5 H), 5.28 (dd, 3JH,F = 17.2, 3JH,H = 6.8 Hz, 0.5 H), 5.17 (d, 3JH,F
74.3 (d, JC,F = 19 Hz), 44.1, 43.7 ppm. 19F NMR (282 MHz,
2
3
= 13.2 Hz, 0.5 H), 4.60–4.31 (m, 2 H), 4.27–4.16 (m, 0.5 H), 4.21
MeOD, 25 °C): δ = –135.3 (d, JF,H = 23 Hz, 0.56 F), –138.9 (d,
(br. s, 1 H) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ = 166.2 (d, 3JF,H = 23 Hz, 0.44 F) ppm. IR (neat): ν
= 3325, 1669, 1438,
˜
max
2JC,F = 21 Hz, 2 C), 136.2, 136.1, 135.8, 135.0, 133.2, 133.1, 132.4
1118 cm–1. C14H13BrFNO2S (358.23): calcd. C 46.94, H 3.66, N
4
4
(2 C), 130.4 (d, JC,F = 2 Hz), 130.2 (d, JC,F = 2 Hz), 130.0 (2 C),
3.91, S 8.95; found C 47.33, H 3.97, N 4.08, S 8.71.
4
4
128.9 (4 C), 128.04, 128.00, 127.8 (d, JC,F = 2 Hz), 127.7 (d, JC,F
(E)-N-Benzyl-2-bromo-2-fluoro-3-hydroxy-4-methyl-5-phenylpent-
4-enamide (3i): Yield 88 mg, 75%, Rf (cyclohexane/EtOAc 8:2) =
0.29, yellow solid, m.p. 144–148 °C. Major diastereoisomer: 1H
NMR (300 MHz, CDCl3, 25 °C): δ = 7.29–7.25 (m, 2 H), 7.24–7.22
(m, 1 H), 7.20–7.14 (m, 4 H), 7.14–7.11 (m, 3 H), 6.72 (br. s, 1 H),
6.62 (s, 1 H), 4.73 (d, 3JH,F = 18.8 Hz, 1 H), 4.48 (dd, 2JH,H = 14.9,
1
= 2 Hz), 127.5 (2 C), 127.4 (2 C), 101.9 (d, JC,F = 273 Hz), 99.6
(d, 1JC,F = 276 Hz), 76.6 (d, 2JC,F = 21 Hz), 75.1 (d, 2JC,F = 21 Hz),
43.6, 43.5 ppm. 19F NMR (282 MHz, MeOD, 25 °C): δ = –129.8
3
3
(d, JF,H = 13 Hz, 0.55 F), –133.3 (d, JF,H = 17 Hz, 0.45 F) ppm.
IR (neat): ν
= 3321, 2925, 1669, 1537, 1024, 700 cm–1
.
˜
max
C16H13BrCl2FNO2 (421.09): calcd. C 45.64, H 3.11, N 3.33; found
C 45.85, H 3.44, N 3.47.
3
3JH,H = 6.3 Hz, 1 H), 4.32 (dd, 2JH,H = 14.9, JH,H = 5.5 Hz, 1 H),
3.56 (s, 1 H), 1.87 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3,
2
N-Benzyl-2-bromo-3-(4-cyanophenyl)-2-fluoro-3-hydroxypropan-
amide (3f): Yield 95 mg, 84%, Rf (cyclohexane/EtOAc 8:2) = 0.21,
white solid, m.p. 142–146 °C. 1H NMR (300 MHz, MeOD, 25 °C):
25 °C): δ = 166.1 (d, JC,F = 21 Hz), 136.5, 132.1, 132.0, 129.2 (2
C), 128.8 (2 C), 128.1 (2 C), 127.82, 127.76, 127.6 (2 C), 127.0,
1
2
104.5 (d, JC,F = 276 Hz), 79.0 (d, JC,F = 19 Hz), 43.6, 14.8 (d,
δ = 7.77 (s, 2 H), 7.59 (s, 2 H), 7.47–7.25 (m, 5 H), 7.09–6.96 (m, 4JC,F = 4 Hz) ppm. 19F NMR (282 MHz, CDCl3, 25 °C): δ =
1 H), 5.47 (d, 3JH,F = 22.5 Hz, 0.5 H), 5.42 (d, 3JH,F = 22.3 Hz, 0.5
–128.4 (d, 3JF,H = 18 Hz) ppm. IR (neat): νmax = 3405, 2925, 1669,
˜
2
2
H), 4.63 (d, JH,H = 15.1 Hz, 0.5 H), 4.58 (d, JH,H = 15.1 Hz, 0.5 1533, 883, 728 cm–1. HRMS (ESI+): calcd. for C19H20BrFNO2 [M
2
2
H), 4.51 (d, JH,H = 14.7 Hz, 0.5 H), 4.20 (d, JH,H = 14.7 Hz, 0.5 + H]+ 392.0661; found 392.0664. Minor diastereoisomer: 1H NMR
H) ppm. 13C NMR (75 MHz, MeOD, 25 °C): δ = 167.3 (d, 2JC,F
=
(300 MHz, CDCl3, 25 °C): δ = 7.29–7.25 (m, 2 H), 7.24–7.19 (m, 8
2
3
23 Hz), 166.7 (d, JC,F = 21 Hz), 143.3, 142.5, 138.3, 137.9, 132.4 H), 6.76 (br. s, 1 H), 6.60 (s, 1 H), 4.82 (d, JH,F = 18.8 Hz, 1 H),
4
4
(2 C), 132.2 (2 C), 130.5 (d, JC,F = 2 Hz, 2 C), 129.8 (d, JC,F
=
4.54–4.41 (m, 2 H), 3.76–3.45 (br. s, 1 H), 1.88 (s, 3 H) ppm. 13C
2 Hz, 2 C), 129.1 (2 C), 129.0 (2 C), 128.0 (2 C), 127.9 (4 C), 119.2, NMR (75 MHz, CDCl3, 25 °C): δ = 166.7 (d, 2JC,F = 22 Hz), 136.6,
1
1
119.1, 112.7, 112.6, 103.6 (d, JC,F = 276 Hz), 102.3 (d, JC,F
=
136.5, 132.8, 132.4, 129.2 (2 C), 128.8 (2 C), 128.1 (2 C), 127.9,
2
2
1
2
277 Hz), 76.81 (d, JC,F = 18 Hz), 76.79 (d, JC,F = 20 Hz), 43.9,
127. 6 (2 C), 127.1, 101.4 (d, JC,F = 276 Hz), 80.8 (d, JC,F =
43.5 ppm. 19F NMR (282 MHz, MeOD, 25 °C): δ = –134.8 (d,
20 Hz), 43.7, 14.4 (d, JC,F = 4 Hz) ppm. 19F NMR (282 MHz,
4
3JF,H = 22 Hz, 0.56 F), –138.8 (d, JF,H = 22 Hz, 0.44 F) ppm. IR
CDCl3, 25 °C): δ = –132.0 (d, JF,H = 19 Hz) ppm. IR (neat): ν
3
3
˜
max
(neat): ν
= 3321, 1664, 1453, 798 cm–1. C17H14BrFN2O2
= 3405, 2925, 1670, 1533, 1053, 752 cm–1. C19H19BrFNO2 (392.26):
˜
max
(377.21): calcd. C 54.13, H 3.74, N 7.43; found C 54.33, H 4.04, N
7.36.
calcd. C 58.18, H 4.88, N 3.57; found C 57.89, H 5.15, N 3.94.
N-Benzyl-2-bromo-2-fluoro-3-hydroxy-5-phenylpentanamide (3j):
Yield 81 mg, 71%, Rf (cyclohexane/EtOAc 8:2) = 0.27, yellow solid,
Methyl 4-[3-(Benzylamino)-2-bromo-2-fluoro-1-hydroxy-3-oxoprop-
yl]benzoate (3g): Yield 89 mg, 72%, Rf (cyclohexane/EtOAc 8:2) = m.p. 122–124 °C. 1H NMR (300 MHz, CDCl3, 25 °C): δ = 7.40–
1
0.18, yellow solid, m.p. 145–148 °C. H NMR (300 MHz, CDCl3,
7.26 (m, 7 H), 7.24–7.16 (m, 3 H), 6.74 (br. s, 1 H), 4.61–4.49 (m,
3
3
2
3
25 °C): δ = 7.97 (t, JH,H = 8.3 Hz, 2 H), 7.51 (d, JH,H = 8.3 Hz, 1.5 H), 4.44 (dd, JH,H = 14.9, JH,H = 5.6 Hz, 0.5 H), 4.34–4.17
3
2 H), 7.35–7.21 (m, 3 H), 7.18–7.10 (m, 1 H), 7.07–6.98 (m, 1 H),
(m, 0.5 H), 4.02–3.90 (m, 0.5 H), 3.79 (br. s, 0.5 H), 3.17 (d, JH,H
= 7.0 Hz, 0.5 H), 3.04–2.89 (m, 1 H), 2.80–2.66 (m, 1 H), 2.36–2.22
(m, 0.5 H), 2.02–1.86 (m, 1.5 H) ppm. 13C NMR (75 MHz, CDCl3,
3
3
6.84 (br. s, 1 H), 6.71 (br. s, 1 H), 5.36 (dd, JH,F = 17.6, JH,H
=
3
6.6 Hz, 0.5 H), 5.29 (d, JH,F = 14.9 Hz, 0.5 H), 4.56–4.24 (m, 3
H), 3.90 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ = 25 °C): δ = 166.9 (d, 2JC,F = 23 Hz), 166.4 (d, 2JC,F = 22 Hz), 141.1,
Eur. J. Org. Chem. 2013, 3278–3289
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3283

X. Pannecoucke et al.
FULL PAPER
141.0, 136.6, 136.5, 128.9 (2 C), 128.8 (2 C), 128.50 (2 C), 128.47
(2 C), 128.45 (2 C), 128.42 (2 C), 128.0, 127.9, 127.7 (2 C), 127.6
2
2
15.4 Hz, 0.5 H), 4.30 (d, JH,H = 15.5 Hz, 0.5 H), 4.28 (d, JH,H
=
15.4 Hz, 0.5 H), 3.90 (d, 2JH,H = 15.5 Hz, 0.5 H), 2.23 (s, 3 H) ppm.
1
1
2
(2 C), 126.1, 126.0, 103.3 (d, JC,F = 271 Hz), 103.6 (d, JC,F
=
13C NMR (75 MHz, DMSO, 25 °C): δ = 164.6 (d, JC,F = 23 Hz,
2
2
2
2
274 Hz), 74.7 (d, JC,F = 22 Hz), 73.3 (d, JC,F = 23 Hz), 43.5 (2
0.5 C), 164.5 (d, JC,F = 23 Hz, 0.5 C), 164.2 (d, JC,F = 21 Hz, 0.5
C), 32.1, 31.8, 31.3, 31.1 (d, JC,F = 3 Hz) ppm. 19F NMR C), 164.1 (d, JC,F = 21 Hz, 0.5 C), 142.39, 142.36, 138.5, 138.4,
4
2
3
(282 MHz, CDCl3, 25 °C): δ = –127.2 (d, JF,H = 8 Hz), –134.5 (d, 137.9, 137.6, 133.2, 133.1, 132.9, 132.1, 131.2 (2 C), 130.9 (2 C),
3JF,H = 19 Hz) ppm. IR (neat): νmax = 3302, 2925, 1674, 1537, 892,
129.0 (2 C), 128.8 (2 C), 128.3 (2 C), 127.94 (2 C), 127.88 (2 C),
˜
4
747 cm–1. C18H19BrFNO2 (380.25): calcd. C 56.86, H 5.04, N 3.68;
found C 56.87, H 5.37, N 3.93.
127.6 (2 C), 127.0 (2 C), 126.9 (2 C), 126.7 (d, JC,F = 2 Hz, 2 C),
126.43 (2 C), 126.38 (2 C), 103.1 (d, 1JC,F = 273 Hz), 101.7 (d, 1JC,F
2
2
= 276 Hz), 63.1 (d, JC,F = 17 Hz), 62.2 (d, JC,F = 19 Hz), 42.5
N-Benzyl-2-bromo-2-fluoro-3-hydroxyoctanamide (3k): Yield 44 mg,
42%, Rf (cyclohexane/EtOAc 8:2) = 0.29, yellow solid, m.p. 85–
88 °C. 1H NMR (300 MHz, CDCl3, 25 °C): δ = 7.26–7.41 (m, 5
(0.5 C), 42.3 (0.5 C), 41.9 (0.5 C), 41.8 (0.5 C), 20.8 (2 C) ppm. 19
NMR (282 MHz, DMSO, 25 °C): δ = –129.62 (d, JF,H = 29 Hz),
F
3
3
3
–129.65 (d, JF,H = 28 Hz), –132.1 (d, JF,H = 32 Hz), –132.2 (d,
2
3
H), 6.78 (br. s, 1 H), 4.54 (dd, JH,H = 14.8, JH,H = 5.9 Hz, 1 H),
3JF,H = 34 Hz) ppm. IR (neat): ν
= 3358, 3195, 1670, 563,
˜
max
2
3
4.48 (dd, JH,H = 14.9, JH,H = 4.6 Hz, 1 H), 3.56 (s, 1 H), 4.09–
533 cm–1. C23H21BrClFN2O3S (539.84): calcd. C 51.17, H 3.92, N
3
3.88 (m, 1 H), 3.56 (d, JH,H = 3.2 Hz, 1 H), 1.66–1.59 (m, 2 H),
5.19, S 5.94; found C 51.30, H 4.27, N 3.60, S 5.68.
1.36–1.24 (m, 6 H), 0.91–0.86 (m, 3 H) ppm. 13C NMR (75 MHz,
2
CDCl3, 25 °C): δ = 166.8 (d, JC,F = 23 Hz), 136.7, 128.8 (2 C),
General Procedure for the Synthesis of Dibromofluoroacetamides 7:
The appropriate amine (2 equiv.) was added to a solution of
Me2AlCl (1.0 n in hexanes, 2 equiv.) in dry CH2Cl2 (1 n) and the
mixture was stirred at room temperature for 3 h. Ethyl dibromo-
fluoroacetate (1 equiv.) was added and the mixture was stirred at
reflux for 14 h. The reaction was quenched by slow addition of
HCl (4 n). The organic layer was separated, the aqueous layer was
extracted with CH2Cl2 (3ϫ), the combined organic layers were
concentrated, and the desired amides 7a–e were either recrystallized
(7a) or purified by silica gel chromatography (7b–e).
1
2
127.9, 127.6 (2 C), 102.8 (d, JC,F = 271 Hz), 74.4 (d, JC,F
=
22 Hz), 43.4, 31.4, 30.5, 25.2, 22.4, 13.9 ppm. 19F NMR (282 MHz,
CDCl3, 25 °C): δ = –127.7 (d, 3JF,H = 10 Hz) ppm. IR (neat): ν
=
˜
max
3307, 2921, 1669, 1645, 1448, 1076 cm–1. C15H21BrFNO2 (346.24):
calcd. C 52.03, H 6.11, N 4.05; found C 52.37, H 6.43, N 3.90.
N-Benzyl-2-bromo-2-fluoro-3-hydroxy-3-phenylbutanamide (3l):
Yield 93 mg, 85%, Rf (cyclohexane/EtOAc 8:2) = 0.19, colourless
oil. Major diastereoisomer: H NMR (300 MHz, CDCl3, 25 °C): δ
1
= 7.55–7.42 (m, 2 H), 7.41–7.28 (m, 5 H), 7.22–7.11 (m, 3 H), 6.63
(d, 3JH,H = 6.1 Hz, 1 H), 5.29 (s, 1 H), 4.42 (dd, 2JH,H = 15.2, 3JH,H
2,2-Dibromo-2-fluoro-1-morpholinoethanone (7a): 100 mmol scale,
recrystallized from cyclohexane. Yield 11.9 g, 78 %, white solid,
2
3
= 7.3 Hz, 1 H), 4.06 (dd, JH,H = 15.2, JH,H = 4.6 Hz, 1 H), 1.81
(s, 3 H) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ = 167.4 (d,
2JC,F = 21 Hz), 139.7, 136.0, 128.7 (2 C), 128.3 (2 C), 128.0, 127.7,
127.1 (2 C), 126.6 (d, 4JC,F = 3 Hz, 2 C), 104.5 (d, 1JC,F = 276 Hz),
1
m.p. 58–60 °C. H NMR (300 MHz, CDCl3, 25 °C): δ = 3.70 (s, 8
3
H) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ = 159.4 (d, JC,F
=
23 Hz), 85.8 (d, JC,F = 323 Hz), 66.4, 65.7, 48.2, 44.5 ppm. 19F
1
2
4
77.4 (d, JC,F = 24 Hz), 24.6 (d, JC,F = 2 Hz) ppm. 19F NMR
NMR (282 MHz, CDCl , 25 °C): δ = –55.9 (s) ppm. IR (neat): ν
˜
3
max
= 2848, 1665, 1434, 1116, 1094, 1036, 802 cm–1. C6H8Br2FNO2
(304.94): calcd. C 26.63, H 2.64, N 4.59; found C 26.82, H 2.82, N
4.74.
(282 MHz, CDCl , 25 °C): δ = –122.7 (s) ppm. IR (neat): ν
=
˜
3
max
3425, 3305, 1640, 1110 cm–1. C17H18BrFNO2 (366.22): calcd. C
55.75, H 4.68, N 3.82; found C 55.57, H 4.43, N 3.70. Minor dia-
stereoisomer: 1H NMR (300 MHz, CDCl3, 25 °C): δ = 7.66–7.55
(m, 2 H), 7.42–7.31 (m, 6 H), 7.31–7.25 (m, 2 H), 6.81 (br. s, 1 H),
5.12 (s, 1 H), 4.55 (d, 3JH,H = 5.9 Hz, 1 H), 1.73 (d, 4JH,H = 1.6 Hz,
2,2-Dibromo-2-fluoro-1-(piperidin-1-yl)ethanone (7b): 1 mmol scale.
Yield 239 mg, 79%, Rf (PE/EtOAc 6:4) = 0.82, colourless oil. 1H
NMR (300 MHz, CDCl3, 25 °C): δ = 3.78–3.35 (br. m, 4 H), 1.62
(br. s) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ = 159.2 (d, 2JC,F
= 22 Hz), 86.3 (d, 1JC,F = 324 Hz), 48.6, 45.7, 25.4 (2 C), 23.9 ppm.
19F NMR (282 MHz, CDCl3, 25 °C): δ = –54.1 (s) ppm. IR (neat):
3 H) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ = 167.9 (d, JC,F
2
= 22 Hz), 139.9, 136.4, 129.0 (2 C), 128.13, 128.06, 127.7 (2 C),
127.6 (2 C), 127.3 (d, 4JC,F = 2 Hz, 2 C), 104.0 (d, 1JC,F = 274 Hz),
2
77.1 (d, JC,F = 21 Hz), 43.7, 24.7 ppm. 19F NMR (282 MHz,
ν
˜
= 3440, 1765, 1689 cm–1. HRMS (ESI+): calcd. for
max
CDCl , 25 °C): δ = –124.6 (s) ppm. IR (neat): ν
= 3330, 2980,
˜
3
max
C7H12Br2FNO [M + H]+ 301.9191; found 301.9195.
1665, 1434, 690, 660 cm–1. C17H18BrFNO2 (366.22): calcd. C 55.75,
H 4.68, N 3.82; found C 55.57, H 4.43, N 3.70.
2,2-Dibromo-N,N-diethyl-2-fluoroacetamide (7c): 1 mmol scale.
Yield 270 mg, 93%, Rf (PE/EtOAc 6:4) = 0.77, yellow liquid. 1H
NMR (300 MHz, CDCl3, 25 °C): δ = 3.40 (dq, JH,H = 7.0, JH,H
N-Benzyl-2-bromo-2-fluoro-2-(1-hydroxycyclohexyl)acetamide (3m):
Yield 44 mg, 42%, Rf (cyclohexane/EtOAc 8:2) = 0.28, yellow oil.
1H NMR (300 MHz, CDCl3, 25 °C): δ = 7.41–7.26 (m, 5 H), 6.81
3
2
3
3
= 2.2 Hz, 2 H), 3.23 (q, JH,H = 7.1 Hz, 2 H), 1.07 (t, JH,H
=
7.0 Hz, 3 H), 0.99 (t, JH,H = 7.1 Hz, 3 H) ppm. 13C NMR
3
3
(br. s, 1 H), 4.52 (d, JH,H = 5.8 Hz, 1 H), 3.93 (s, 1 H), 2.13–1.98
2
(m, 1 H), 1.76–1.40 (m, 8 H), 1.20–1.04 (m, 1 H) ppm. 13C NMR
(75 MHz, CDCl3, 25 °C): δ = 159.6 (d, JC,F = 22 Hz), 88.2 (d,
4
1JC,F = 327 Hz), 43.1 (d, JC,F = 5 Hz), 42.4, 13.1, 11.3 ppm. 19F
(75 MHz, CDCl3, 25 °C): δ = 167.6 (d, 2JC,F = 23 Hz), 136.6, 129.0
(2 C), 128.1, 127.7 (2 C), 106.3 (d, 1JC,F = 277 Hz), 75.0 (d, 2JC,F
=
NMR (282 MHz, CDCl , 25 °C): δ = –55.9 (s) ppm. IR (neat): ν
˜
3
max
= 3440, 1763; 1688 cm–1. HRMS (ESI+): calcd. for C6H12Br2FNO
20 Hz), 43.5, 31.2, 30.9, 25.2, 21.4, 20.8 ppm. 19F NMR (282 MHz,
[M + H]+ 289.9191; found 289.9188.
CDCl , 25 °C): δ = –125.1 (s) ppm. IR (neat): ν
= 3337, 1669,
˜
3
max
1076, 916, 794 cm–1. HRMS (mode): calcd. for C15H20BrFNO2 [M
+ H]+ 344.0661; found 344.0657.
N-Benzyl-2,2-dibromo-2-fluoro-N-methylacetamide (7d): 1 mmol
scale. Yield 296 mg, 87%, Rf (PE/EtOAc 6:4) = 0.82, colourless oil,
mixture (3:1) of rotamers; only major rotamer is described. 1H
NMR (300 MHz, CDCl3, 25 °C): δ = 7.43–7.23 (m, 5 H), 4.66 (br.
s, 2 H), 3.19 (br. s, 3 H) ppm. 13C NMR (75 MHz, CDCl3, 25 °C):
N-Benzyl-2-bromo-3-(4-chlorophenyl)-2-fluoro-3-(4-methyl-
phenylsulfonamido)propanamide (6): Mixture of rotamers of both
diastereoisomers. Yield 71 mg, 44%, Rf (cyclohexane/EtOAc 8:2) =
0.27, white solid, m.p. 120–126 °C. 1H NMR (300 MHz, DMSO,
25 °C): δ = 7.41–6.86 (m, 13 H), 6.57 (br. s, 0.5 H), 6.55 (br. s, 0.5
H), 5.30–5.11 (m, 0.5 H), 5.11–4.94 (m, 0.5 H), 4.45 (d, JH,H
2
δ = 160.9 (d, JC,F = 22 Hz), 135.4, 128.7 (2 C), 127.7 (2 C), 126.9,
1
4
87.6 (d, JC,F = 326 Hz), 53.7, 36.6 (d, JC,F = 6 Hz) ppm. 19F
2
=
NMR (282 MHz, CDCl , 25 °C): δ = –55.3 (s) ppm. IR (neat): ν
˜
3 max
3284
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 3278–3289

Synthesis of Fluorinated Amides
3
= 3440, 1762, 1688 cm–1. HRMS (ESI+): calcd. for C10H11Br2FNO
[M + H]+ 337.9191; found 337.9187.
= 3.8, JH,H = 2.3 Hz, 1 H), 4.93 (br. m, 1 H), 3.95–3.50 (m, 8
H) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ = 165.3 (d, JC,F
=
=
2
1
23 Hz), 135.3, 128.8, 128.7 (2 C), 127.6 (2 C), 102.8 (d, JC,F
2,2-Dibromo-2-fluoro-N-methoxy-N-methylacetamide (7e): 1 mmol
scale. Standard procedure was followed with 3 equiv. of both Me2-
AlCl and amine. Yield 221 mg, 81%, Rf (cyclohexane/EtOAc 95:5)
= 0.18, yellow oil. 1H NMR (300 MHz, CDCl3, 25 °C): δ = 3.75
(s, 3 H), 3.27 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ
= 161.3 (d, 2JC,F = 22 Hz), 86.2 (d, 1JC,F = 322 Hz), 61.6, 35.0 ppm.
19F NMR (282 MHz, CDCl3, 25 °C): δ = –60.2 (s) ppm. IR (neat):
276 Hz), 75.5 (d, 2JC,F = 26 Hz), 66.5, 66.1, 47.6 (d, 4JC,F = 11 Hz),
43.6 ppm. 19F NMR (282 MHz, CDCl3, 25 °C): δ = –122.4 (br.
s) ppm. IR (neat): νmax = 3437, 2862, 1634, 1059, 611 cm–1. HRMS
˜
(ESI+): calcd. for C13H16BrFNO3 [M + H]+ 332.0298; found
332.0299.
(Z)-3-(Benzo[d][1,3]dioxol-5-yl)-2-fluoro-1-morpholinoprop-2-en-1-
one (8ac): Yield 58 mg, 52%, Rf (PE/EtOAc 6:4) = 0.47, white solid,
m.p. 131–135 °C. 1H NMR (300 MHz, CDCl3, 25 °C): δ = 7.14 (d,
ν
= 3440, 1763, 1689 cm–1. C4H6Br2FNO2 (278.90): calcd. C
˜
max
17.23, H 2.17, N 5.02; found C 17.37, H 2.09, N 4.71.
5JH,F = 1.3 Hz, 1 H), 6.98 (d, JH,H = 8.1 Hz, 1 H), 6.78 (d, JH,F
3
5
General Procedure for the Synthesis of α,β-Unsaturated Amides (Z)-
8 and α-Bromo-α-fluoro-β-hydroxy Amides syn-9: Et2Zn (1.0 n in
hexanes, 1 mL, 1.00 mmol, 2.5 equiv.) was added to a solution of
an aldehyde 1 (0.40 mmol, 1 equiv.) and an amide 7 (135 mg,
0.44 mmol, 1.1 equiv.) in dry CH2Cl2 (1 mL) and the reaction mix-
ture was stirred at room temperature for 3 h. The reaction mixture
was then quenched by dropwise addition of HCl (4 n, 25 μL). After
the addition of silica gel, solvents were evaporated and the crude
residue, adsorbed on silica gel, was purified by column chromatog-
raphy to furnish the desired products 8 and 9 as single stereoiso-
mers.
3
= 8.1 Hz, 1 H), 6.52 (d, JH,F = 38.2 Hz, 1 H), 5.96 (s, 2 H), 3.74–
3.67 (m, 4 H), 3.67–3.61 (m, 4 H) ppm. 13C NMR (75 MHz,
2
1
CDCl3, 25 °C): δ = 161.9 (d, JC,F = 28 Hz), 150.0 (d, JC,F
276 Hz), 148.0 (d, JC,F = 3 Hz), 147.9, 125.5 (d, JC,F = 3 Hz),
=
6
3
4
2
4
124.8 (d, JC,F = 7 Hz), 116.0 (d, JC,F = 4 Hz), 109.2 (d, JC,F
=
10 Hz), 66.8 (2 C), 47.6–42.5 (br, 2 C) ppm. 19F NMR (282 MHz,
3
CDCl3, 25 °C): δ = –117.1 (d, JF,H = 38 Hz) ppm. IR (neat): ν
˜
max
= 1634, 1259, 672, 635 cm–1. C14H14FNO4 (279.26): calcd. C 60.21,
H 5.05, N 5.02; found C 60.42, H 5.14, N 4.79.
syn-3-(Benzo[d][1,3]dioxol-5-yl)-2-bromo-2-fluoro-3-hydroxy-1-
morpholinopropan-1-one (9ac): Yield 66 mg, 44%, Rf (PE/EtOAc
6:4) = 0.28, white solid, m.p. 79–82 °C. 1H NMR (300 MHz,
(Z)-2-Fluoro-1-morpholino-3-(3,4,5-trimethoxyphenyl)prop-2-en-1-
one (8aa): Yield 70 mg, 54%, Rf (PE/EtOAc 6:4) = 0.12, white solid,
2
CDCl3, 25 °C): δ = 7.04 (s, 1 H), 6.93 (d, JH,H = 8.1 Hz, 1 H),
1
m.p. 96–98 °C. H NMR (300 MHz, CDCl3, 25 °C): δ = 6.77 (s, 2
2
3
6.78 (d, JH,H = 8.1 Hz, 1 H), 5.96 (s, 2 H), 5.06 (dd, JH,F = 3.8,
3
H), 6.49 (d, JH,F = 38.1 Hz, 1 H), 3.81 (s, 9 H), 3.72–3.59 (m, 8
3JH,H = 1.8 Hz, 1 H), 4.92 (br. s, 1 H), 3.94–3.47 (m, 8 H) ppm.
2
H) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ = 161.6 (d, JC,F
=
13C NMR (75 MHz, CDCl3, 25 °C): δ = 165.3 (d, JC,F = 23 Hz),
2
1
28 Hz), 152.9 (2 C), 150.0 (d, JC,F = 278 Hz), 138.6, 126.7, 115.9
147.8, 147.1, 129.1, 122.5 (d, 4JC,F = 2 Hz), 109.1 (d, 4JC,F = 2 Hz),
107.5, 102.8 (d, 1JC,F = 275 Hz), 75.2 (d, 2JC,F = 26 Hz), 66.5, 66.1,
3
4
(d, JC,F = 4 Hz), 106.8 (d, JC,F = 8 Hz, 2 C), 66.6, 60.6, 55.8 (2
C), 45.8 (br), 44.3 (br) ppm. 19F NMR (282 MHz, CDCl3, 25 °C):
47.6 (d, JC,F = 11 Hz), 43.6 ppm. 19F NMR (282 MHz, CDCl3,
4
3
δ = –116.0 (d, JF,H = 39 Hz) ppm. IR (neat): ν
= 2925, 1641,
˜
max
25 °C): δ = –122.1 (br. s) ppm. IR (neat): ν
= 2917, 2862, 1646,
˜
max
1415, 1250, 1133, 1104 cm–1. C16H20FNO5 (325.33): calcd. C 59.07,
1446, 1101 cm–1. C14H15BrFNO5 (376.18): calcd. C 44.70, H 4.02,
H 6.20, N 4.31; found C 59.31, H 6.60, N 4.18.
N 3.72; found C 44.57, H 4.34, N 3.59.
syn-2-Bromo-2-fluoro-3-hydroxy-1-morpholino-3-(3,4,5-trimeth-
oxyphenyl)propan-1-one (9aa): Yield 69 mg, 41%, Rf (PE/EtOAc
6:4) = 0.21, yellow solid, m.p. 115–118 °C. 1H NMR (300 MHz,
(Z)-3-(4-Chlorophenyl)-2-fluoro-1-morpholinoprop-2-en-1-one (8ad):
Yield 66 mg, 61%, Rf (PE/EtOAc 6:4) = 0.33, white solid, m.p.
111–113 °C. 1H NMR (300 MHz, CDCl3, 25 °C): δ = 7.47 (d, 3JH,H
3
3
3
3
CDCl3, 25 °C): δ = 6.72 (s, 2 H), 5.07 (dd, JH,F = 3.8, JH,H
=
= 8.6 Hz, 2 H), 7.30 (d, JH,H = 8.6 Hz, 2 H), 6.54 (d, JH,F
=
38.1 Hz, 1 H), 3.77–3.67 (m, 4 H), 3.66–3.59 (m, 4 H) ppm. 13C
NMR (75 MHz, CDCl3, 25 °C): δ = 161.4 (d, 2JC,F = 28 Hz), 152.3
(d, 1JC,F = 280 Hz), 134.6 (d, 6JC,F = 3 Hz), 130.8 (d, 4JC,F = 8 Hz,
2.3 Hz, 1 H), 4.95 (br. m, 1 H), 3.85 (s, 6 H), 3.83 (s, 3 H), 3.81–
3.51 (m, 8 H) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ = 165.3
(d, 2JC,F = 22 Hz), 152.5 (2 C), 138.1, 130.7, 105.8 (d, 4JC,F = 2 Hz,
1
2
3
2
2 C), 102.6 (d, JC,F = 275 Hz), 75.4 (d, JC,F = 25 Hz), 66.5, 66.1,
2 C), 129.8 (d, JC,F = 3 Hz), 128.8 (2 C), 114.7 (d, JC,F = 5 Hz),
60.7, 56.0 (2 C), 47.6 (d, JC,F = 11 Hz), 43.6 ppm. 19F NMR
4
66.7 (2 C), 46.3 (br), 43.6 (br) ppm. 19F NMR (282 MHz, CDCl3,
25 °C): δ = –113.8 (d, JF,H = 38 Hz) ppm. IR (neat): ν
3
(282 MHz, CDCl , 25 °C): δ = –122.0 (br. s) ppm. IR (neat): ν
˜
3
max
= 2862,
˜
max
= 3424, 2925, 1627, 1114, 1081 cm–1. C16H21BrFNO6 (422.24):
1646, 1610, 1114, 1083, 817 cm–1. C13H13ClFNO2 (269.70): calcd.
calcd. C 45.51, H 5.01, N 3.32; found C 46.71, H 4.41, N 3.36.
C 57.89, H 4.86, N 5.19; found C 57.95, H 5.26, N 5.08.
(Z)-2-Fluoro-1-morpholino-3-phenylprop-2-en-1-one (8ab): Yield
62 mg, 66%, Rf (cyclohexane/EtOAc 8:2) = 0.17, colourless oil. 1H
NMR (300 MHz, CDCl3, 25 °C): δ = 7.60–7.53 (m, 2 H), 7.43–7.26
(m, 3 H), 6.60 (d, 3JH,F = 38.5 Hz, 1 H), 3.77–3.69 (m, 4 H), 3.69–
3.62 (m, 4 H) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ = 161.3
syn-2-Bromo-3-(4-chlorophenyl)-2-fluoro-3-hydroxy-1-morpholino-
propan-1-one (9ad): Yield 50 mg, 34%, Rf (PE/EtOAc 6:4) = 0.50,
1
white solid, m.p. 77–80 °C. H NMR (300 MHz, CDCl3, 25 °C): δ
3
= 7.43 (d, JH,H = 8.2 Hz, 2 H), 7.33 (d, 3JH,H = 8.2 Hz, 2 H), 5.12
(br. s, 1 H), 5.0 (br. s, 1 H), 3.96–3.46 (m, 8 H) ppm. 13C NMR
(75 MHz, CDCl3, 25 °C): δ = 165.1 (d, 2JC,F = 23 Hz), 134.6, 133.8,
130.1 (d, 4JC,F = 2 Hz, 2 C), 127.8 (2 C), 102.4 (d, 1JC,F = 275 Hz),
2
1
3
(d, JC,F = 28 Hz), 150.1 (d, JC,F = 279 Hz), 131.1 (d, JC,F
=
4
6
3 Hz), 129.3 (d, JC,F = 8 Hz, 2 H), 128.6 (d, JC,F = 3 Hz), 128.3
2
2
4
(2 C), 115.4 (d, JC,F = 5 Hz), 66.3 (2 C), 46.0 (br), 43.4 (br) ppm.
74.8 (d, JC,F = 26 Hz), 66.5, 66.1, 47.6 (d, JC,F = 11 Hz),
3
19F NMR (282 MHz, CDCl3, 25 °C): δ = –114.53 (d, JF,H
=
43.6 ppm. 19F NMR (282 MHz, CDCl3, 25 °C): δ = –122.7 (br.
s) ppm. IR (neat): ν
= 2916, 1640, 833 cm–1. HRMS
= 3425, 2862, 1640, 1114, 1078, 575 cm–1.
39 Hz) ppm. IR (neat): ν
˜
max
˜
max
(ESI+): calcd. for C13H15FNO2 [M + H]+ 236.1087; found
C13H14BrClFNO3 (366.61): calcd. C 42.59, H 3.85, N 3.82; found
C 42.91, H 4.19, N 3.73.
236.1093.
syn-2-Bromo-2-fluoro-3-hydroxy-1-morpholino-3-phenylpropan-1- (Z)-3-(3,4-Dichlorophenyl)-2-fluoro-1-morpholinoprop-2-en-1-one
one (9ab): Yield 37 mg, 28%, Rf (cyclohexane/EtOAc 8:2) = 0.27,
(8ae): Yield 79 mg, 65%, Rf (PE/EtOAc 6:4) = 0.77, white solid,
m.p. 82–84 °C. 1H NMR (300 MHz, CDCl3, 25 °C): δ = 7.64 (d,
4JH,H = 1.6 Hz, 1 H), 7.40 (d, 3JH,H = 8.3 Hz, 1 H), 7.34 (dd, 3JH,H
1
colourless solid, m.p. 112–114 °C. H NMR (300 MHz, CDCl3,
3
25 °C): δ = 7.56–7.44 (m, 2 H), 7.42–7.32 (m, 3 H), 5.16 (dd, JH,F
Eur. J. Org. Chem. 2013, 3278–3289
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3285

X. Pannecoucke et al.
FULL PAPER
= 8.3, JH,H = 1.6 Hz, 1 H), 6.50 (d, JH,F = 37.4 Hz, 1 H), 3.74–
4
3
4
1
128.83 (2 C), 128.80 (d, JC,F = 2 Hz, 2 C), 102.4 (d, JC,F
=
=
2
4
3.67 (m, 4 H), 3.67–3.59 (m, 4 H) ppm. 13C NMR (75 MHz, 276 Hz), 75.1 (d, JC,F = 25 Hz), 66.5, 66.1, 52.1, 47.6 (d, JC,F
2
1
CDCl3, 25 °C): δ = 161.1 (d, JC,F = 27 Hz), 152.1 (d, JC,F
=
10 Hz), 43.6 ppm. 19F NMR (282 MHz, CDCl3, 25 °C): δ = –122.7
6
3
282 Hz), 132.84 (d, JC,F = 3 Hz), 132.78, 131.3 (d, JC,F = 3 Hz),
(br. s) ppm. IR (neat): ν
= 3424, 2958, 1720, 1622, 830,
˜
max
4
4
131.1 (d, JC,F = 3 Hz), 130.5, 128.8 (d, JC,F = 3 Hz), 113.8 (d,
530 cm–1. HRMS (ESI+): calcd. for C15H18BrFNO5 [M + H]+
2JC,F = 5 Hz), 66.7 (2 C), 47.8 (br), 43.7 (br) ppm. 19F NMR 390.0352; found 390.0359.
3
(282 MHz, CDCl3, 25 °C): δ = –111.9 (d, JF,H = 38 Hz) ppm. IR
(Z)-2-Fluoro-1-morpholino-3-(thiophen-2-yl)prop-2-en-1-one (8ah):
Yield 39 mg, 40%, Rf (PE/EtOAc 6:4) = 0.38, brown oil. 1H NMR
(neat): ν
= 2962, 1624, 1110, 833 cm–1. HRMS (ESI+): calcd.
˜
max
for C13H13Cl2FNO2 [M + H]+ 304.0307; found 304.0310.
3
(300 MHz, CDCl3, 25 °C): δ = 7.38 (d, JH,H = 5.1 Hz, 1 H), 7.19
3
3
syn-2-Bromo-3-(3,4-dichlorophenyl)-2-fluoro-3-hydroxy-1-morph- (d, JH,H = 3.1 Hz, 1 H), 7.04–6.97 (m, 1 H), 6.94 (d, JH,F
=
olinopropan-1-one (9ae): Yield 55 mg, 34%, Rf (PE/EtOAc 6:4) =
37.1 Hz, 1 H), 3.73–3.56 (m, 8 H) ppm. 13C NMR (75 MHz,
1
2
1
0.57, yellow oil. H NMR (300 MHz, CDCl3, 25 °C): δ = 7.61 (s,
CDCl3, 25 °C): δ = 161.1 (d, JC,F = 27 Hz), 149.6 (d, JC,F
=
3
3
4
6
1 H), 7.43 (d, JH,H = 8.3 Hz, 1 H), 7.32 (d, JH,H = 8.3 Hz, 1 H), 277 Hz), 133.6 (d, JC,F = 4 Hz), 130.3 (d, JC,F = 4 Hz), 129.0 (d,
5.10 (s, 1 H), 5.06 (s, 1 H), 3.92–3.52 (m, 8 H) ppm. 13C NMR
(75 MHz, CDCl3, 25 °C): δ = 165.0 (d, 2JC,F = 22 Hz), 135.6, 132.8,
131.9, 130.7 (d, 4JC,F = 2 Hz), 129.6, 128.0 (d, 4JC,F = 3 Hz), 102.0
3JC,F = 10 Hz), 127.2, 111.2 (d, 2JC,F = 9 Hz), 66.8 (2 C), 47.4–43.3
(br, 2 C) ppm. 19F NMR (282 MHz, CDCl3, 25 °C): δ = –113.8 (d,
3JF,H = 38 Hz) ppm. IR (neat): ν
= 2862, 1644, 1104, 833 cm–1.
˜
max
1
2
(d, JC,F = 276 Hz), 74.4 (d, JC,F = 26 Hz), 66.5, 66.1, 47.6 (d,
HRMS (ESI+): calcd. for C11H13FNO2S [M + H]+ 242.0651; found
4JC,F = 10 Hz), 43.6 ppm. 19F NMR (282 MHz, CDCl3, 25 °C): δ
242.0654.
= –122.8 (br. s) ppm. IR (neat): ν
= 3425, 2916, 1640, 840,
˜
max
syn-2-Bromo-2-fluoro-3-hydroxy-1-morpholino-3-(thiophen-2-yl)-
propan-1-one (9ah): Yield 57 mg, 42%, Rf (PE/EtOAc 6:4) = 0.52,
brown solid, m.p. 116–118 °C. 1H NMR (300 MHz, CDCl3, 25 °C):
532 cm–1. HRMS (ESI+): calcd. for C13H14BrCl2FNO3 [M + H]+
399.9518; found 399.9524.
3
3
(Z)-4-(2-Fluoro-3-morpholino-3-oxoprop-1-enyl)benzonitrile (8af):
Yield 60 mg, 58%, Rf (PE/EtOAc 6:4) = 0.19, white solid, m.p.
δ = 7.35 (d, JH,H = 5.0 Hz, 1 H), 7.13 (br. s, 1 H), 7.02 (bt, JH,H
3
3
= 5.0 Hz, 1 H), 5.43 (dd, JH,F = 5.0, JH,H = 2.6 Hz, 1 H), 4.96
120–123 °C. 1H NMR (300 MHz, CDCl3, 25 °C): δ = 7.62 (s, 4 H),
(dd, JH,F = 1.4, JH,H = 2.6 Hz, 1 H), 3.93–3.45 (m, 8 H) ppm.
4
3
3
2
6.57 (d, JH,F = 37.3 Hz, 1 H), 3.89–3.46 (m, 8 H) ppm. 13C NMR 13C NMR (75 MHz, CDCl3, 25 °C): δ = 164.8 (d, JC,F = 23 Hz),
2
4
1
(75 MHz, CDCl3, 25 °C): δ = 160.8 (d, JC,F = 28 Hz), 153.0 (d, 138.2, 127.1 (d, JC,F = 3 Hz), 126.3, 126.2, 101.4 (d, JC,F
=
1JC,F = 275 Hz), 135.8 (d, 3JC,F = 3 Hz), 132.3 (2 C), 129.9 (d, 4JC,F
= 8 Hz, 2 C), 118.3, 114.0 (d, 2JC,F = 4 Hz), 112.0 (d, 6JC,F = 3 Hz),
66.6 (2 C), 46.9 (br), 43.5 (br) ppm. 19F NMR (282 MHz, CDCl3,
276 Hz), 73.2 (d, 2JC,F = 27 Hz), 66.5, 66.1, 47.6 (d, 4JC,F = 11 Hz),
43.5 ppm. 19F NMR (282 MHz, CDCl3, 25 °C): δ = –122.5 (br.
s) ppm. IR (neat): ν = 3361, 2927, 1622, 1112, 993, 892,
˜
max
25 °C): δ = –122.8 (br. s) ppm. IR (neat): ν
= 2917, 1622, 1259,
776 cm–1. C11H13BrFNO3S (338.19): calcd. C 39.07, H 3.87, N
˜
max
1107, 842, 533 cm–1. C14H13FN2O2 (260.26): calcd. C 64.61, H 4.14, S 9.48; found C 39.47, H 4.17, N 4.24, S 9.03.
5.03, N 10.76; found C 64.25, H 5.39, N 10.49.
(2Z,4E)-2-Fluoro-4-methyl-1-morpholino-5-phenylpenta-2,4-dien-1-
4-(syn-2-Bromo-2-fluoro-1-hydroxy-3-morpholino-3-oxopropyl)- one (8ai): Yield 46 mg, 42%, Rf (PE/EtOAc 6:4) = 0.35, yellow oil.
benzonitrile (9af): Yield 47 mg, 33%, Rf (PE/EtOAc 6:4) = 0.30, 1H NMR (300 MHz, CDCl3, 25 °C): δ = 7.38–7.12 (m, 5 H), 6.65
3
white solid, m.p. 147–150 °C. 1H NMR (300 MHz, CDCl3, 25 °C): (s, 1 H), 6.27 (d, JH,F = 38.7 Hz, 1 H), 3.80–3.49 (m, 8 H), 2.11
3
3
4
δ = 7.66 (d, JH,H = 8.4 Hz, 2 H), 7.63 (d, JH,H = 8.4 Hz, 2 H),
5.20 (br. s, 1 H), 5.11 (br. s, 1 H), 3.89–3.51 (m, 8 H) ppm. 13C
NMR (75 MHz, CDCl3, 25 °C): δ = 164.9 (d, 2JC,F = 23 Hz), 140.5,
(dd, JH,H = 2.8, 1.0 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3,
2
1
25 °C): δ = 162.2 (d, JC,F = 29 Hz), 149.3 (d, JC,F = 278 Hz),
136.6, 135.7 (d, JC,F = 6 Hz), 131.1 (d, JC,F = 5 Hz, 2 H), 129.2
4
5
4
2
131.4 (2 C), 129.5 (d, JC,F = 2 Hz, 2 C), 118.6, 112.5, 101.9 (d,
(2 C), 128.2 (2 C), 127.3, 120.7 (d, JC,F = 4 Hz), 66.8 (2 C), 48.6–
1JC,F = 276 Hz), 74.6 (d, JC,F = 25 Hz), 66.5, 66.0, 47.6 (d, JC,F
41.7 (br, 2 C), 16.6 (d, JC,F = 7 Hz) ppm. 19F NMR (282 MHz,
2
4
4
= 11 Hz), 43.6 ppm. 19F NMR (282 MHz, CDCl3, 25 °C): δ = CDCl3, 25 °C): δ = –116.6 (d, JF,H = 39 Hz) ppm. IR (neat): ν
3
˜
max
–123.0 (br. s) ppm. IR (neat): ν
= 3431, 2850, 1640, 1083, 660,
= 2856, 1634, 1440, 1259, 1120, 751, 702 cm–1. HRMS (ESI+):
˜
max
570 cm–1. C14H14BrFN2O3 (357.17): calcd. C 47.08, H 3.95, N 7.84; calcd. for C16H19FNO2 [M + H]+ 276.1400; found 276.1405.
found C 47.25, H 4.33, N 7.73.
syn-(E)-2-Bromo-2-fluoro-3-hydroxy-4-methyl-1-morpholino-5-phen-
Methyl (Z)-4-(2-Fluoro-3-morpholino-3-oxoprop-1-enyl)benzoate ylpent-4-en-1-one (9ai): Yield 31 mg, 21%, Rf (PE/EtOAc 6:4) =
(8ag): Yield 81 mg, 69%, Rf (PE/EtOAc 6:4) = 0.27, orange oil. 1H
NMR (300 MHz, CDCl3, 25 °C): δ = 7.96 (d, JH,H = 8.4 Hz, 2
0.45, white solid, m.p. 74–77 °C. 1H NMR (300 MHz, CDCl3,
25 °C): δ = 7.35–7.23 (m, 4 H), 7.23–7.10 (m, 1 H), 6.74 (s, 1 H),
4.75 (br. s, 1 H), 4.58 (br. s, 1 H), 3.95–3.60 (m, 7 H), 3.60–3.39
3
3
3
H), 7.55 (d, JH,H = 8.4 Hz, 2 H), 6.55 (d, JH,F = 38.0 Hz, 1 H),
3.84 (s, 3 H), 3.74–3.53 (m, 8 H) ppm. 13C NMR (75 MHz, CDCl3, (m, 1 H), 1.94 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ
25 °C): δ = 166.3, 161.3 (d, JC,F = 28 Hz), 152.3 (d, JC,F
283 Hz), 135.6 (d, JC,F = 3 Hz), 130.0 (d, JC,F = 2 Hz), 129.7 (2
2
1
2
=
= 165.6 (d, JC,F = 23 Hz), 137.0, 132.2, 131.5, 129.2 (2 C), 128.0
3
3
1
1
(2 C), 126.8, 103.8 (d, JC,F = 276 Hz), 75.6 (d, JC,F = 27 Hz),
4
2
C), 129.5 (d, JC,F = 6 Hz), 114.7 (d, JC,F = 4 Hz), 66.7 (2 C),
66.5, 66.2, 47.7 (d, 2JC,F = 11 Hz), 43.6, 16.9 (d, 4JC,F = 5 Hz) ppm.
52.1, 46.8 (br), 43.6 (br) ppm. 19F NMR (282 MHz, CDCl3, 25 °C): 19F NMR (282 MHz, CDCl3, 25 °C): δ = –121.6 (br. s) ppm. IR
3
δ = –111.2 (d, JF,H = 38 Hz) ppm. IR (neat): ν
= 2862, 1715, (neat): νmax = 3429, 3307, 2855, 1631, 1250, 1114, 751 cm–1. HRMS
˜
˜
max
1646, 1114 cm–1. HRMS (ESI+): calcd. for C15H17FNO4
[M + H]+ 294.1142; found 294.1146.
(ESI+): calcd. for C16H20BrFNO3 [M + H]+ 372.0611; found
372.0614.
Methyl syn-4-(2-Bromo-2-fluoro-1-hydroxy-3-morpholino-3-oxo-
propyl)benzoate (9ag): Yield 28 mg, 18 %, Rf (PE/EtOAc 6:4) =
(Z)-2-Fluoro-1-morpholino-5-phenylpent-2-en-1-one (8aj): Yield
56 mg, 53%, Rf (PE/EtOAc 6:4) = 0.27, colourless oil. 1H NMR
(300 MHz, CDCl3, 25 °C): δ = 7.25–7.16 (m, 2 H), 7.16–7.06 (m, 3
1
0.43, orange oil. H NMR (300 MHz, CDCl3, 25 °C): δ = 8.01 (d,
3
3
3
3JH,H = 8.3 Hz, 2 H), 7.58 (d, JH,H = 8.3 Hz, 2 H), 5.20 (br. s, 1 H), 5.60 (dt, JH,F = 36.1, JH,H = 7.8 Hz, 1 H), 3.74–3.09 (m, 8
H), 5.05 (br. s, 1 H), 3.88–3.50 (m, 8 H) ppm. 13C NMR (75 MHz, H), 2.68 (t, JH,H = 7.4 Hz, 2 H), 2.68 (m, 2 H) ppm. 13C NMR
3
2
2
CDCl3, 25 °C): δ = 166.8, 165.1 (d, JC,F = 22 Hz), 140.3, 130.4,
(75 MHz, CDCl3, 25 °C): δ = 161.5 (d, JC,F = 30 Hz), 151.5 (d,
3286
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 3278–3289

Synthesis of Fluorinated Amides
4
1JC,F = 267 Hz), 140.6, 128.4 (2 C), 128.3 (2 C), 126.0, 116.1 (d,
2JC,F = 26 Hz), 66.5, 66.1, 55.2, 47.7 (d, JC,F = 11 Hz), 43.6 ppm.
2JC,F = 8 Hz), 66.7 (2 C), 46.6 (br), 42.9 (br), 34.5 (d, 4JC,F = 2 Hz), 19F NMR (282 MHz, CDCl3, 25 °C): δ = –122.3 (br. s) ppm. IR
25.4 (d, JC,F = 3 Hz) ppm. 19F NMR (282 MHz, CDCl3, 25 °C):
(neat): ν
= 2921, 2860, 1645, 1260, 1109 cm–1. C14H17BrFNO4
3
˜
max
3
δ = –118.4 (d, JF,H = 36 Hz) ppm. IR (neat): ν
= 2917, 1622, (362.19): calcd. C 46.43, H 4.73, N 3.87; found C 46.80, H 5.05, N
˜
max
1107, 530 cm–1. HRMS (ESI+): calcd. for C15H19FNO2 [M + H]+
3.94.
264.1400; found 264.1403.
(Z)-2-Fluoro-3-(4-hydroxyphenyl)-1-morpholinoprop-2-en-1-one
syn-2-Bromo-2-fluoro-3-hydroxy-1-morpholino-5-phenylpentan-1- (8ao): Yield 61 mg, 61%, Rf (PE/EtOAc 6:4) = 0.25, white solid,
1
one (9aj): Yield 33 mg, 23%, Rf (PE/EtOAc 6:4) = 0.52, colourless
oil. H NMR (300 MHz, CDCl3, 25 °C): δ = 7.28–7.08 (m, 5 H),
m.p. 94–97 °C. H NMR (300 MHz, CDCl3, 25 °C): δ = 7.29 (br.
1
3
s, 1 H), 7.21 (t, JH,H = 8.1 Hz, 1 H), 7.12–7.05 (m, 2 H), 6.89–
3
4.34 (br. s, 1 H), 3.90–3.76 (m, 2 H), 3.76–3.58 (m, 6 H), 3.54–3.39 6.79 (m, 1 H), 6.44 (d, JH,F = 38.3 Hz, 1 H), 3.80–3.62 (m, 8
3
2
2
(m, 1 H), 2.92 (ddd, JH,H = 13.9, 5.7, JH,H = 8.5 Hz, 1 H), 2.68
H) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ = 161.2 (d, JC,F
=
(ddd, JH,H = 16.8, 8.5, JH,H = 8.5 Hz, 1 H) ppm. 13C NMR 28 Hz), 156.4, 150.6 (d, JC,F = 278 Hz), 132.3 (d, JC,F = 3 Hz),
3
2
1
4
3
4
(75 MHz, CDCl3, 25 °C): δ = 165.1 (d, 2JC,F = 24 Hz), 141.5, 128.6
129.9, 121.8 (d, JC,F = 8 Hz), 116.7 (2 C), 116.6 (d, JC,F = 2 Hz),
1
1
(2 C), 128.4 (2 C), 125.9, 103.9 (d, JC,F = 276 Hz), 73.1 (d, JC,F
66.7 (2 C), 47.3 (br), 43.8 (br) ppm. 19F NMR (282 MHz, CDCl3,
2
4
3
= 26 Hz), 66.5, 66.2, 47.6 (d, JC,F = 11 Hz), 43.4, 32.0 (d, JC,F
=
25 °C): δ = –114.2 (d, JF,H = 38 Hz) ppm. IR (neat): ν
= 2925,
˜
max
1.1 Hz), 31.2 ppm. 19F NMR (282 MHz, CDCl3, 25 °C): δ = –123.6
1644, 1438, 1095, 752 cm–1. HRMS (ESI+): calcd. for C13H15FNO3
(br. s) ppm. IR (neat): νmax = 3425, 2920, 1622, 1120 cm–1. HRMS [M + H]+ 252.1036; found 252.1035.
˜
(ESI+): calcd. for C15H20BrFNO3 [M + H]+ 360.0611; found
syn-2-Bromo-2-fluoro-3-hydroxy-3-(4-hydroxyphenyl)-1-morpholino-
360.0617.
propan-1-one (9ao): Yield 46 mg, 33%, Rf (PE/EtOAc 6:4) = 0.26,
(E)-2-Fluoro-1-morpholino-3-phenylbut-2-en-1-one (8al): Yield
99 mg, 99%, Rf (PE/EtOAc 6:4) = 0.32, colourless oil. 1H NMR
white solid, m.p. 133–136 °C. 1H NMR (300 MHz, CDCl3, 25 °C):
3
3
δ = 7.20 (t, JH,H = 8.1 Hz, 1 H), 7.03 (s, 1 H), 6.99 (d, JH,H
=
3
4
(300 MHz, CDCl3, 25 °C): δ = 7.34–7.24 (m, 3 H), 7.24–7.16 (m, 2 8.1 Hz, 1 H), 6.83 (dd, JH,H = 8.1, JH,H = 1.8 Hz, 1 H), 6.13 (br.
3
H), 3.51–3.27 (m, 4 H), 3.13–3.00 (m, 2 H), 2.97–2.85 (m, 2 H),
s, 1 H), 5.13 (d, JH,F = 4.9 Hz, 1 H), 5.12 (br. s, 1 H), 3.93–3.39
2.05 (d, JH,F = 4.3 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3,
(m, 8 H) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ = 165.3 (d,
4
2
1
4
25 °C): δ = 162.0 (d, JC,F = 34 Hz), 145.5 (d, JC,F = 256 Hz),
2JC,F = 24 Hz), 155.3, 136.9, 128.9, 121.0 (d, JC,F = 3 Hz), 115.8,
136.6 (d, 3JC,F = 7 Hz), 128.7 (2 C), 128.5, 127.8 (d, JC,F = 3 Hz),
115.7 (d, JC,F = 3 Hz), 102.6 (d, JC,F = 276 Hz), 75.3 (d, JC,F =
4
4
1
2
2
3
4
120.4 (d, JC,F = 16 Hz), 66.0, 65.9, 46.7, 41.8, 15.4 (d, JC,F
=
25 Hz), 66.5, 66.1, 47.7 (d, JC,F = 11 Hz), 43.7 ppm. 19F NMR
15 Hz) ppm. 19F NMR (282 MHz, CDCl3, 25 °C): δ = –113.2 (q,
(282 MHz, CDCl3, 25 °C): δ = –122.6 (d, JF,H = 4 Hz) ppm. IR
3
4JF,H = 5 Hz) ppm. IR (neat): ν
= 2858, 1622, 1444, 1110, 832,
(neat): νmax = 3283, 2925, 1627, 110, 949, 700 cm–1. HRMS (ESI+):
˜
˜
max
533 cm–1. HRMS (ESI+): calcd. for C14H17FNO2 [M + H]+ calcd. for C13H16BrFNO4 [M + H]+ 348.0247; found 348.0253.
250.1243; found 250.1250.
(E)-3-[4-(Benzyloxy)phenyl]-2-fluoro-1-morpholinopent-2-en-1-one
2-Cyclohexylidene-2-fluoro-1-morpholinoethanone (8am): Yield
84 mg, 92%, Rf (PE/EtOAc 6:4) = 0.42, colourless oil. 1H NMR
(300 MHz, CDCl3, 25 °C): δ = 3.74–3.52 (m, 6 H), 3.51–3.33 (br. 7.08 (d, JH,H = 8.8 Hz), 6.85 (d, JH,H = 8.8 Hz), 4.97 (s, 2 H),
(8ap): Yield 126 mg, 85%, Rf (PE/EtOAc 6:4) = 0.47, colourless
1
oil. H NMR (300 MHz, CDCl3, 25 °C): δ = 7.36–7.17 (m, 5 H),
3
3
m, 2 H), 2.28–2.16 (br. m, 2 H), 2.16–2.05 (br. m, 2 H), 1.50 (s, 6 3.39–3.26 (m, 4 H), 3.08–2.99 (m, 2 H), 2.96–2.86 (m, 2 H), 2.46
2
3
4
3
H) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ = 161.8 (d, JC,F
=
(dq, JH,H = 7.4, JH,F = 3.6 Hz, 2 H), 0.89 (t, JH,H = 7.4 Hz, 3
1
2
2
34 Hz), 142.2 (d, JC,F = 252 Hz), 124.4 (d, JC,F = 10 Hz), 66.8,
H) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ = 162.0 (d, JC,F
=
=
4
4
1
4
66.5, 46.9 (d, JC,F = 4 Hz), 42.0, 27.5 (d, JC,F = 4 Hz), 27.0 (d,
34 Hz), 158.6, 144.3 (d, JC,F = 255 Hz), 136.4, 129.3 (d, JC,F
3
3
4JC,F = 2 Hz), 26.4 (d, JC,F = 2 Hz), 25.8, 25.4 (d, JC,F
=
3 Hz, 2 C), 128.4 (2 C), 127.3, 127.2 (2 C), 125.6 (d, 2JC,F = 15 Hz),
7 Hz) ppm. 19F NMR (282 MHz, CDCl3, 25 °C): δ = –123.8 (br. 114.9 (2 C), 69.7, 65.9, 65.8, 46.5, 41.5, 22.4 (d, 3JC,F = 5 Hz), 12.2
4
s) ppm. IR (neat): ν
= 2855, 1624, 1100 cm–1. HRMS (ESI+):
(d, JC,F = 2 Hz) ppm. 19F NMR (282 MHz, CDCl3, 25 °C): δ =
˜
max
calcd. for C12H19FNO2 [M + H]+ 228.1400; found 228.1410.
–116.2 (bm) ppm. IR (neat): ν
= 2958, 1646, 1114, 840, 636,
˜
max
532 cm–1. HRMS (ESI+): calcd. for C22H25FNO3 [M + H]+
370.1818; found 3701824.
(Z)-2-Fluoro-3-(4-methoxyphenyl)-1-morpholinoprop-2-en-1-one
(8an): Yield 63 mg, 59%, Rf (PE/EtOAc 6:4) = 0.25, white solid,
m.p. 72–77 °C. 1H NMR (300 MHz, CDCl3, 25 °C): δ = 7.52 (d, (E)-5-Chloro-2-fluoro-1-morpholino-3-phenylpent-2-en-1-one (8aq):
3JH,H = 8.9 Hz, 2 H), 6.88 (d, JH,H = 8.9 Hz, 2 H), 6.56 (d, JH,F
Yield 100 mg, 84%, Rf (PE/EtOAc 6:4) = 0.41, colourless oil. 1H
NMR (300 MHz, CDCl3, 25 °C): δ = 7.36–7.26 (m, 3 H), 7.26–7.16
3
3
= 38.9 Hz, 1 H), 3.80 (s, 3 H), 3.75–3.57 (m, 8 H) ppm. 13C NMR
2
3
(75 MHz, CDCl3, 25 °C): δ = 162.0 (d, JC,F = 28 Hz), 159.9 (d, (m, 2 H), 3.46 (t, JH,H = 7.0 Hz, 2 H), 3.39 (br. s, 4 H), 3.24–3.17
6JC,F = 3 Hz), 149.8 (d, JC,F = 275 Hz), 131.2 (d, JC,F = 8 Hz, 2 (m, 2 H), 3.10–3.03 (m, 2 H), 2.95 (dt, JH,H = 7.0, 4JH,F = 3.2 Hz,
1
4
3
3
2
2
C), 124.0 (d, JC,F = 3 Hz), 115.8 (d, JC,F = 5 Hz), 114.0 (2 C),
2 H) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ = 161.3 (d, JC,F
66.7 (2 C), 47.7–42.5 (br, 2 C) ppm. 19F NMR (282 MHz, CDCl3,
= 33 Hz), 147.6 (d, 1JC,F = 262 Hz), 134.1 (d, 3JC,F = 7 Hz), 128.91
3
4
2
25 °C): δ = –117.9 (d, JF,H = 39 Hz) ppm. IR (neat): ν
= 3424,
(2 C), 128.88, 128.4 (d, JC,F = 3 Hz), 120.0 (d, JC,F = 14 Hz),
˜
max
2925, 1598, 1429, 1250, 1118, 1020 cm–1. C14H16FNO3 (265.28): 66.2, 66.0, 46.7, 41.8, 41.6 (d, JC,F = 3 Hz), 32.7 (d, JC,F
=
4
4
calcd. C 63.39, H 6.08, N 5.28; found C 63.21, H 6.16, N 4.94.
4 Hz) ppm. 19F NMR (282 MHz, CDCl3, 25 °C): δ = –111.7
(s) ppm. IR (neat): ν
= 2858, 1622, 986, 540 cm–1. HRMS
˜
max
syn-2-Bromo-2-fluoro-3-hydroxy-3-(4-methoxyphenyl)-1-morph-
olinopropan-1-one (9an): Yield 36 mg, 32%, Rf (PE/EtOAc 6:4) =
0.30, white solid, m.p. 142–146 °C. 1H NMR (300 MHz, CDCl3,
(ESI+): calcd. for C15H18ClFNO2 [M + H]+ 298.1010; found
297.0999.
3
3
25 °C): δ = 7.43 (d, JH,H = 7.6 Hz, 2 H), 6.90 (d, JH,H = 7.6 Hz,
2-Fluoro-1-morpholino-3,3-diphenylprop-2-en-1-one (8ar): Yield
120 mg, 96%, Rf (PE/EtOAc 6:4) = 0.43, white solid, m.p. 162–
3
3
2 H), 5.11 (dd, JH,F = 3.8, JH,H = 2.3 Hz, 1 H), 4.89 (br. m, 1
H), 3.95–3.47 (m, 8 H), 3.81 (s, 3 H) ppm. 13C NMR (75 MHz, 166 °C. H NMR (300 MHz, CDCl3, 25 °C): δ = 7.31–7.18 (m, 8
1
2
4
CDCl3, 25 °C): δ = 165.4 (d, JC,F = 22 Hz), 159.9, 129.9 (d, JC,F
H), 7.18–7.09 (m, 2 H), 3.48–3.33 (m, 4 H), 3.28–3.19 (m, 2 H),
= 2 Hz, 2 C), 127.4, 113.1 (2 C), 103.1 (d, 1JC,F = 275 Hz), 75.2 (d, 3.08–2.98 (m, 2 H) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ =
Eur. J. Org. Chem. 2013, 3278–3289
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3287

X. Pannecoucke et al.
FULL PAPER
2
1
3
2
161.7 (d, JC,F = 33 Hz), 145.2 (d, JC,F = 266 Hz), 135.6 (d, JC,F
3 H) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ = 166.2 (d, JC,F
= 5 Hz), 135.2 (d, 3JC,F = 2 Hz), 129.8 (d, 4JC,F = 3 Hz, 2 C), 129.7
= 22 Hz), 134.5, 134.2, 130.1 (d, JC,F = 2 Hz, 2 C), 127.8 (2 C),
3
3
1
2
4
(d, JC,F = 4 Hz), 128.6, 128.5 (2 C), 128.2, 128.0 (2 C), 125.2 (d,
102.7 (d, JC,F = 276 Hz), 75.2 (d, JC,F = 26 Hz), 43.2 (d, JC,F
=
2JC,F = 12 Hz), 65.9, 65.8, 46.5, 41.6 ppm. 19F NMR (282 MHz,
10 Hz), 42.1, 13.8, 11.7 ppm. 19F NMR (282 MHz, CDCl3, 25 °C):
CDCl , 25 °C): δ = –112.2 (s) ppm. IR (neat): ν
= 2862, 1622,
δ = –122.9 (br. s) ppm. IR (neat): ν
= 3424, 1640, 1617, 1391,
˜
˜
3
max
max
745, 696 cm–1. C19H18FNO2 (311.35): calcd. C 73.29, H 5.83, N
1029, 878 cm–1. HRMS (ESI+): calcd. for C13H17BrClFNO2 [M +
H]+ 352.0115; found 352.0120.
4.50; found C 73.11, H 5.96, N 4.52.
2-Fluoro-1-morpholino-2-(tricyclo[3.3.1.13,7]dec-2-ylidene)prop-2-en-
1-one (8as): Yield 70 mg, 63%, Rf (PE/EtOAc 6:4) = 0.57, white
solid, m.p. 67–70 °C. 1H NMR (300 MHz, CDCl3, 25 °C): δ =
3.76–3.55 (m, 6 H), 3.55–3.39 (br. m, 2 H), 3.08–2.97 (br. m, 1 H),
2.64–2.77 (br. m, 1 H), 2.04–1.66 (m, 12 H) ppm. 13C NMR
N-Benzyl-2-bromo-3-(4-chlorophenyl)-2-fluoro-3-hydroxy-N-methyl-
propanamide (9dd): Yield 30 mg, 19%, Rf (PE/EtOAc 6:4) = 0.80,
colourless oil. Mixture of syn and anti diastereoisomers; only major
diastereoisomer is described. H NMR (300 MHz, CDCl3, 25 °C):
δ = 7.52–7.42 (m, 2 H), 7.42–7.27 (m, 5 H), 7.24–7.13 (m, 2 H),
1
2
3
3
(75 MHz, CDCl3, 25 °C): δ = 161.8 (d, JC,F = 34 Hz), 139.6 (d,
5.22 (dd, JH,H = 7.5, JH,F = 4.6 Hz, 1 H), 5.10 (br. m, 1 H), 4.78
2
4
1JC,F = 251 Hz), 132.7 (d, JC,F = 9 Hz), 66.9, 66.6, 47.0 (d, JC,F
3
3
(d, JH,H = 4.8 Hz, 1 H), 5.22 (d, JH,H = 4.8 Hz, 1 H), 3.15 (d,
4
4JH,F = 4.7 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ
= 4 Hz), 42.0, 38.6 (d, JC,F = 3 Hz, 2 C), 38.04 (2 C), 36.4, 30.8
(d, 3JC,F = 5 Hz), 28.6 (d, 4JC,F = 7 Hz), 27.6 (2 C) ppm. 19F NMR
2
3
= 166.9 (d, JC,F = 23 Hz), 135.4, 134.7, 134.0, 130.2 (d, JC,F
=
(282 MHz, CDCl , 25 °C): δ = –128.5 (br. s) ppm. IR (neat): ν
˜
3
max
3 Hz, 2 C), 128.9 (2 C), 127.9 (2 C), 127.7 (2 C), 127.1, 103.0 (d,
= 2911, 2856, 1640, 1440 cm–1. C16H22FNO2 (279.35): calcd. C
1JC,F = 276 Hz), 75.3 (d, 2JC,F = 25 Hz), 52.8, 36.2 ppm. 19F NMR
68.79, H 7.94, N 5.01; found C 68.64, H 8.16, N 5.00.
(282 MHz, CDCl , 25 °C): δ = –122.8 (br. s) ppm. IR (neat): ν
˜
3
max
= 3424, 2961, 1642, 1106, 957, 833, 546 cm–1. C17H17BrClFNO2
(400.67): calcd. C 50.96, H 4.03, N 3.50; found C 51.27, H 4.33, N
3.66.
(Z)-3-(4-Chlorophenyl)-2-fluoro-1-(piperidin-1-yl)prop-2-en-1-one
(8bd): Yield 47 mg, 32%, Rf (PE/EtOAc 6:4) = 0.53, white solid,
m.p. 76–79 °C. 1H NMR (300 MHz, CDCl3, 25 °C): δ = 7.50 (d,
3
3
3JH,H = 8.6 Hz, 2 H), 7.33 (d, JH,H = 8.6 Hz, 2 H), 6.44 (d, JH,F
= 38.1 Hz, 1 H), 3.56 (br. s, 4 H), 1.74–1.53 (m, 6 H) ppm. 13C
NMR (75 MHz, CDCl3, 25 °C): δ = 161.6 (d, 2JC,F = 28 Hz), 152.3
(d, 1JC,F = 281 Hz), 134.4 (d, 6JC,F = 3 Hz), 130.8 (d, 4JC,F = 8 Hz,
Multi-Cycle Procedure for the Preparation of Pure 8ab: The stan-
dard procedure was followed for the preparation of 8ab and syn-
9ab from 1b (0.6 mL, 6 mmol). The recovered pure syn-α-bromo-
α-fluoro-β-hydroxy amide 9ab was then dissolved in dry CH2Cl2
(3 mL) and Et2Zn (2 equiv.) was added. The mixture was for stirred
2 h at room temperature. Standard workup and purification gave
pure 8ab and remaining syn-9ab. Repeating this procedure once
again finally gave a total of 1.17 g (83%) of 8ab.
3
2
2 C), 130.3 (d, JC,F = 3 Hz), 128.9 (2 C), 113.6 (d, JC,F = 5 Hz),
47.8 (br), 44.3 (br), 26.4 (br), 25.6 (br), 24.5 ppm. 19F NMR
3
(282 MHz, CDCl3, 25 °C): δ = –111.8 (d, JF,H = 38 Hz) ppm. IR
(neat): ν
= 2935, 2850, 1603, 1443, 827 cm–1. C14H15ClFNO
˜
max
(267.73): calcd. C 62.81, H 5.65, N 5.23; found C 62.47, H 5.85, N
5.09.
Supporting Information (see footnote on the first page of this arti-
1
cle): Copies of the H NMR and 13C NMR spectra.
syn-2-Bromo-3-(4-chlorophenyl)-2-fluoro-3-hydroxy-1-(piperidin-1-
yl)propan-1-one (9bd): Yield 58 mg, 54 %, Rf (PE/EtOAc 6:4) =
0.72, colourless oil. 1H NMR (300 MHz, CDCl3, 25 °C): δ = 7.49–
7.41 (m, 2 H), 7.38–7.30 (m, 2 H), 5.24 (br. s, 1 H), 5.11 (br. s, 1
Acknowledgments
H), 3.80–3.65 (m, 2 H), 3.65–3.51 (m, 2 H), 1.78–1.49 (m, 6
This work was partially supported by the INSA-ROUEN, the Uni-
versity of Rouen, the Région Haute-Normandie, the Centre
National de la Recherche Scientifique (CNRS), the European Fund
for Research Development (EFRD) and the LABEX SynOrg.
EFRD 32819 (FEDER 32819) is gratefully acknowledged for a
postdoctoral fellowship to G. L.
2
H) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ = 164.9 (d, JC,F
=
22 Hz), 134.5, 134.2, 130.1 (d, 3JC,F = 2 Hz, 2 C), 128.7 (2 C), 102.6
(d, 1JC,F = 274 Hz), 75.0 (d, 2JC,F = 26 Hz), 48.0 (d, 4JC,F = 11 Hz),
44.7, 25.7, 25.5, 24.1 ppm. 19F NMR (282 MHz, CDCl3, 25 °C): δ
= –121.7 (br. s) ppm. IR (neat): ν
= 3425, 1631, 1363, 1175,
˜
max
1024, 944 cm–1. C14H16BrClFNO2 (364.64): calcd. C 46.11, H 4.42,
N 3.84; found C 46.00, H 4.15, N 3.64.
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(Z)-3-(4-Chlorophenyl)-N,N-diethyl-2-fluoroacrylamide (8cd): Yield
40 mg, 39%, Rf (PE/EtOAc 6:4) = 0.57, white solid, m.p. 56–58 °C.
1H NMR (300 MHz, CDCl3, 25 °C): δ = 7.49 (d, JH,H = 8.5 Hz,
3
2 H), 7.32 (d, 3JH,H = 8.6 Hz, 2 H), 6.56 (d, JH,F = 37.9 Hz, 1 H),
3
3
3.42 (q, JH,F = 7.0 Hz, 4 H), 1.31–1.06 (m, 6 H) ppm. 13C NMR
2
(75 MHz, CDCl3, 25 °C): δ = 161.9 (d, JC,F = 28 Hz), 152.5 (d,
6
4
1JC,F = 282 Hz), 134.4 (d, JC,F = 3 Hz), 130.8 (d, JC,F = 8 Hz, 2
3
2
C), 130.3 (d, JC,F = 3 Hz), 128.8 (2 C), 113.6 (d, JC,F = 5 Hz),
42.9 (br), 41.2 (br), 14.6 (br), 12.5 (br) ppm. 19F NMR (282 MHz,
3
CDCl3, 25 °C): δ = –113.9 (d, JF,H = 38 Hz) ppm. IR (neat): ν
˜
max
= 2973, 1613, 1438, 1278, 794 cm–1. C13H15ClFNO (255.72): calcd.
C 61.06, H 5.91, N 5.48; found C 60.94, H 6.21, N 5.26.
syn-2-Bromo-3-(4-chlorophenyl)-N,N-diethyl-2-fluoro-3-hydroxy-
propanamide (9cd): Yield 54 mg, 38%, Rf (PE/EtOAc 6:4) = 0.76,
colourless oil. 1H NMR (300 MHz, CDCl3, 25 °C): δ = 7.46 (d,
3
3JH,H = 8.2 Hz, 2 H), 7.33 (d, JH,H = 8.2 Hz, 2 H), 5.32 (br. s, 1
H), 5.11 (br. s, 1 H), 4.00–3.78 (m, 1 H), 3.67–3.48 (m, 1 H), 3.33–
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3288
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 3278–3289

Synthesis of Fluorinated Amides
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[11] At the outset of the project we found that carrying out the
reaction at room temperature with a 2:1 Et2Zn/amide ratio was
crucial to ensure complete conversion of the amide 2.
[12] When 2.2 equiv. of Et2Zn were used, anti-9ad (9%) remained
at the end of the reaction.
[13] Dibromofluoroacetamides were readily synthesized by a one-
step procedure from the corresponding amines and ethyl di-
bromofluoroacetate; see Exp. Section for details.
[5] For selected examples of α,β-unsaturated amides transforma-
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[6] For reviews on the preparation of fluorinated olefins, see: a)
G. Landelle, N. Bergeron, M.-O. Turcotte-Savard, J.-F. Paquin,
Chem. Soc. Rev. 2011, 40, 2867–2908; b) H. Yanai, T. Taguchi,
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[14] The relative configurations of olefins 8al and 8ap were deter-
1
mined by H-19F HOESY. See the Supporting Information for
details.
[15] CCDC-919940 (for 9ac) and CCDC-919939 (for 8ad) contain
the supplementary crystallographic data for this paper. These
data can be obtained free of charge from The Cambridge Crys-
tallographic
Data
Centre
via
www.ccdc.cam.ac.uk/
data_request/cif.
Received: January 26, 2013
Published Online: April 15, 2013
Eur. J. Org. Chem. 2013, 3278–3289
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3289