Enantioselective Reformatsky reaction of ethyl iododifluoroacetate with ketones

Article abstract of DOI:10.1039/c2ob25081k

Two approaches have been developed for the enantioselective Reformatsky reaction of ethyl iododifluoroacetate with ketones to form a quaternary carbon centre using (1R,2S)-1-phenyl-2-(1-pyrrolidinyl)-1-propanol as the chiral ligand. Good yields and high e

Full text of DOI:10.1039/c2ob25081k

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PAPER
Enantioselective Reformatsky reaction of ethyl iododifluoroacetate with
ketones†
Michal Fornalczyk, Kuldip Singh and Alison M. Stuart*
Received 11th January 2012, Accepted 23rd February 2012
DOI: 10.1039/c2ob25081k
Two approaches have been developed for the enantioselective Reformatsky reaction of ethyl
iododifluoroacetate with ketones to form a quaternary carbon centre using (1R,2S)-1-phenyl-2-
(1-pyrrolidinyl)-1-propanol as the chiral ligand. Good yields and high enantioselectivities (80–91% ee)
were achieved with a range of alkyl aryl ketones in a convenient one-pot protocol using ethyl
iododifluoroacetate and diethylzinc to form the difluorinated Reformatsky reagent homogeneously. In the
traditional two-step Reformatsky reaction using the preformed Reformatsky reagent generated from ethyl
iododifluoroacetate and zinc dust, good yields and good enantioselectivities (75–84% ee) were also
obtained.
enantioselective Reformatsky reactions of α-halogenated esters
with aldehydes and ketones have been promoted by BINOL
Introduction
Over the last 60 years fluorinated molecules have proved crucial
in the development of new pharmaceuticals and ten of the top
thirty best selling pharmaceutical products in 2008 contained at
least one fluorine atom.1 Although it is relatively straightforward
to introduce fluorine regioselectively, one of the most demanding
challenges in organofluorine chemistry is to design new methods
for the enantioselective synthesis of fluorinated organic com-
pounds. Outstanding progress has been made in recent years,2
but further work is required for chiral fluorinated molecules to be
increasingly used in medicinal chemistry.
The classical Reformatsky reaction between α-halogenated
esters, zinc dust and carbonyl compounds provides a convenient
synthesis of β-hydroxy esters.3 Since the heterogeneous reaction
conditions made the development of a catalytic asymmetric reac-
tion difficult, stoichiometric amounts of chiral ligands were
required to promote the enantioselective Reformatsky reaction
until recently.4 Homogeneous Reformatsky-type reactions have
now been developed and can be promoted either by using α-bro-
moesters/α-iodoesters with dialkylzincs in the presence of cata-
lysts or additives,5 or by the direct iodine–zinc exchange
between α-iodoesters with either diethylzinc or diisopropylzinc.6
The first catalytic enantioselective Reformatsky reaction of ethyl
iodoacetate was reported by Cozzi in 2006 using 20 mole% of a
chiral manganese salen catalyst and dimethylzinc to generate the
zinc reagent homogeneously.7k Since then, the catalytic
derivatives, chiral aminoalcohols, a chiral Schiff base and a
chiral bisoxazolidine.7
The Reformatsky reaction of ethyl bromodifluoroacetate is one
of the most efficient methods for the synthesis of medicinally-
important compounds containing a difluoromethylene group.8 In
contrast to the enantioselective Reformatsky reaction with
α-halogenated esters, there are only three reports of an enantio-
selective reaction with the difluorinated Reformatsky reagent
giving α,α-difluoro-β-hydroxy esters in good enantiomeric
excess in the presence of stoichiometric amounts of chiral ami-
noalcohols (Scheme 1).4a,9 A two-step procedure is normally
used and the Reformatsky reagent is prepared in the first step by
refluxing ethyl bromodifluoroacetate with freshly-activated zinc
Department of Chemistry, University of Leicester, Leicester, LE1 7RH,
UK. E-mail: Alison.Stuart@le.ac.uk
†Electronic supplementary information (ESI) available. NMR spectra
and CCDC 842560–842566. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c2ob25081k
Scheme 1 Enantioselective
Reformatsky
reaction
with
benzaldehyde.4a,9b
3332 | Org. Biomol. Chem., 2012, 10, 3332–3342
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dust, before cooling to room temperature and adding the difluori-
nated Reformatsky reagent to a mixture of the aromatic aldehyde
and the chiral aminoalcohol in the second step.
difluorinated Reformatsky reagent. This is in agreement with
recent work by Jubault who has shown that the Reformatsky
reaction between ethyl dibromofluoroacetate and carbonyl sub-
strates can be promoted by diethylzinc without any rhodium cat-
alyst in synthetic routes to α-fluoroacrylates and fluorinated
glycidic esters.12 In the enantioselective reactions (runs 2–8) the
excess of diethylzinc was used to deprotonate the chiral amino-
alcohol as well as to form the Reformatsky reagent in situ and
there was no trace of the product resulting from the addition of
diethylzinc to acetophenone in any of the reactions. As the
amount of (1S,2R)-N-methylephedrine was increased from 0.2 to
1.0 equivalent in runs 2 to 5, the enantiomeric excess increased
from 40 to 68% ee but the yield decreased from 51 to 23%. In
order to improve the yield (23%) with 1 equivalent of (1S,2R)-
N-methylephedrine, the reaction was repeated under exactly the
same conditions but with 1 mole% of Wilkinson’s catalyst incor-
porated (run 6). Although the yield increased to 60%, unfortu-
nately, the enantiomeric excess dropped to only 50% ee.
Consequently, Wilkinson’s catalyst was not used in runs 7 and 8
when the addition of further aliquots of ethyl bromodifluoroace-
tate and diethylzinc had the desired effect of improving the yield
to 53 and 72% respectively, but the enantiomeric excess
decreased to 61 and 57% ee.
Since the enantioselective Reformatsky reaction of ethyl bro-
modifluoroacetate is limited to aldehydes, we were interested in
extending this reaction to ketones in order to prepare quaternary
stereocenters. The asymmetric synthesis of quaternary carbon
centres is highly desirable, but it is a formidable goal because
ketones are less reactive electrophiles than aldehydes, they often
contain enolisable protons and there is less differentiation
between the two groups on the carbonyl substrate compared to
aldehydes.10 We have developed and report herein the first enan-
tioselective Reformatsky reaction of ethyl iododifluoroacetate
with ketones by two distinct strategies: (i) firstly, using diethyl-
zinc to generate the difluorinated Reformatsky reagent homoge-
neously and (1R,2S)-1-phenyl-2-(1-pyrrolidinyl)-1-propanol as
the chiral aminoalcohol; (ii) secondly, using the same chiral
ligand with the preformed Reformatsky reagent generated from
ethyl iododifluoroacetate and zinc dust.11 Good yields and high
enantioselectivities (up to 91% ee) have been obtained for a
broad range of alkyl aryl ketones.
Results and discussion
The effects of adding different substrates dropwise, as well as
different orders of substrate addition, were investigated but despite
many different combinations, there were no further improvements
in the reaction. The first real step forward was when ethyl iodo-
difluoroacetate was used instead of ethyl bromodifluoroacetate and
the yield improved dramatically from 23 to 72% with only a small
drop in the enantiomeric excess from 68 to 63% ee (Table 2,
Optimisation of the enantioselective Reformatsky-type reaction
with ethyl iododifluoroacetate and diethylzinc
We started our investigation with the reaction between acetophe-
none and ethyl bromodifluoroacetate using diethylzinc to gener-
ate the difluorinated Reformatsky reagent homogeneously and
(1S,2R)-N-methylephedrine as a cheap, chiral ligand (Table 1).
In run 1 a 100% conversion to ethyl-2,2-difluoro-3-hydroxy-3-
phenylbutanoate 1 was obtained without any chiral aminoalcohol
confirming that Wilkinson’s catalyst was not required to form the
Table 2 Enantioselective Reformatsky-type reaction with ethyl
iododifluoroacetate and diethylzinc
Table 1 Enantioselective Reformatsky-type reaction with ethyl
bromodifluoroacetate and diethylzinc
ICF2CO2Et
(equiv.)
Et2Zn
(equiv.)
Temp.
(° C)
Yielda,b
(%)
eec
(%)
Run
BrCF2CO2Et
Run (equiv.)
Et2Zn
(equiv.)
N-Me-Eph
(equiv.)
Yielda
(%)
eeb
(%)
1d
2d,f
3
1.5
1.5 + 0.5
1.5
1.5 + 0.5
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0 + 0.5
2.0
2.0 + 0.5
2.5
2.5
2.5
2.5
2.5
2.5
0
0
0
0
72 (59)
97 (87)
61 (54)
94 (66)
99 (92)
98 (95)
98 (95)
88
63e
58e
76
74
71
80
87
70
91
91
1
2
1.5
1.5
1.5
1.6
1.7
1.8
2.0
2.0
2.0 + 0.5
2.0 + 0.5
+ 0.5
0
100
51
49
49
23
60
53
72
NA
40
57
59
68
50
61
57
4f
5
0.2
0.4
0.6
1.0
1.0
1.0
1.0
0
3
4
1.5
1.5
6
−20
−40
−40
−50
−78
7
5
1.5
1.5
8g
9
6c
7d
8e
56 (46)
50 (41)
1.5 + 0.5
1.5 + 0.5 + 0.5
10
a Determined by GC using ditolyl ether as the internal standard in runs
1–5 and by 1H NMR spectroscopy in runs 6–9. b Isolated yield in
parenthesis. c Determined by chiral HPLC. d (1S,2R)-N-Methylephedrine
(1.0 equiv.) was used as the chiral aminoalcohol. e Major enantiomer
a Determined by GC using ditolyl ether as the internal standard.
b Determined by chiral HPLC. c Incorporation of Wilkinson’s catalyst
(1 mole%). d Further aliquots of ethyl bromodifluoroacetate (0.5 equiv.)
and diethylzinc (0.5 equiv.) were added after 2 hours. e Further aliquots
of ethyl bromodifluoroacetate (0.5 equiv.) and diethylzinc (0.5 equiv.)
were added after 2 and 4 hours.
formed
was
(R)-ethyl-2,2-difluoro-3-hydroxy-3-phenylbutanoate.
f Further aliquots of ethyl iododifluoroacetate (0.5 equiv.) and
diethylzinc (0.5 equiv.) were added after 2 hours. g 0.2 Equivalents of
(1R,2S)-1-phenyl-2-(1-pyrrolidinyl)-propan-1-ol were used.
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run 1). The better yields are presumably due to a more efficient
iodine–zinc exchange reaction between ethyl iododifluoroacetate
and diethylzinc than the bromine–zinc exchange reaction
between ethyl bromodifluoroacetate and diethylzinc. When
further aliquots of ethyl iododifluoroacetate and diethylzinc were
added after 2 hours in run 2 the yield increased to 97% but the
enantiomeric excess decreased to 58% ee. By changing the
chiral aminoalcohol to (1R,2S)-1-phenyl-2-(1-pyrrolidinyl)-
propan-1-ol the enantiomeric excess increased to 76% ee in run
3 albeit with a slightly lower yield. However, the yield was
improved to 94% by adding further aliquots of ethyl iododifluoro-
acetate and diethylzinc in run 4. A more convenient protocol
was used in runs 5 to 10 when 2 equivalents of ethyl iododifluoro-
acetate and 2.5 equivalents of diethylzinc were added in one
portion at the beginning of the reaction. As the reaction tempera-
ture was lowered from 0 to −78 °C, the yield decreased but the
enantiomeric excess increased to an excellent 91% ee. Run
7 gave the best result providing an excellent isolated yield (95%)
with an excellent enantiomeric excess (87% ee) at −40 °C.
Although the reaction can be performed with a catalytic amount
of chiral ligand (0.2 equivalents) at −40 °C, the enantiomeric
excess decreased to 70% ee (run 8) probably because of the
competitive uncatalysed pathway.
hydroxy-3-phenylbutanoate 1 was obtained in only a 19% yield
(vide supra). However, the yield increased as the amount
of (1R,2S)-1-phenyl-2-(1-pyrrolidinyl)propan-1-ol was increased
from 0.4 to 1.4 equivalents and the same enantiomeric excess
(83% ee) was obtained whether 0.6, 0.8, 1.0 or 1.4 equivalents
of the chiral aminoalcohol were used. Surprisingly, a lower enan-
tiomeric excess (73% ee) and a lower yield (81%) was obtained
with ethyl bromodifluoroacetate in run 6 compared to using ethyl
iododifluoroacetate in run 5. When the reaction was carried out
at −10 °C in run 7, the yield decreased dramatically and disap-
pointingly, there was no improvement in the enantiomeric excess.
Similar to the one-pot protocol, the optimum yield and enantio-
meric excess was obtained when the reaction was mediated with
1 equivalent of (1R,2S)-1-phenyl-2-(1-pyrrolidinyl)propan-1-ol
(run 5). However, even the best conditions for the two-step proto-
col still required a larger excess of ethyl iododifluoroacetate,
gave a lower yield and a lower enantiomeric excess than the best
one-step protocol described above (Table 2, run 7).
Since the homogeneous and heterogeneous protocols gave
different yields in the uncatalysed Reformatsky reaction
(Table 1, run 1 versus Table 3, run 1), preliminary experiments
directed towards differentiating between the mechanisms of
these reactions were undertaken. Firstly, 19F NMR spectroscopy
was used to probe the active zinc intermediates formed in the
reactions between ethyl iododifluoroacetate and either zinc dust
or diethylzinc, and secondly, both enantioselective Reformatsky
reactions were monitored at 0 °C in the presence of 1 equivalent
of (1R,2S)-1-phenyl-2-(1-pyrrolidinyl)propan-1-ol.
Comparison of the heterogeneous and homogeneous
Reformatsky reactions
The classical two-step reaction using the preformed difluorinated
Reformatsky reagent, generated from ethyl iododifluoroacetate
and zinc dust, was also investigated with the same chiral ligand
in THF at 0 °C (Table 3) for a direct comparison with the homo-
geneous one-step protocol. The difluorinated Reformatsky
reagent was prepared by the procedure described by Knochel
et al.4a and a large excess was used in order to deprotonate the
chiral aminoalcohol as well as to react with acetophenone.
Without chiral aminoalcohol (run 1), ethyl-2,2-difluoro-3-
Initially, two singlets were observed in the 19F NMR spectrum
of the Reformatsky reagent, generated from ethyl bromodifluoro-
acetate and zinc dust in THF, showing that carbon-metallated
enolates were formed as reported in similar work by Burton and
Easdon (eqn (1)) and there was no sign of an AB pattern for
oxygen-metallated enolates.13 In addition, there were also two
minor singlets at −120.7 and −127.9 ppm corresponding to the
Wurtz coupled by-product, (CF2CO2Et)2 and difluoroacetate
respectively (see Fig. S5 in the ESI†).
Table 3 Enantioselective
Reformatsky
reaction
with
ethyl
iododifluoroacetate and Zn dust
ð1Þ
In the reactions between ethyl iododifluoroacetate and either
zinc dust or diethylzinc, singlets were observed in the 19F NMR
spectra showing that carbon-metallated enolates were formed in
both protocols. The proposed zinc intermediates and their
Schlenk equilibria are summarised in eqn (2) and (3), whilst the
19F NMR spectra are shown in Fig. S6 and S7 in the ESI.† As
expected, IZnCF2CO2Et was the main species formed in the zinc
insertion method with only small amounts of the diorganozinc
reagent present (eqn (2)). In the iodine–zinc exchange reaction
using diethylzinc, however, there was a 70–30 mixture of
EtZnCF2CO2Et and Zn(CF2CO2Et)2 respectively (eqn (3)).14
The latter reaction using diethylzinc also gave a cleaner reaction
with no organic by-products formed, whilst small amounts of
(CF2CO2Et)2 and difluoroacetate were observed in the zinc inser-
tion method (eqn (2)). These data confirm that different zinc
intermediates are formed by the two different procedures and
account for their different reactivity since it is well-established
ICF2CO2Et
(equiv.)
Chiral ligand
(equiv.)
Yielda,b
(%)
eec
(%)
Run
1
2
3
4
1.5
1.9
2.1
2.3
2.5
2.5
2.5
2.9
0
19
NA
76
83
83
84
73
84
82
0.4
0.6
0.8
1.0
1.0
1.0
1.4
62 (58)
69 (61)
78 (63)
91 (75)
81 (70)
26 (22)
92 (87)
5
6d
7e
8
a Determined by GC using ditolyl ether as the internal standard.
b Isolated yield in parenthesis. c Determined by chiral HPLC. d Reaction
with ethyl bromodifluoroacetate. e Reaction at −10 °C.
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that diorganozinc reagents (R2Zn) are more reactive than organo-
zinc halides (RZnX).15
alkyl aryl ketones under the optimum reaction conditions
(Table 4). Overall, the homogeneous enantioselective Refor-
matsky-type reaction gave higher enantioselectivities (Method A:
81–91% ee) than the heterogeneous protocol (Method B: 75–84%
ee) and both methods gave good isolated yields. For the iodine–
zinc exchange reaction using diethylzinc, the excellent enantio-
meric excess was maintained at 85–91% ee when the aromatic
ring was substituted with either electron-donating or electron-
withdrawing substituents (entries 1–4). The reaction also worked
well when the methyl group was substituted either by an ethyl
(81% ee), propyl (81% ee) or even a relatively bulky iso-butyl
group (84% ee). In addition, good yields and excellent enantio-
meric excesses (84–89% ee) were obtained with the two cyclic
ketones, indanone and tetralone (entries 9–10). As expected from
Kumadaki et al.’s work,16 the reaction with the α,β-unsaturated
ketone, trans-4-phenyl-3-buten-2-one, did not work with the one-
pot protocol and only a very low enantiomeric excess (13% ee)
was obtained in the two-step asymmetric Reformatsky reaction.
A number of crystals of the product esters suitable for X-ray
crystallography were grown by slow evaporation from either
hexane or 10% ethyl acetate in hexane and the molecular struc-
tures of ethyl 2,2-difluoro-3-hydroxy-3-phenylpentanoate 5,
ethyl 2,2-difluoro-3-hydroxy-3-phenylhexanoate 6, ethyl 2,2-
difluoro-3-hydroxy-5-methyl-3-phenylhexanoate 7 and ethyl-3-
(2,3-dihydro-1H-inden-1-yl)-2,2-difluoro-3-hydroxybutanoate 9
are reported in the ESI (Fig. S9–S12†).
ð2Þ
ð3Þ
In the one-step and two-step enantioselective Reformatsky
reactions the reaction monitoring began with the addition of
diethylzinc and the preformed Reformatsky reagent, IZnCF2-
CO2Et, respectively and the results are shown in Fig. 1. There
was a dramatic difference in the profiles for the two reactions
and the homogeneous protocol was a surprisingly fast reaction
which was complete after 30 min at 0 °C. In fact, when the
homogeneous Reformatsky-type reaction was repeated under
identical conditions and quenched 10 min after the addition of
diethylzinc, a 74% conversion and 75% ee was obtained
showing that the reaction was finished in just 10 min. Therefore,
the chiral zinc catalyst generated in the homogeneous protocol is
different to the chiral catalyst generated from IZnCF2CO2Et and
(1R,2S)-1-phenyl-2-(1-pyrrolidinyl)propan-1-ol.
In order to determine the absolute configuration of the product
esters, ethyl-2,2-difluoro-3-hydroxy-3-phenylbutanoate 1 (72%
Results from screening a range of ketones in both
enantioselective Reformatsky reactions
ee) and ethyl-2,2-difluoro-3-hydroxy-3-phenylpentanoate
5
(78% ee) were reacted with the lithium salt of (S)-(1-phenyl-
The scope of both enantioselective Reformatsky reactions with
ethyl)amine to form the two diastereomers (Scheme 2). In each
ethyl iododifluoroacetate was investigated with a broad range of
Fig. 1 Reaction monitoring of the one-step and two-step protocols at 0 °C.
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Table 4 Enantioselective Reformatsky reaction with ethyl iododifluoroacetate
Method A
Et2Zn, −40 °C, 4.5 hours
Method B
Zn, 0 °C, 6.5 hours
Entry
Ar
R
Product
Yielda,b (%)
Eec,d (%)
Yielda,b (%)
eec,d (%)
1
2
3
4
5
6
7
8
9
10
Ph
Me
Me
Me
Me
1
2
3
4
5
6
7
8
9
10
97 (90)
66 (57)
93 (78)
99 (79)
72 (59)
85 (62)
79 (62)
100 (88)
88 (85)
80 (69)
86 (S)
91
89
85
80 (S)
81
84
76 (S)
84
98 (94)
76 (63)
95 (94)
88 (81)
46 (40)
95 (69)
46 (29)
100 (71)
100 (99)
100 (86)
80 (S)
82
84
80
79 (S)
80
75
78 (S)
82
2-MeOC6H4
4-MeOC6H4
4-ClC6H4
Ph
Ph
Ph
Et
Propyl
iso-Butyl
H
Ph
1-Indanone
1-Tetralone
89 (S)
83 (S)
1
a Determined by H NMR spectroscopy. b Isolated yield in parenthesis. c Determined by chiral HPLC. d In entries 1, 5 and 10 the product esters were
reacted with the lithium salt of (S)-(1-phenylethyl)amine and the absolute configuration was determined by X-ray crystallographic analysis; the
absolute configuration for ethyl-2,2-difluoro-3-hydroxy-3-phenylpropanoate in entry 8 was determined by comparing retention times of HPLC
analysis with those reported by Knochel et al.;4a the stereochemistry of the other product esters was tentatively assumed by analogy.
Scheme 2 Determination of the absolute configuration of ethyl 2,2-
difluoro-3-hydroxy-3-phenylbutanoate and ethyl 2,2-difluoro-3-hydroxy-
3-phenylpentanoate.
Fig. 3 Molecular structure of 2,2-difluoro-3(R)-hydroxy-3-phenyl-N-
((S)-1-phenylethyl)pentanamide showing 50% displacement ellipsoids.
(1)–H(1) and O(2) in both molecular structures which are shown
in Fig. 2 and 3. Both structures revealed that the minor diastereo-
mer has the (1′S,3R)-configuration and so, the major enantiomer
formed in the enantioselective Reformatsky reactions mediated
by (1R,2S)-1-phenyl-2-(1-pyrrolidinyl)propan-1-ol is the (S)-
Fig. 2 Molecular structure of 2,2-difluoro-3(R)-hydroxy-3-phenyl-N-
((S)-1-phenylethyl)butanamide showing 50% displacement ellipsoids.
enantiomer resulting from nucleophilic addition to the Re face of
the ketone. This facial selectivity is the same as that obtained in
the asymmetric Reformatsky reaction between ethyl bromo-
difluoroacetate and benzaldehyde9 and in the catalytic enantio-
selective Reformatsky reaction with ethyl iodoacetate,7c–f as well
as in the aminoalcohol promoted additions of dialkylzinc to
reaction the two diastereomers were separated by column chrom-
atography and a single crystal of the minor diastereomer was
obtained. There is intramolecular hydrogen bonding between O
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purification process and the only aim was to obtain small crystals
that were convenient to use. The dry aminoalcohols were stored
in a flushbox under nitrogen. The zinc dust (<10 μm, 98+%),
purchased from Aldrich, was washed with 17% HCl for 10
seconds and the acid was removed by suction filtration. The zinc
dust was washed with water, ethanol and diethyl ether before it
was dried under vacuum at 120 °C for 2 hours. The activated
zinc dust was stored and handled under a nitrogen atmosphere.
Fig. 4 Proposed transition state for the enantioselective Reformatsky-
type reaction using diethylzinc.
aldehydes.17 Consequently, we have proposed that the stereo-
selectivity in the enantioselective Reformatsky-type reaction
using diethylzinc can be accounted for by Noyori’s classic anti
transition state (Fig. 4).17
General procedure for Table 1
Each reaction was run in duplicate and the average yield and
enantiomeric excess is reported. ATHF solution of acetophenone
(0.600 g, 5.0 mmol) and ditolyl ether (0.496 g, 2.5 mmol) was
made up in a 10 mL volumetric flask and was transferred into a
Schlenk flask. Under argon a three neck round bottom flask was
charged with THF (6 mL) and the THF solution (2 mL) of aceto-
phenone (0.12 mL, 1.0 mmol) and tolyl ether (0.099 g,
0.5 mmol). After cooling the reaction mixture to 0 °C, ethyl bro-
modifluoroacetate (0.19 mL, 1.5 mmol) and the required amount
of (1S,2R)-(+)-N-methylephedrine (0.179 g, 1.0 mmol for runs
5–8) were added. The reaction mixture was then stirred at 0 °C
for 30 min before the required amount of diethylzinc (2.0 mL,
1.0 M solution in hexane, 2.0 mmol for runs 5–8) was added.
Two hours after the initial injection of diethylzinc, a further
aliquot of ethyl bromodifluoroacetate (0.06 mL, 0.5 mmol) fol-
lowed by an aliquot of diethylzinc (0.5 mL, 0.5 mmol) were
added in run 7. In run 8 further aliquots of both ethyl bromo-
difluoroacetate (0.06 mL, 0.5 mmol) and diethylzinc (0.5 mL,
0.5 mmol) were added after two and four hours. The reaction
mixture was quenched with 1 M HCl (10 mL) 4.5 hours after the
first addition of diethylzinc, was extracted with ethyl acetate (3 ×
10 mL) and the organic layer was washed with 1 M HCl
(30 mL), brine (30 mL) and water (30 mL) before being dried
over magnesium sulfate. A sample (1.0 mL) from the crude
product was filtered through a short plug of silica gel (1 g) and
the conversion was determined by GC. The product was purified
by column chromatography (25% EtOAc in hexane) on silica gel
to give ethyl-2,2-difluoro-3-hydroxy-3-phenylbutanoate 1 as a
colourless oil. The characterisation data was in agreement with
the literature.18,19 The enantiomers were separated on a chiralpak
AS column eluted with 4% IPA in hexane. The flow rate of the
mobile phase was set at 1.0 mL min−1. Rt = 8.55 min ((R)-enan-
tiomer), 12.37 min ((S)-enantiomer). The enantiomers were also
separated on a chiralcel OD-H column eluted with 4% IPA in
hexane. The flow rate of the mobile phase was set at 1.0 mL
min−1. Rt = 7.65 min ((R)-enantiomer), 8.35 min ((S)-
enantiomer).
Conclusions
The first enantioselective Reformatsky reaction between ethyl
iododifluoroacetate and ketones has been accomplished by two
different procedures using (1R,2S)-1-phenyl-2-(1-pyrrolidinyl)-
1-propanol as the chiral ligand. Good yields and high enantio-
selectivities (up to 91% ee) were achieved with a range of alkyl
aryl ketones using ethyl iododifluoroacetate and diethylzinc to
form the difluorinated Reformatsky reagent homogeneously. The
heterogeneous Reformatsky reaction using ethyl iododifluoroace-
tate and zinc dust was also investigated, but proved inferior
requiring more ethyl iododifluoroacetate and giving lower enan-
tioselectivity (up to 84% ee) compared to the homogeneous
protocol.
Experimental
Proton, 19F and 13C NMR spectra were recorded on a Bruker
DRX 400 spectrometer at 400.13, 376.46 and 100.62 MHz
respectively and were referenced to external SiMe4 (1H), external
CFCl3 (19F) and to external SiMe4 (13C) using the high fre-
quency positive convention. Elemental analyses were performed
by the Elemental Analysis Service at the University of North
London. Electron impact (EI) and fast atom bombardment
(FAB) mass spectra were recorded on a Kratos concept 1 H,
double focussing, forward geometry mass spectrometer. 3-Nitro-
benzyl alcohol was used as the matrix for the FAB spectra. Elec-
trospray mass spectra were obtained on a Micromass Quatro LC.
High performance liquid chromatography was carried out on a
Perkin Elmer HPLC Liquid Chromatograph supported with
either an OD-H (Daicel) or an AS (Daicel) column and a
UV-VIS detector. X-ray crystallography data were collected on a
Bruker Apex SMART 2000 diffractometer using graphite-mono-
chromated Mo-Kα radiation (λ = 0.71073 Å). Optical rotation
data were collected on a Perkin Elmer 341 Polarimeter and the
concentration of the samples were 1g per 100 mL.
General procedure for Table 2
THF was obtained dry from a distillation machine model Pure-
solveTM, and was stored in sealed ampoules over 4 Å molecular
sieves under an atmosphere of dry nitrogen. (1S,2R)-N-Methyl-
ephedrine and (1R,2S)-1-phenyl-2-(1-pyrrolidinyl)propan-1-ol
were dried using the Kugelröhr oven at 100 °C under oil pump
vacuum for 30 min. After cooling, the crystals of the chiral ami-
noalcohols were dissolved in dry diethyl ether and the solvent
was removed under vacuum. The second step was not a
Each reaction was run in duplicate and the average yield and
enantiomeric excess is reported. A three neck round bottom flask
was charged with THF (8 mL) and acetophenone (0.12 mL,
1.0 mmol) under argon. After cooling to the required tempera-
ture (0 to −78 °C), ethyl iododifluoroacetate (0.22 mL,
1.5 mmol) and either (1S,2R)-(+)-N-methylephedrine (0.179 g,
1.0 mmol) or (1R,2S)-1-phenyl-2-(1-pyrrolidinyl)1-propanol
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 3332–3342 | 3337

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(0.205 g, 1.0 mmol) were added. The reaction mixture was then
stirred at the required temperature for 30 min before diethylzinc
(2.0 mL, 1.0 M solution in hexane, 2.0 mmol) was added. Two
hours after the initial injection of diethylzinc, a further aliquot of
ethyl iododifluoroacetate (0.07 mL, 0.5 mmol) followed by an
aliquot of diethylzinc (0.5 mL, 0.5 mmol) were added in runs 2
and 4. The reaction mixture was quenched with 1 M HCl
(10 mL) 4.5 hours after the first addition of diethylzinc, was
extracted with ethyl acetate (3 × 10 mL) and the organic layer
was washed with 1 M HCl (30 mL), brine (30 mL) and water
(30 mL) before being dried over magnesium sulfate. A sample
(0.8 mL) from the crude product was filtered through a short
plug of silica gel (1 g) and the conversion was determined
by GC in runs 1–5. In runs 6–9 the solvent was removed and
the conversion was determined by 1H NMR spectroscopy
on the crude product. The product was purified by column
chromatography (10% EtOAc in hexane) on silica gel to give a
colourless oil.
(30 mL), brine (30 mL) and water (30 mL) before being dried
over magnesium sulfate. The solvent was removed and the
product was purified by column chromatography (EtOAc–
hexane) on silica gel.
Ethyl 2,2-difluoro-3-hydroxy-3-(2′-methoxyphenyl)butanoate
2. The crude product was purified by column chromatography
(20% EtOAc in hexane) to give ethyl 2,2-difluoro-3-hydroxy-3-
(2′-methoxyphenyl)butanoate as a colourless oil (0.157 g, 57%,
91% ee). [α]D (CHCl3) −14.5° (c = 1); δH (CDCl3) 1.20 (3H, t,
4
3JHH 7.2 Hz, OCH2CH3), 1.72 (3H, t, JHF 2.0 Hz, CF2C(OH)
3
CH3), 3.84 (3H, s, OCH3), 4.19 (2H, q, JHH 7.2 Hz,
3
OCH2CH3), 5.88 (1H, br s, OH), 6.89 (1H, dd, JHH 8.2 Hz,
3
4
4JHH 1.2 Hz, ArH), 6.94 (1H, td, JHH 7.8 Hz, JHH 1.2 Hz,
3
ArH), 7.22 (1H, d, JHH 8.2 Hz, ArH), 7.26 (1H, m, ArH); δF
(CDCl3) −113.50 (1F, d, JFF 246.5 Hz, CFAFB), −115.60 (1F,
d, JFF 246.5 Hz, CFAFB); δC (CDCl3) 13.9 (CH3), 23.0 (CH3),
56.2 (CH3), 62.6 (CH2), 77.8 (t, JCF 25.2 Hz, C), 112.3 (CH),
115.9 (t, JCF 260.6 Hz, CF2), 121.5 (CH), 126.6 (C), 129.5
(CH), 130.0 (CH), 158.2 (C), 163.7 (t, JCF 32.2 Hz, CO); m/z
2
2
2
1
2
(FAB) 297.0918 (MNa+. C13H16F2O4Na requires 297.0914).
The enantiomers were separated on a chiralpak AS column
eluted with 4% IPA in hexane. The flow rate of the mobile phase
was set at 1.0 mL min−1. Rt = 7.76 min (minor enantiomer),
8.73 min (major enantiomer).
General procedure for Table 3
Preparation of the solution of Reformatsky reagent. A two
neck round bottom flask was charged with acid-washed zinc dust
(0.565 g, 5.7 mmol) and dry THF (15.2 mL). The suspension
was heated to 60 °C, and the heating was stopped before ethyl
iododifluoroacetate (0.83 mL, 5.7 mmol) was added dropwise
over 2–3 min. The Reformatsky reagent was used after a further
2 min of stirring.
Ethyl 2,2-difluoro-3-hydroxy-3-(4′-methoxyphenyl)butanoate
3. The crude product was purified by column chromatography
(10% EtOAc in hexane) to give ethyl 2,2-difluoro-3-hydroxy-3-
(4′-methoxyphenyl)butanoate as a colourless oil (0.214 g, 78%,
89% ee). [α]D (CHCl3) 17.5° (c = 1). The characterisation data is
reported in the literature.19 The enantiomers were separated on a
chiralcel OD-H column eluted with 2% IPA in hexane. The flow
rate of the mobile phase was set at 1.0 mL min−1. Rt =
14.68 min (major enantiomer), 16.41 min (minor enantiomer).
The asymmetric Reformatsky reaction with acetophenone. A
three neck round bottom flask was charged with THF (1 mL),
acetophenone (0.12 mL, 1 mmol) and the required amount of
(1R,2S)-1-phenyl-2-(1-pyrrolidinyl)1-propanol
(0.205
g,
1.0 mmol in runs 5–7) under argon. After cooling to 0 °C, the
required amount of the solution of the Reformatsky reagent
(7 mL, 2.5 mmol in runs 5–7) was added and the reaction
mixture was stirred for 4.5 hours at 0 °C. The reaction mixture
was quenched with 1 M HCl (10 mL), extracted with ethyl
acetate (3 × 10 mL) and the organic layer was washed with 1 M
HCl (30 mL), brine (30 mL) and water (30 mL) before being
dried over magnesium sulfate. The solvent was removed and the
product was purified by column chromatography (EtOAc–
hexane = 1 : 9) on silica gel to give a colourless oil. Each reac-
tion was run in duplicate and the average yield and enantiomeric
excess is reported.
Ethyl
2,2-difluoro-3-hydroxy-3-(4′-chlorophenyl)butanoate
4. The crude product was purified by column chromatography
(20% EtOAc in hexane) to give ethyl 2,2-difluoro-3-hydroxy-3-
(4′-chlorophenyl)butanoate as a colourless oil (0.219 g, 79%,
85% ee). [α]D (CHCl3) 14.7° (c = 1). The characterisation data is
reported in the literature.19 The enantiomers were separated on a
chiralpak AS column eluted with 4% IPA in hexane. The flow
rate of the mobile phase was set at 1.0 mL min−1. Rt =
10.17 min (minor enantiomer), 16.80 min (major enantiomer).
Ethyl 2,2-difluoro-3-hydroxy-3-phenylpentanoate 5. The
crude product was purified by column chromatography (10%
EtOAc in hexane) to give ethyl 2,2-difluoro-3-hydroxy-3-phe-
nylpentanoate as white crystals (0.152 g, 59%, 81% ee). [α]D
(CHCl3) 5.5° (c = 1); mp 38–39 °C; anal. calcd for C13H16F2O3:
C 60.5, H 6.2%; found: C 60.5, H 6.3%. δH (CDCl3) 0.69 (3H,
General procedure for Table 4
Method A. Each reaction was run in duplicate and the average
yield and enantiomeric excess is reported. A three neck round
bottom flask under argon was charged with ketone (1.0 mmol)
and THF (8 mL). After cooling the reaction mixture to −40 °C,
ethyl iododifluoroacetate (0.29 mL, 2.0 mmol) and (1R,2S)-1-
phenyl-2-(1-pyrrolidinyl)1-propanol (0.205 g, 1.0 mmol) were
added. The reaction mixture was then stirred for a further 30 min
at −40 °C before diethylzinc (2.5 mL, 1.0 M solution in hexane,
2.5 mmol) was added. After 4.5 hours the reaction mixture was
quenched with 1 M HCl (10 mL), extracted with ethyl acetate
(3 × 10 mL) and the organic layer was washed with 1 M HCl
3
3
t, JHH 7.4 Hz, CH2CH3), 1.00 (3H, t, JHH 7.0 Hz, OCH2CH3),
2.02 (1H, m, CHAHBCH3), 2.13 (1H, m, CHAHBCH3), 2.92
3
(1H, s, OH), 4.02 (2H, q, JHH 7.0, OCH2CH3), 7.21–7.34 (3H,
3
m, ArH), 7.41 (2H, d, JHH 7.0 Hz, ArH); δF (CDCl3) −115.43
2
2
(1F, d, JFF 257.4 Hz, CFAFB), −116.14 (1F, d, JFF 257.4 Hz,
CFAFB); δC (CDCl3) 6.6 (CH3), 13.6 (CH3), 27.1 (CH2), 62.8
2
1
(CH2), 78.5 (t, JCF 23.6 Hz, C), 115.1 (t, JCF 261.6 Hz, CF2),
126.5 (CH), 128.0 (CH), 128.1 (CH), 137.3 (C), 163.6 (t, JCF
2
3338 | Org. Biomol. Chem., 2012, 10, 3332–3342
This journal is © The Royal Society of Chemistry 2012

View Article Online
32.2 Hz, CO); m/z (EI) 258.10641 (M+. C13H16F2O3 requires
258.10635), 229 (18%), 201 (23%), 135 (100%). Crystals suit-
able for X-ray crystallography were grown on the side of a round
bottom flask from the pure product without using solvent. The
enantiomers were separated on a chiralpak AS column eluted
with 4% IPA in hexane. The flow rate of the mobile phase was
set at 1.0 mL min−1. Rt = 6.77 min ((R)-enantiomer), 11.49 min
((S)-enantiomer).
Ethyl 2,2-difluoro-3-hydroxy-3-phenylpropanoate 8. The
crude product was purified by column chromatography (20%
EtOAc in hexane) to yield ethyl 2,2-difluoro-3-hydroxy-3-phe-
nylpropanoate as a colourless oil (0.202 g, 88%, 76% ee). [α]D
(CHCl3) 12.5 ° (c = 1). The characterisation data is reported in
the literature.18 The enantiomers were separated on a chiralpak
AS column eluted with 10% IPA in hexane. The flow rate of the
mobile phase was set at 1 mL min−1. Rt = 11.09 min ((S)-ethyl-
2,2-difluoro-3-hydroxy-3-phenylpropanoate), 15.74 min ((R)-
ethyl-2,2-difluoro-3-hydroxy-3-phenylpropanoate).
Ethyl 2,2-difluoro-3-hydroxy-3-phenylhexanoate 6. The crude
product was purified by column chromatography (10% EtOAc in
hexane) to yield ethyl 2,2-difluoro-3-hydroxy-3-phenylhexanoate
as white crystals (0.165 g, 62%, 81% ee). [α]D (CHCl3) 15.5 ° (c
= 1). mp 41–43 °C; anal. calcd for C14H18F2O3: C 61.75, H
Ethyl
2,2-difluoro-2-(1-hydroxy-2,3-dihydro-1H-inden-1-yl)
acetate 9. The crude product was purified by column chromato-
graphy (2% EtOAc in hexane) to yield ethyl 2,2-difluoro-2-(1-
hydroxy-2,3-dihydro-1H-inden-1-yl)acetate as white crystals
(0.216 g, 85%, 84% ee). [α]D (CHCl3) −7.7° (c = 1); mp
56–58 °C; anal. calcd for C13H14F2O3: C 60.9, H 5.5%; found:
3
6.7%; found: C 61.85, H 6.65%. δH (CDCl3) 0.80 (3H, t, JHH
7.0 Hz, CH2CH2CH3), 0.90 (1H, m, CH2CHAHBCH3), 1.00
(3H, t, 3JHH 7.0 Hz, OCH2CH3), 1.31 (1H, m, CH2CHAHBCH3),
2
3
3
1.94 (1H, ddd, JHH 14.0 Hz, JHH 11.5 Hz, JHH 4.5 Hz,
CHCHDCHAHBCH3), 2.07 (1H, m, CHCHDCHAHBCH3), 2.96
(1H, br s, OH), 4.04 (2H, q, 3JHH 7.0 Hz, OCH2CH3), 7.21–7.31
3
C 61.0, H 5.5%. δH (CDCl3) 1.23 (3H, t, JHH 7.0 Hz,
OCH2CH3), 2.11 (1H, m, CF2C(OH)CHAHB), 2.72–3.04 (4H,
m, CF2C(OH)CHAHBCH2 and OH), 4.25 (2H, m, OCH2CH3),
3
(3H, m, ArH), 7.41 (2H, d, JHH 7.0 Hz, ArH); δF (CDCl3)
3
7.17–7.23 (2H, m, ArH), 7.27 (1H, t, JHH 7.4 Hz, ArH), 7.42
2
2
−115.46 (1F, d, JFF 257.4 Hz, CFAFB), −116.16 (1F, d, JFF
257.4 Hz, CFAFB); δC (CDCl3) 13.6 (CH3), 14.3 (CH3), 15.7
3
2
(1H, d, JHH 8.2 Hz, ArH); δF (CDCl3) −114.57 (1F, d, JFF
2
260.2 Hz, CFAFB), −117.59 (1F, d, JFF 260.2 Hz, CFAFB); δC
(CDCl3) 13.8 (CH3), 29.9 (CH2), 35.7 (CH2), 63.1 (CH2), 84.7
(t, JCF 24.1 Hz, C), 115.3 (t, JCF 259.1 Hz, CF2), 124.9 (CH),
2
(CH2), 36.4 (CH2), 62.8 (CH2), 78.3 (t, JCF 24.1 Hz, C), 115.0
(t, JCF 261.6 Hz, CF2), 126.4 (CH), 128.0 (CH), 128.1 (CH),
137.8 (C), 163.6 (t, JCF 32.2 Hz, CO); m/z (FAB) 273.1306
1
2
1
2
125.1 (CH), 126.9 (CH), 129.8 (CH), 139.8 (C), 145.0 (C),
(MH+. C14H19F2O3 requires 273.1302). Crystals suitable for X-
ray crystallography were grown by slow evaporation from a sol-
ution of ethyl 2,2-difluoro-3-hydroxy-3-phenylhexanoate in
hexane. The enantiomers were separated on a chiralpak AS
column eluted with 4% IPA in hexane. The flow rate of the
mobile phase was set at 1.0 mL min−1. Rt = 5.76 min (minor
enantiomer), 10.44 min (major enantiomer).
2
163.8 (t, JCF 32.2 Hz, CO); m/z (EI) 256.09065 (M+.
C13H14F2O3 requires 256.09075), 165 (10%), 133 (100%). Crys-
tals suitable for X-ray crystallography were grown by slow evap-
oration from a solution of ethyl 2,2-difluoro-2-(1-hydroxy-2,3-
dihydro-1H-inden-1-yl)acetate in 20% EtOAc in hexane. The
enantiomers were separated on a chiralcel OD-H column eluted
with 4% IPA in hexane. The flow rate of the mobile phase was
set at 1.0 mL min−1. Rt = 8.40 min (major enantiomer),
10.79 min (minor enantiomer).
Ethyl
2,2-difluoro-3-hydroxy-5-methyl-3-phenylhexanoate
7. The crude product was purified by column chromatography
(10% EtOAc in hexane) to yield ethyl 2,2-difluoro-3-hydroxy-5-
methyl-3-phenylhexanoate as white crystals (0.179 g, 62%, 84%
ee). [α]D (CHCl3) 3.8 ° (c = 1); mp 63–64 °C; anal. calcd for
C15H20F2O3: C 62.9, H 7.0%; found: C 63.1, H 6.9%; δH
Ethyl 2,2-difluoro-2-(1-hydroxy-1,2,3,4-tetrahydronaphthalen-
1-yl)acetate 10. The crude product was purified by column
chromatography (10% EtOAc in hexane) to give ethyl 2,2-
difluoro-2-(1-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)acetate
as a colourless oil (0.187 g, 69%, 90% ee). [α]D (CHCl3) 1.3° (c
= 1); anal. calcd for C14H16F2O3: C 62.2, H 6.0%; found: C
62.3, H 6.0%. δH (CDCl3) 1.26 (3H, t, 3JHH 7.4 Hz, OCH2CH3),
1.85 (1H, m, CF2C(OH)CHAHB), 2.05 (2H, m,
CHAHBCH2CH2), 2.30 (1H, m, CF2C(OH)CHAHB), 2.85 (3H,
m, ArCH2 and OH), 4.29 (2H, m, OCH2CH3), 7.16 (1H, m,
ArH), 7.22–7.31 (2H, m, ArH), 7.69 (1H, d, 3JHH 7.4 Hz, ArH);
3
3
(CDCl3) 0.61 (3H, d, JHH 6.7 Hz, CHCH3), 0.86 (3H, d, JHH
3
6.7 Hz, CHCH3), 0.98 (3H, t, JHH 7.0 Hz, OCH2CH3), 1.50
2
3
(1H, m, CH(CH3)2), 1.82 (1H, dd, JHH 14.5 Hz, JHH 7.4 Hz,
2
3
CHAHBCH(CH3)2), 2.09 (1H, ddt, JHH 14.5 Hz, JHH 5.1 Hz,
4JHF 1.6 Hz, CHAHBCH(CH3)2), 2.95 (1H, br s, OH), 4.02 (2H,
3
q, JHH 7.0 Hz, OCH2CH3), 7.21–7.31 (3H, m, ArH), 7.42 (2H,
d, JHH 7.0 Hz, ArH); δF (CDCl3) −116.02 (2F, s, CF2); δC
(CDCl3) 13.5 (CH3), 23.5 (CH3), 24.0 (CH3), 24.4 (CH), 41.9
3
2
1
2
(CH2), 62.8 (CH2), 78.8 (t, JCF 23.1 Hz, C), 114.9 (t, JCF
δF (CDCl3) −111.58 (1F, d, JFF 257.4 Hz, CFAFB), −113.24
2
263.6 Hz, CF2), 126.6 (CH), 127.98 (CH), 128.02 (CH), 137.9
(1F, d, JFF 257.4 Hz, CFAFB); δC (CDCl3) 13.7 (CH3), 18.7
2
2
(C), 163.6 (t, JCF 32.2 Hz, CO); m/z (TOF) 285.1311 ((M −
(CH2), 29.5 (CH2), 33.2 (CH2), 63.0 (CH2), 73.7 (t, JCF 22.6
H)+. C15H19F2O3 requires 285.1302). Crystals suitable for X-ray
crystallography were grown by slow evaporation from a solution
of ethyl 2,2-difluoro-3-hydroxy-5-methyl-3-phenylhexanoate in
hexane. The enantiomers were separated on a chiralpak AS
column eluted with 4% IPA in hexane. The flow rate of the
mobile phase was set at 1.0 mL min−1. Rt = 4.81 min (minor
enantiomer), 7.14 min (major enantiomer).
Hz, C), 116.0 (t, JCF 261.6 Hz, CF2), 126.2 (CH), 127.9 (CH),
1
2
128.6 (CH), 129.1 (CH), 133.7 (C), 138.9 (C), 163.8 (t, JCF
32.2 Hz, CO); m/z (EI) 270.10642 (M+. C14H16F2O3 requires
270.10635), 147 (100%). The enantiomers were separated on a
chiralcel OD-H column eluted with 4% IPA in hexane. The flow
rate of the mobile phase was set at 1.0 mL min−1. Rt = 8.20 min
((S)-enantiomer), 9.88 min ((R)-enantiomer).
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 3332–3342 | 3339

View Article Online
General procedure for Table 4
dried over magnesium sulphate. The solvent was removed and
the crude product consisted of a 6 : 1 mixture of (S,S)- and (R,S)-
diastereomers according to the H NMR spectrum. The diaster-
Method B – Preparation of the solution of Reformatsky
reagent. A two neck round bottom flask was charged with acid-
washed zinc dust (0.565 g, 5.7 mmol) and dry THF (10 mL).
The suspension was heated to 60 °C and the heating was
stopped before ethyl iododifluoroacetate (0.83 mL, 5.7 mmol) in
THF (5.2 mL) was added dropwise over 2–3 min. The Refor-
matsky reagent was used after a further 2 min of stirring.
1
eoisomers were separated by silica gel column chromatography
(15% EtOAc in hexane) to give diastereomerically pure 2,2-
difluoro-3(S)-hydroxy-3-phenyl-N-((S)-1-phenylethyl)butanamide
as colourless crystals (0.50 g, 63%); mp 81–85 °C; [α]D
(CHCl3) −42.5° (c = 1); anal. calcd for C18H19F2NO2: C 67.7,
H 6.0, N 4.4%; found: C 67.85, H 5.6, N 4.3%. δH (CDCl3) 1.46
3
(3H, d, JHH 7.0 Hz, CHCH3), 1.74 (3H, s, CF2C(OH)CH3),
Method B – The asymmetric Reformatsky reaction with
ketones. A three neck round bottom flask was charged with
THF (1 mL), ketone (1 mmol) and (1R,2S)-1-phenyl-2-(1-pyrro-
lidinyl)1-propanol (0.205 g, 1.0 mmol) under argon. After
cooling to 0 °C, the solution of the Reformatsky reagent (7 mL,
2.5 mmol) was added and the reaction mixture was stirred for
6.5 hours at 0 °C. The reaction mixture was quenched with 1 M
HCl (10 mL), extracted with ethyl acetate (3 × 10 mL) and the
organic layer was washed with 1 M HCl (30 mL), brine (30 mL)
and water (30 mL) before being dried over magnesium sulfate.
The solvent was removed and the product was purified by
column chromatography (EtOAc–hexane) on silica gel. Each
reaction was run in duplicate and the average yield and enantio-
meric excess is reported.
4.72 (1H, s, OH), 4.96 (1H, quintet, 3JHH 7.0 Hz, CHCH3), 6.40
(1H, br s, NH), 6.79–6.82 (2H, m, ArH), 7.19–7.25 (3H, m,
ArH), 7.31–7.36 (3H, m, ArH), 7.49–7.53 (2H, m, ArH); δF
2
(CDCl3) −115.40 (1F, d, JFF 257.4 Hz, CFAFB), −117.96 (1F,
2
d, JFF 257.4 Hz, CFAFB); δC (CDCl3) 20.9 (CH3), 22.5 (CH3),
2
1
48.7 (CH), 76.1 (t, JCF 24.1 Hz, C), 114.4 (t, JCF 262.6 Hz,
CF2), 125.7 (CH), 126.3 (CH), 127.5 (CH), 128.1 (CH), 128.3
2
(CH), 128.7 (CH), 140.1 (C), 140.9 (C), 163.5 (t, JCF 29.2 Hz,
CO); m/z (ES+) 320.1465 (MH+. C18H20F2NO2 requires
320.1462).
The pure diastereomer 2,2-difluoro-3(R)-hydroxy-3-phenyl-N-
((S)-1-phenylethyl)butanamide was obtained as colourless crys-
tals (0.04 g, 5%); mp 84–86 °C; [α]D (CHCl3) −38.6° (c = 1);
anal. calcd for C18H19F2NO2: C 67.7, H 6.0, N 4.4%; found: C
3
Ethyl
(E)-2,2-difluoro-3-hydroxy-3-methyl-5-phenylpent-4-
67.6, H 5.8, N 4.2%. δH (CDCl3) 1.03 (3H, d, JHH 7.0 Hz,
4
enoate 11. The crude product was purified by column chromato-
graphy (10% EtOAc in hexane) to give a colourless oil (0.263 g,
97%); anal. calcd for C14H16F2O3: C 62.22, H 5.97%; found: C
CHCH3), 1.63 (3H, t, JHF 1.2 Hz, CF2C(OH)CH3), 4.49 (1H,
br s, OH), 4.83 (1H, quintet, 3JHH 7.0 Hz, CHCH3), 6.30 (1H, br
3
s, NH), 7.08 (2H, dm, JHH 8.0 Hz, ArH), 7.16–7.30 (6H, m,
3
ArH), 7.41–7.46 (2H, m, ArH); δF (CDCl3) −116.55 (1F, d, 2JFF
62.12; H 5.87%. δH (CDCl3) 1.28 (3H, t, JHH 7.0 Hz,
4
2
CH2CH3), 1.46 (3H, t, JHF 1.6 Hz, CF2C(OH)CH3), 2.50 (1H,
257.4 Hz, CFAFB), −117.45 (1F, d, JFF 257.4 Hz, CFAFB); δC
br s, OH), 4.24 (2H, q, 3JHH 7.0, OCH2CH3), 6.21 (1H, dt, 3JHH
2
(CDCl3) 20.6 (CH3), 22.6 (CH3), 48.9 (CH), 76.1 (t, JCF 24.0
4
3
1
16.0 Hz, JHF 1.6 Hz, ArCHvCHC(OH)), 6.75 (1H, d, JHH
16.0 Hz, ArCH), 7.17–7.22 (1H, m, ArH), 7.23–7.28 (2H, m,
ArH), 7.30–7.34 (2H, m, ArH); δF (CDCl3) −116.52 (1F, d, 2JFF
Hz, C), 114.5 (t, JCF 262.6 Hz, CF2), 126.1 (CH), 126.3 (CH),
127.9 (CH), 128.1 (CH), 128.2 (CH), 128.9 (CH), 140.1 (C),
2
141.2 (C), 163.3 (t, JCF 29.2 Hz, CO); m/z (TOF) 320.1465
2
(MH+. C18H20F2NO2 requires 320.1462). Crystals suitable for
X-ray crystallography were grown by slow evaporation from a
solution of 2,2-difluoro-3(R)-hydroxy-3-phenyl-N-((S)-1-phenyl-
ethyl)butanamide in 20% EtOAc in hexane.
260.2 Hz, CFAFB), −117.82 (1F, d, JFF 260.2 Hz, CFAFB); δC
(CDCl3) 13.9 (CH3), 21.8 (CH3), 63.1 (CH2), 75.1 (t, JCF 25.2
Hz, C), 114.8 (t, JCF 260.6 Hz, CF2), 126.8 (CH), 127.6 (CH),
128.2 (CH), 128.7 (CH), 131.3 (CH), 136.0 (C), 163.6 (t, JCF
2
1
2
32.2 Hz, CO); m/z (FAB) 293.0960 (MNa+. C14H16F2O3Na
requires 293.0965). The characterisation data was in agreement
with literature.16 The enantiomers were separated on a chiralcel
OD-H column eluted with 4% IPA in hexane. The flow rate of
the mobile phase was set at 1.0 mL min−1. Rt = 10.18 min
(minor enantiomer), 11.55 min (major enantiomer).
Determination of the absolute configuration of the new chiral
centre in ethyl 2,2-difluoro-3-hydroxy-3-phenylpentanoate
The procedure above was repeated using (S)-(1-phenylethyl)
amine (0.22 mL, 1.7 mmol), n-butyllithium (1.6 mL, 1.6 M in
hexane, 2.6 mmol), (S)-ethyl 2,2-difluoro-3-hydroxy-3-phenyl-
pentanoate 5 (0.18 g, 0.7 mmol, 78% ee) and THF (8 mL). The
crude product consisted of a 7.3 : 1 mixture of (S,S)- and (R,S)-
Determination of the absolute configuration of the new chiral
centre in ethyl 2,2-difluoro-3-hydroxy-3-phenylbutanoate
1
diastereomers according to the H NMR spectrum. The diaster-
Under an argon atmosphere a dry three neck flask was charged
with THF (30 mL), (S)-(1-phenylethyl)amine (0.81 mL,
6.3 mmol) and n-butyllithium (5.7 mL, 1.6 M in hexane,
9.1 mmol). After 30 min of stirring at 0 °C, a solution of (S)-
eoisomers were separated by silica gel column chromatography
(10% EtOAc in hexane) to give diastereomerically pure 2,2-
difluoro-3(S)-hydroxy-3-phenyl-N-((S)-1-phenylethyl)pentana-
mide as white crystals (0.18 g, 77%); mp 88–90 °C. [α]D
3
ethyl 2,2-difluoro-3-hydroxy-3-phenylbutanoate
1
(0.60 g,
(CHCl3) −44.5° (c = 1); δH (CDCl3) 0.66 (3H, t, JHH 7.4 Hz,
2.5 mmol, 72% ee) in THF (2 mL) was added. The dropping
funnel was washed with THF (2 mL) and the reaction mixture
was stirred for 24 hours at 0 °C. After quenching the reaction
mixture with 1 M HCl (20 mL), it was extracted with ethyl
acetate (2 × 20 mL). The organic layer was washed with 1 M
HCl (20 mL), brine (20 mL) and water (20 ml) before being
CH2CH3), 1.36 (3H, d, 3JHH 7.0 Hz, CHCH3), 2.07 (2H, q, 3JHH
3
7.4 Hz, CH2CH3), 4.55 (1H, br s, OH), 4.83 (1H, quintet, JHH
7.4 Hz, CHCH3), 6.29 (1H, br s, NH), 6.64–6.69 (2H, m, ArH),
7.07–7.16 (3H, m, ArH), 7.22–7.27 (3H, m, ArH), 7.36–7.41
2
(2H, m, ArH); δF (CDCl3) −115.35 (1F, d, JFF 257.5 Hz,
2
CFAFB), −118.65 (1F, d, JFF 257.5 Hz, CFAFB); δC (CDCl3)
3340 | Org. Biomol. Chem., 2012, 10, 3332–3342
This journal is © The Royal Society of Chemistry 2012

View Article Online
6.5 (CH3), 20.9 (CH3), 26.7 (CH2), 48.6 (CH), 78.6 (t, 2JCF 23.1
Hz, C), 114.7 (t, JCF 263.6 Hz, CF2), 125.7 (CH), 126.8 (CH),
2JCF 29.2 Hz, CO); m/z (ES+) 346.1628 (MH+. C20H22F2NO2
requires 346.1619). Crystals suitable for X-ray crystallography
were grown on the side of a round bottom flask from the pure
product without using solvent. The molecular structure is shown
in Fig. S8 in the ESI.†
1
127.5 (CH), 127.9 (CH), 128.3 (CH), 128.7 (CH), 138.0 (C),
2
140.9 (C), 163.7 (t, JCF 28.2 Hz, CO); m/z (ES+) 334.1620
(MH+. C19H22F2NO2 requires 334.1619).
The procedure above was repeated using (S)-(1-phenylethyl)
amine (0.77 mL, 5.9 mmol), n-butyllithium (5.4 mL, 1.6 M in
hexane, 8.6 mmol), racemic ethyl 2,2-difluoro-3-hydroxy-3-phe-
nylpentanoate 5 (0.31 g, 1.2 mmol) and THF (28 mL). The
crude product consisted of a 1 : 1 mixture of (S,S)- and (R,S)-dia-
The procedure above was repeated using (S)-(1-phenylethyl)
amine (0.28 mL, 2.25 mmol), n-butyllithium (2.0 mL, 1.6 M in
hexane, 3.2 mmol), (S)-ethyl-2,2-difluoro-2-(1-hydroxy-1,2,3,4-
tetrahydronaphthalen-1-yl)acetate 10 (0.24 g, 0.9 mmol, 88% ee)
and THF (11 mL). The crude product consisted of
a
1
stereomers according to the H NMR spectrum. The diastereo-
10 : 1 mixture of (S,S)- and (R,S)-diastereomers according to the
19F NMR spectrum and the 19F NMR data revealed that the
crystal structure was obtained from the major diastereomer, 2,2-
difluoro-3(S)-(1-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)-N-
((S)-1-phenyl-ethyl)acetamide.
isomers were separated by silica gel column chromatography
(10% EtOAc in hexane) to give diastereomerically pure 2,2-
difluoro-3(R)-hydroxy-3-phenyl-N-((S)-1-phenylethyl)pentana-
mide as colourless crystals (0.06 g, 15%); mp 131–132 °C. [α]D
3
(CHCl3) −40.7° (c = 1); δH (CDCl3) 0.78 (3H, t, JHH 7.4 Hz,
3
CH2CH3), 1.14 (3H, d, JHH 6.7 Hz, CHCH3), 2.07–2.23 (2H,
Acknowledgements
3
m, CH2CH3), 4.49 (1H, br s, OH), 4.91 (1H, quintet, JHH 7.0
Hz, CHCH3), 6.34 (1H, br s, NH), 7.17–7.21 (2H, m, ArH),
We would like to thank the Royal Society (AMS) for financial
support.
3
7.27–7.42 (6H, m, ArH), 7.49–7.54 (2H, dm, JHH 8.0 Hz,
2
ArH); δF (CDCl3) −116.69 (1F, d, JFF 254.7 Hz, CFAFB),
2
−118.40 (1F, d, JFF 254.7 Hz, CFAFB); δC (CDCl3) 6.6 (CH3),
References
2
20.5 (CH3), 26.6 (CH2), 48.8 (CH), 78.6 (t, JCF 23.1 Hz, C),
1
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2,2-difluoro-3(R)-hydroxy-3-phenyl-N-((S)-1-phenylethyl)-
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The procedure above was repeated using (S)-(1-phenylethyl)
amine (0.32 mL, 2.5 mmol), n-butyllithium (2.3 mL, 1.6 M in
hexane, 3.7 mmol), racemic ethyl-2,2-difluoro-2-(1-hydroxy-
1,2,3,4-tetrahydronaphthalen-1-yl)acetate 10 (0.14 g, 0.5 mmol)
and THF (12 mL). The crude product consisted of
a
1 : 1 mixture of (S,S)- and (R,S)-diastereomers according to the
1H NMR spectrum. The diastereoisomers were separated by
silica gel column chromatography (10% EtOAc in hexane) to
give diastereomerically pure 2,2-difluoro-3(S)-(1-hydroxy-
1,2,3,4-tetrahydronaphthalen-1-yl)-N-((S)-1-phenylethyl)aceta-
mide as colourless crystals (0.03 g, 17%); mp 153–155 °C; [α]D
(CHCl3) −20.4° (c = 1); anal. calcd for C20H21F2NO2: C 69.55,
H 6.1, N 4.05%; found: C 69.4, H 6.2, N 4.1%. δH (CDCl3) 1.44
3
(3H, d, JHH 7.0 Hz, CH3), 1.66–1.78 (1H, m, CF2COH-
3
CHAHB), 1.88 (2H, d, JHH 11.0 Hz, CH2CH2CH2), 2.24 (1H,
m, CF2COHCHAHB), 2.62–278 (2H, m, ArCH2), 4.05 (1H, br s,
3
OH), 5.04 (1H, quintet, JHH 7.0 Hz, CHCH3), 6.52 (1H, br s,
NH), 7.02–7.06 (2H, m, ArH), 7.12–7.32 (6H, m, ArH), 7.51
3
2
(1H, d, JHH 7.8 Hz, ArH); δF (CDCl3) −112.76 (1F, d, JFF
2
257.4 Hz, CFAFB), −113.65 (1F, d, JFF 257.4 Hz, CFAFB); δC
(CDCl3) 19.0 (CH2), 21.2 (CH3), 29.5 (CH2), 33.2 (CH2), 49.3
(CH), 73.7 (t, JCF 23.1 Hz, C), 115.7 (t, JCF 261.6 Hz, CF2),
126.2 (2 × CH), 127.9 (CH), 128.0 (CH), 128.4 (CH), 128.9
(CH), 129.0 (CH), 134.0 (C), 139.1 (C), 141.4 (C), 163.6 (t,
2
1
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 3332–3342 | 3341

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3342 | Org. Biomol. Chem., 2012, 10, 3332–3342
This journal is © The Royal Society of Chemistry 2012