Enantioenriched 1-aryl-2-fluoroethylamines. Efficient lipase-catalysed resolution and limitations to the Mitsunobu inversion protocol

Article abstract of DOI:10.1016/j.tet.2010.06.081

Both enantiomers of eight 1-aryl-2-fluoroethylamines have been synthesised starting with 1-aryl-2-fluoroethanones. Kinetic resolution of the amines using lipase B from Candida antarctica with ethyl methoxyacetate as the acyl donor gave the (R)-amines in 96-99% ee and the (S)-methoxyacetamides in >99.5% ee. The resolution was robust with respect to variation in reaction temperature, acyl donor concentration, water activity and substrate structure. Nine other lipase preparations failed to catalyse the reaction or gave a low enantioselectivity. Secondly, a Mitsunobu inversion protocol starting with enantioenriched 1-aryl-2-fluoroethanols using phthalimide as nucleophile was employed in the synthesis of the (S)-1-aryl-2-fluoroethylamines. Both the inversion efficiency and yield depended on the aromatic substituents. For six of the substrates, clean inversion of the stereochemistry was observed. However, racemisation and low yields were the result when electron-donating substituents were present at the aromatic ring. When substituted with a cyano or a nitro group, an unexpected fluorine elimination occurred, limiting the yield for these transformations. The absolute configuration of the 1-aryl-2-fluoroethylamines was determined using circular dichroism.

Full text of DOI:10.1016/j.tet.2010.06.081

Tetrahedron 66 (2010) 6733e6743
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Enantioenriched 1-aryl-2-fluoroethylamines. Efficient lipase-catalysed resolution
and limitations to the Mitsunobu inversion protocol
,
,
*
Thor Håkon Krane Thvedt a b, Erik Fuglseth a, Eirik Sundby b, Bård Helge Hoff a
a Department of Chemistry, Norwegian University of Science and Technology, Høgskoleringen 5, NO-7491 Trondheim, Norway
b Sør-Trøndelag University College, E. C. Dahls Gate 2, NO-7004 Trondheim, Norway
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 5 May 2010
Received in revised form 18 June 2010
Accepted 28 June 2010
Available online 3 July 2010
Both enantiomers of eight 1-aryl-2-fluoroethylamines have been synthesised starting with 1-aryl-2-
fluoroethanones. Kinetic resolution of the amines using lipase B from Candida antarctica with ethyl
methoxyacetate as the acyl donor gave the (R)-amines in 96e99% ee and the (S)-methoxyacetamides in
>99.5% ee. The resolution was robust with respect to variation in reaction temperature, acyl donor
concentration, water activity and substrate structure. Nine other lipase preparations failed to catalyse the
reaction or gave a low enantioselectivity. Secondly, a Mitsunobu inversion protocol starting with
enantioenriched 1-aryl-2-fluoroethanols using phthalimide as nucleophile was employed in the syn-
thesis of the (S)-1-aryl-2-fluoroethylamines. Both the inversion efficiency and yield depended on the
aromatic substituents. For six of the substrates, clean inversion of the stereochemistry was observed.
However, racemisation and low yields were the result when electron-donating substituents were present
at the aromatic ring. When substituted with a cyano or a nitro group, an unexpected fluorine elimination
occurred, limiting the yield for these transformations. The absolute configuration of the 1-aryl-2-fluo-
roethylamines was determined using circular dichroism.
Keywords:
Fluoroamines
Lipase B from Candida antarctica
Kinetic resolution
Mitsunobu inversion
Asymmetric transfer hydrogenation
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
fluorinated analogues, a few 2,2-difluoro- and 2,2,2-trifluoro-1-
arylethylamines have been resolved by hydrolysis of the corr-
1-Arylethylamines are useful building blocks for the preparation
esponding chloroacetamides using the Pseudomonas fluorescens
lipase.17,18 The use of hydrolases to resolve compounds containing
a 1,2-fluoroamine moiety has not been documented.
Another common route to enantioenriched amines is by con-
verting enantioenriched alcohols using the Mitsunobu inversion
with phthalimide or azide as nucleophiles.19 Although various
types of fluorinated reactants have been used in the Mitsunobu
coupling,20e23 the conversion of 1,2-fluorohydrins to 1,2-fluoro-
amines has not been investigated.
With the aim of preparing enantiopure 1-aryl-2-fluo-
roethylamines, we have studied the lipase-catalysed resolution
of 1-aryl-2-fluoroethylamines and the Mitsunobu inversion of
1-aryl-2-fluoroethanols.
of biological active compounds.1e4 Introduction of fluorine atoms in
the
a-position of amines enables tuning of the basicity of the
compounds in question.5 This can be used to modify the binding
properties, increase bioavailability, reduce toxicity or to increase
metabolic stability of a drug candidate. Recently, 1-arylethylamines
containing fluoroalkyl groups have emerged as a new class of
building blocks for medicinal use.6e8
Although a vast amount of research have been devoted to the
preparationof enantioenriched 1-arylethylamines, onlya fewroutes
to the monofluorinated derivatives are known. One method is based
on the reductive amination of a-fluoroketones with enantiopure
amines.9 A stereoselective fluoromethylation of enantioenriched
N-(tert-butanesulfinyl)imines10 and cinchona-catalysed mono-
fluorination of N-Boc a
-amido sulfones have also been reported.11
Enzyme-catalysed resolution is a well-known method for syn-
thesising enantiopure amines.12e14 Hydrolases are able to catalyse
the amidation of primary amines using activated esters as acyl
donors. A number of 1-arylethylamines have been resolved, often
with a high enantiomeric ratio (E-value).15,16 In the case of
2. Results and discussion
2.1. Lipase catalysed resolution
2.1.1. Preparation of racemic starting materials. The racemic amines
2aehwere preparedfromthe correspondinga-fluoroacetophenones
1aeh. The fluoroketones 1aeb were synthesised by fluorination of
* Corresponding author. E-mail address: bhoff@chem.ntnu.no (B.H. Hoff).
the corresponding trimethylsilyl enol ethers using Selectfluor,24
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.06.081

6734
T.H.K. Thvedt et al. / Tetrahedron 66 (2010) 6733e6743
O
F
while 1ceh were more conveniently prepared by a MW assisted
fluorination of acetophenones.25
OMe
NH2
F
HN
NH2
F
O
CAL-B
A reductive amination using ammonium acetate and NaBH3CN,
chosen for its simplicity, gave only mediocre conversion (33e44%).
However, the use of ammonia in EtOH in the presence of titanium
isopropoxide followed by sodium borohydride reduction,26 was
more successful and gave 68e92% yield (Scheme 1).
OMe
EtO
Br
Br
Br
(S)-3e
2e
(R)-2e
CAL-B
H2O
O
2e
OMe
1) NH3 in EtOH,
+
EtOH
HO
O
NH2
F
Ti(i-OPr)4
CAL-B
2) NaBH4
2e
F
R
R
O
1a-h
2a-h
OMe
NH3
O
Scheme 1. Synthesis of 2aeh from 1aeh, R¼OMe (a), OBn (b), H (c), F (d), Br (e), CF3
(f), CN (g), NO2 (h).
F
Br
2.1.2. Lipase and solvent selection. Compared to their non-fluori-
nated counterparts, the amines 2aeh have lower basicity and were
expected to have altered reactivity. With the aim of identifying
catalysts displaying a high activity and enantioselectivity towards
these substrates, the use of 10 different lipase preparations was
investigated. Being intermediate in both electronic character and
size, 1-(4-bromophenyl)-2-fluoroethylamine (2e) was used as
model substrate, and the reactions were performed in four different
solvents. Ethyl methoxyacetate was used as acyl donor and the
reactions were monitored for 72 h. Table 1 summarises the degree
of conversion after 6 h.
I
Scheme 2. The enzymatic kinetic resolution and the equilibrium involving the acyl
donor and water.
Table 2
Conversion and E-value after resolution of 2e varying the reaction temperature,
water activity and equivalents of acyl donor
Conversionb (%)
E-valuec
a
Temp (ꢀC)
aw
Equiv acyl donor
1 h
2 h
6 h
20
20
20
20
40
40
60
60
60
60
0.33
0.33
w0
w0
0.12
1
3
1
3
2
2
1
3
1
3
11
13
14
19
32
34
45
43
44
41
16
21
22
27
43
45
49
43
49
47
34
42
37
42
50
50
50
49
50
49
>200
>200
>200
>200
>200
>200
>200
>200
>200
>200
Table 1
The conversion of 2e to 3e after kinetic resolution (6 h) catalysed by different en-
zymes in different solvents
0.12
0.33
0.33
Enzyme
Conversionb (%)
THF Toluene Hexane Dodecane
Seven lipase preparationsa
Pseudomonas cepacia
Candida antarctica lipase A (Novozym 735)
Candida antarctica lipase B (Novozym 435) 23 39
0
2
0
0
0
8
0
0
14
50
0
0
16
50
w0
w0
a
Water activity (aw) was fixed by equilibration in the presence of aqueous sat-
urated salt solutions: MgCl2$7H2O (aw¼0.33), LiCl (aw¼0.12), dried over molecular
sieves 4 Å (aw¼w0).
a
Aspergillus niger, Aspergillus oryzae, Candida rugosa, Candida rugosa IM, Pseudo-
monas fluorescens, Rhizomucor miehei, Thermomyces lanuginosa.
b
The conversion was calculated by the formula conv.¼ees/(eepþees), where ees
and eep are the ee of the substrate and product, respectively.27
b
The conversion was calculated by the formula conv.¼ees/(eepþees),27 where
c
E-values were calculated by the method of Rakels et al. for irreversible
ees and eep are the ee of the substrate and product, respectively.
reactions.27
Of the catalysts tested, only the two lipases from Candida ant-
arctica, showed noticeable conversion within 72 h. The use of lipase
B from C. antarctica (CAL-B) gave 50% conversion after 6 h in both
hexane and dodecane, whereas 24 h were needed in THF and tol-
uene. A high enantioselectivity (E>200) was experienced in all
solvents. Using lipase A from C. antarctica as catalyst, a lower rate of
reaction and a lower enantiomeric ratio (E¼4e5) was observed.
CAL-B was by far the best catalyst, and hexane was selected as
solvent for further studies.
Within the experimental constrains, the only statistically sig-
nificant variable was found to be the reaction temperature (see
Pareto chart in Fig. 1). A reaction temperature of 60 ꢀC gave the
highest rate, reaching 50% conversion in 2 h using 1 equiv of acyl
donor. However, a temperature of 40 ꢀC also offered acceptable
Pareto chart of the standardised effects
(response is conversion 2 h, alpha = 0.05)
12.7
Factor Name
A
B
C
Water activity
Temperature
Acyl donor eq
B
BC
A
2.1.3. Reaction temperature, water activity and amount of acyl
donor. The hydrolysis of ethyl methoxyacetate to produce
methoxyacetic acid and ethanol was a side-reaction in the resolu-
tion. It was noticed that methoxyacetic acid and the amine 2e
formed the salt pair I, a process expected to reduce the reaction rate
(see Scheme 2).
The reaction temperature, the concentration of acyl donor and
the water activity were pinpointed as important parameters in the
salt pair formation. Therefore, a two-level factorial design was
performed with these three parameters as variables. The reaction
temperature was varied from 20 to 60 ꢀC, the amount of acyl donor
from 1 to 3 equiv and the water activity (aw) from w0 to 0.33. The
degree of conversion and enantioselectivity of the experiments are
shown in Table 2.
AB
AC
ABC
C
0
5
10
15
20
25
Standardised effect
Figure 1. Pareto chart of the factorial design varying the amount of acyl donor, water
activity and temperature.

T.H.K. Thvedt et al. / Tetrahedron 66 (2010) 6733e6743
6735
reaction times at aw¼0.11 and 2 equiv of acyl donor. The enantio-
meric ratio of the reactions was excellent under all conditions.
The amountof acyl donor was nota significant variable. However,
at 20 ꢀC the conversion increased when applying higher levels of
acyl donor, whereas at 60 ꢀC the highest conversion was obtained
using 1 equiv of acyl donor. This observation could be accounted for
by the rather complex equilibrium shown in Scheme 2. The reaction
temperature is expected tohavedifferenteffects on the relative rates
for the amidation reaction, the non-productive hydrolysis of the acyl
donorand the equilibrium between the freeamine and the salt pair I.
The effect of changing the water activity was not significant.
However, keeping a constant water activity was still considered to
be important for the reproducibility of the resolutions.
It was further investigated if methoxyacetic acid could be used
as acyl donor in the resolution of 2e. Performing the resolution at
60 ꢀC using 1 equiv of methoxyacetic acid, a 49% conversion was
obtained after 6 h. This showed that the formation of I is reversible
and that the resolution also can be performed under such condi-
tions. Attempts to reduce the amount of acyl donor to 0.6 equiv led
to an incomplete conversion after 6 h.
investigated. However, solvent tuning as demonstrated in the small-
scale reaction of 2a and 2h is likely to bring conversion from 49 to
50% and thereby increasing the ee of the remaining substrate.
2.2. The Mitsunobu approach
The (S)-enantiomers of the fluoroamines 2aeh were obtained
from the ketones 1aeh by asymmetric reduction followed by
a Mitsunobu inversion protocol as depicted in Scheme 3.
O
F
R
Cl
NH
Ru
Ts
1a-h
N
Cat. 6
Ph
Ph
Cat. 6
Phthalimide
PPh3
O
O
NH2
F
OH
N
1. NH2NH2,
MeOH
DEAD
2. HCl (aq)
F
THF
F
R
R
R
2.1.4. Effect of substrate structure on conversion and selectivity.
Seven other 1-aryl-2-fluoroethylamines, 2aed and 2feh were then
submitted to lipase-catalysed resolution using CAL-B and ethyl
methoxyacetate (1 equiv) in hexane at 60 ꢀC. The small-scale re-
actions of 2beg proceeded with rate comparable to that of the
resolution of 1e and with excellent enantioselectivity. A lower rate
of reaction was observed for the resolution of 2a, and the reaction
stopped at 30% conversion. However, by adding fresh enzyme or
diluting the reaction mixture the resolution could be driven to
completion. Probably, some kind of reversible product or substrate
inhibition occurs. The nitro-derivative 2h had limited solubility in
hexane and therefore reacted slowly. An increase in rate was ob-
served when toluene was used as solvent.
(R)-4a-h
(S)-5a-h
(S)-2a-h
Scheme 3. Synthesis of (S)-2aeh from 1aeh using asymmetric transfer hydrogenation
and Mitsunobu inversion.
2.2.1. Preparation of enantioenriched fluoroalcohols. Based on our
previous findings,28 the fluoroalcohols (R)-4aeh were synthesised
from the corresponding
a-fluoroacetophenones 1aeh by asym-
metric transfer hydrogenation catalysed by [RuCl2(mesitylene)]2
complexed with (1S,2S)-N-p-tosyl-1,2-diphenylethylenediamine
((S,S)-TsDPEN). The alcohols (R)-4aee and (R)-4geh were syn-
thesised in a formic acid/triethylamine (5/2 mol ratio) medium,
while (R)-4f was prepared using water with sodium formate as
hydrogen donor. The yields and ee are summarised in Table 4. The
reactions performed in formic acid/triethylamine gave the product
alcohols in 61e91% yield and with good to excellent ee. However, in
the reaction performed in water, the alcohol (R)-3f was isolated in
a moderate 52% yield. The reason for this is somewhat unclear. 1H
NMR spectroscopy analysis of the distillation residue gave a spec-
trum with complex splitting pattern in the range of 4.2e5.3 ppm,
indicating the presence of several structures containing alkyl
fluoride fragments.
Preparative kinetic resolutions were then performed on
a 2.5 mmol scale. Based on results for the resolution of 2e, a 16-fold
more concentrated reaction mixture was used in the preparative
resolutions. The ee of the product and substrate, conversions, en-
antiomeric ratio after 6 h and by completion are compiled in Table 3.
Table 3
CAL-B catalysed kinetic resolution of 2aeh (2.5 mmol scale) at 60 ꢀC using ethyl
methoxyacetate (1 equiv) as acyl donor in hexane
R
6 h
24 h
Table 4
Isolated yields and ee of the alcohols (R)-4aeh, N-substituted phthalimides (S)-
5aeh, and fluoroamines (S)-2aeh
Conversionc
(%)
2 of
ee (%)
3 of
ee (%)
Conversionc
(%)
2 of
ee (%)
3 of
ee (%)
OMe (a)a
OBn (b)
H (c)
F (d)
Br (e)
CF3 (f)
CN (g)
NO2 (h)b
49.5
48.0
49.5
50.0
50.0
50.0
47.0
d
97.0
92.5
98.5
>99.5
>99.5
>99.5
87.0
d
>99.5
>99.5
>99.5
>99.5
>99.5
>99.5
>99.5
d
49.5
49.0
50.0
d
97.0
96.0
>99.5
d
>99.5
>99.5
>99.5
d
R
(R)-4
(S)-5
(S)-2
ee (%)
Yield (%)
ee (%)
Yield (%)
ee (%)
Yield (%)
OMe (a)
OBn (b)
H (c)
F (d)
Br (e)
CF3 (f)
CN (g)
NO2 (h)
96.0
99.5
98.0
93.0
91.0
92.5
87.0
85.0
76
61
86
79
79
52
85
91
53.0
60.0
99.0
92.5a
90.0
92.0
87.5
84.0
32
37
77
77
83
78
66
34
53.5
60.0
98.5
92.5
90.5
91.5
87.5
84.0
73
72
66
75
66
71
75
80
d
d
d
d
d
d
50.0
50.0
99.0
>99.5
>99.5
>99.5
a
Hexane: 24 mL, CAL-B: 2 equiv wt.
b
c
Toluene: 12 mL, CAL-B: 1 equiv wt , 48 h reaction time.
The conversion was calculated by the formula conv.¼ees/(eepþees),27 where
a
Analysed as 2d.
ees and eep are the enantiomeric excess of the substrate and product, respectively.
The enantiomeric ratio was excellent in all cases (E>200) and the
product (S)-amides 3aeh could all be obtained in enantiomerically
pure form. The kinetic resolution of 2def gave full conversion and
>99% ee of the amines within 6 h reaction time. The other substrates
reacted slightly slower, thus, the amines 2a and 2b were after 24 h
obtained in 97 and 96% ee, respectively. If the lower conversion is
due to inhibition, low solubility of the amines or a displacement of
the equilibrium towards the amine salt I, has not been further
2.2.2. Mitsunobu inversion. The alcohols (R)-4aeh were then
reacted with phthalimide in the presence of diethyl
azodicarboxylate (DEAD) and triphenylphosphine to yield the cor-
responding N-substituted phthalimides (S)-5aeh. The isolated
yields and the ee of the products are shown in Table 4.
The N-substituted phthalimides (S)-5cef were isolated in
77e83% yield and with clean inversion of the stereochemistry.
Somewhat disappointingly, the reactions leading to (S)-5aeb, were

6736
T.H.K. Thvedt et al. / Tetrahedron 66 (2010) 6733e6743
plagued by racemisation and poor yields. Other alcohols have been
shown to partly racemise under similar conditions.29e33 The re-
actions have been found to proceed via the intermediate ROPPh3þ
(II), which is attacked by a nucleophile in an SN2 type mechanism
(Scheme 4). However, when the substrate enables stabilisation of
a developing positive charge, II can convert to III and IV.
traced, we propose a concerted mechanism to 7geh via the known
Mitsunobu intermediate II (Scheme 5). The nitro and the cyano
group increase the acidity of the benzylic proton, possibly
explaining why only 4geh reacted by this pathway in the presence
of phthalimide.
O
X-
PR3
Ar
O
1h
F
Ar
PPh3
O
III
PR3
F
F
O
O
O
Nu
Nu
O
Nu-
Nu-
Ar
F
Ar
Ar
Ar
Ar
Ar
Ar
H
(R)-8h
F
F
II
7h
II
OH
O
CO2Et
PPh3
Ar
N
N
Ar
9h
EtO2C
F
IV
Scheme 5. Possible explanation for the formation of the acetophenones 7geh in the
Mitsunobu reaction.
Scheme 4. Mechanistic rationale for the observed racemisation.29
To produce the target amines (S)-2aeh, (S)-5aeh were dis-
solved in methanol and reacted with hydrazine and hydrochloric
acid. These hydrazinolysis reactions proceeded smoothly, giving
the amines (S)-2aeh in good to moderate yields without altering
the ee (Table 4).
These intermediates might react with nucleophiles via an SN1
type mechanism to form a racemic product.29,34 The low yields
experienced indicated that other side products also might be
formed via these pathways.
The alcohols (R)-4geh reacted to (S)-5g and (S)-5h without
racemisation, but in moderate and poor yields, respectively. The
major by-product was the corresponding acetophenones 7geh.
Further experiments performed on (R)-4h and racemic 4h showed
that 7h was formed also in the absence of phthalimide. DEAD is
able to oxidise alcohols to ketones,35,36 but in this case a reaction
using only DEAD failed to give 7h. Thus, both DEAD and triphe-
nylphosphine were required for the transformation. In an attempt
to identify reaction intermediates, the reaction was run in THF-d8
and continuously monitored by 1H NMR spectroscopy. The reaction
took place, but within the time scale of NMR no distinct in-
termediates could be detected. Having no indication of the possible
mechanism, 2-fluoro-1-(4-nitrophenyl)ethanone (1h), (R)-2-(4-
nitrophenyl)oxirane ((R)-8h) and 1-(4-nitrophenyl)ethanol (9h)
were reacted with DEAD and triphenylphosphine to investigate if
these compounds could be reaction intermediates. Compound 7h
was not observed in any of these experiments, excluding these
possibilities.
2.3. Determination of the absolute configuration
Optical rotation data have previously only been reported for the
hydrochloride salts of (S)-2a and (S)-2c.10,11 These data were in
agreement with our measurements.
The configuration of the previously unknown fluoroamines was
strongly indicated by the stereoselectivity of the lipase-catalysed
resolution and the Mitsunobu inversion. However, to un-
ambiguously confirm this, the absolute configuration of the amines
was determined by circular dichroism spectroscopy (CD) of the N-
substituted phthalimides (S)-5aeh using the exciton chirality
method.44e46 The most stable conformation of the N-substituted
phthalimides was predicted using semiempirical AM1 calculations.
All the compounds showed the same preferred conformation, with
the hydrogen attached to the stereogenic centre arranged in the
same plane as the disubstituted phenyl ring (see Fig. 2A).
Alcohols have been reported to undergo dehydrations, elimi-
nations and rearrangement reactions under Mitsunobu con-
ditions.37e41 Phosphorus is known to have affinity for fluoride
anions, and triphenylphosphine has been used as a defluorinating
agent.42,43 Based on this, and since no intermediates could be
For (S)-5aeh an anticlockwise rotation of the disubstituted
phenyl ring brings it onto the phthalimide dipole, thus a negative
first Cotton effect was predicted. This was confirmed by CD mea-
surements, exemplified by the CD spectrum of (S)-5f in Figure 2B.
All the CD measurements are summarised in Table 5.
Figure 2. Favoured conformation (A) and CD and UV spectrum of (S)-5f (B).

T.H.K. Thvedt et al. / Tetrahedron 66 (2010) 6733e6743
6737
Table 5
Agilent 1100 series system with a DAD detector. GC was performed
using a Varian 3380. Accurate mass determination (ESI) was per-
formed on an Agilent G1969 TOF MS instrument equipped with
a dual electrospray ion source. Samples were injected into the MS
using an Agilent 1100 series HPLC and analysis was performed as
a direct injection analysis without any chromatography. FTIR spectra
were recorded on a Thermo Nicolet Avatar 330 infrared spectro-
photometer. All melting points are uncorrected and measured by
a Büchi melting point instrument. CD spectra were recorded on an
OLIS DSM 1000 spectrophotometer in a 1 cm cell, at concentration
0.01 mg/mL in MeCN.
The ee of the amines 2aeh was determined as follows: com-
pounds 2b and 2h were analysed as their trifluoroacetamides by
HPLC using a Daicel Chiralcel OD-H column with detection at
230 nm. Compound 2b (trifluoroacetamide): hexane/2-propanol
(85/15), flow rate 1.0 mL/min, (S)-2b: 9.2 min, (R)-2a: 13.0 min.
Compound 2h (trifluoroacetamide): hexane/2-propanol (90/10),
flow rate 1.0 mL/min, (S)-2h: 12.4 min, (R)-2a: 16.8 min. Com-
pounds 2a and 2ceg were analysed derivatised as their acetamides
on GC using a CP-Chirasil-Dex CB column at 10 psi. Isothermal
programs were used in each case. Compounds 2a and 2g: 160 ꢀC,
(R)-2a: 21.1 min, (S)-2a: 21.8 min, (R)-2g: 41.0 min, (S)-2g:
42.1 min, 2c: 125 ꢀC, (R)-2c: 26.5 min, (S)-2c: 28.9 min, 2d: 135 ꢀC,
(R)-2d: 19.6 min, (S)-2d: 21.3 min, 2e: 150 ꢀC, (R)-2e: 38.5 min, (S)-
2e: 40.9 min, 2f: 140 ꢀC, (R)-2f: 16.5 min, (S)-2f: 18.2 min.
Enantiomeric excess, molar extinction (De) and absorption maximum for the first
Cotton effect (
l
) for (S)-5aeh
Compound
R
ee (%)
D
e
l (nm)
(S)-5a
(S)-5b
(S)-5c
(S)-5d
(S)-5e
(S)-5f
(S)-5g
(S)-5h
OMe
OBn
H
F
Br
CF3
CN
NO2
53.0
60.0
99.0
92.5a
90.0
92.0
87.5
84.0
ꢂ1.3
ꢂ3.8
ꢂ3.5
ꢂ1.6
ꢂ3.9
ꢂ4.8
ꢂ2.7
ꢂ1.4
232
234
223
223
230
225
237
228
a
Analysed as 2d.
3. Conclusions
Starting with
a-fluoroacetophenones, a lipase-catalysed reso-
lution and a Mitsonobu inversion have been investigated for the
preparation of enantioenriched 1-aryl-2-fluoroethylamines.
Using CAL-B as catalyst and ethyl methoxyacetate as acyl donor,
the resolutions proceeded with high enantioselectivity and pro-
vided the product (R)-amines and (S)-amides in 96e99% and
>99.5% ee, respectively. The method proved to be fairly robust with
respect to the amount of acyl donor, water activity and the reaction
temperature. One of the substrates (2h) had to be resolved in tol-
uene due to limited solubility in hexane.
The ee of the methoxyacetamides 3aeh was determined as
follows: compounds 3a and 3cef were analysed on GC using a CP-
Chirasil-Dex CB column at 10 psi. Isothermal programs were used in
each case. Compound 3a: 160 ꢀC, (R)-3a: 24.8 min, (S)-3a: 25.8 min,
3c: 125 ꢀC, (R)-3c: 38.0 min, (S)-3c: 40.0 min, 3d: 135 ꢀC, (R)-3d:
26.0 min, (S)-3d: 27.1 min, 3e: 150 ꢀC, (R)-3e: 49.0 min, (S)-3e:
51.5 min, 3f: 140 ꢀC, (R)-3f: 19.5 min, (S)-3f: 20.9 min. Compound 3b
was analysed by HPLC using a Daicel Chiralcel OD-H column, eluting
with hexane/2-propanol (90/10), flow rate 1.0 mL/min, detection at
230 nm: (S)-3b: 31.7 min, (R)-3b: 38.5 min. Compounds 3geh:
The Mitsunobu protocol gave clean inversion of the stereo-
chemistry of the alcohols (R)-4cef. The amines (S)-2cef could be
isolated in 90.5e98.5% ee. In the case of substrates containing
electron-donating substituents, racemisation occurred. The yield
decreased when both electron donating and strongly electron
withdrawing substituents were present. For the latter substrates,
a fluorine elimination was identified as the major side reaction.
The drawback of a kinetic resolution is the limitation of a max-
imum 50% yield. Therefore, despite the fact that the enzymatic
resolution approach is one step shorter, the overall yields of the two
routes were comparable in the case of 2ceg. However, the resolu-
tion method appears more attractive since it gives the products in
higher ee and involves only two simple steps from the ketone
without the use of hazardous chemicals.
analysed by an Astec Chirobiotic V2 column, 5
m
m, 4.6ꢁ250 mm
(Supelco, Pennsylvania, USA) for 3g eluting with hexane/EtOH
(concn 0.5% TFA), 91/9, flow rate: 1.0 mL/min, detection at 230 nm,
(S)-3g: 47.7 min, (R)-3g: 49.2 min and for 3h eluting with hexane/
EtOH (concn 0.5% TFA), 98/2, flow rate: 3.0 mL/min, detection at
230 nm, (R)-3g: 50.1 min and (S)-3h: 53.8 min.
4. Experimental
The ee of the alcohols (S)-4aeh was determined by HPLC
analysis using a Daicel Chiralcel OD column (0.46 cmꢁ25 cm)
with mobile phase: hexane/2-propanol (98/2) at a flow rate of
1.0 mL/min.49
4.1. Chemicals and equipment
The
a
-fluoroacetophenones, 1aeh,24,25 and [RuCl2(mesity-
The ee of 5aec and 5eeh was determined by HPLC using a Daicel
Chiralcel OD-H column with detection at 270 nm. Compounds 5a, 5e
and5f: eluent: hexane/2-propanol (90/10), flow rate 1.0 mL/min, (S)-
5a: 11.2 min, (R)-5a: 12.6 min, (R)-5e: 8.9 min, (S)-5e: 10.1 min,
(R)-5f: 7.5 min, (S)-5f: 8.1 min. Compound 5b: eluent: hexane/2-
propanol (99/1), flow rate: 1.0 mL/min, (S)-5b: 33.5 min, (R)-5b:
36.2 min. Compound 5c:eluent: hexane/2-propanol(98/2), flow rate
1.0 mL/min, (R)-5c: 11.3 min, (S)-5c: 14.0 min. Compound 5g: eluent:
hexane/2-propanol (90/10), flow rate 1.2 mL/min, (R)-5g: 22.7 min,
(S)-5g: 26.5 min. Compound 5h: eluent: hexane/isopropanol (95/5),
flow rate 1.0 mL/min, (R)-5h: 26.9 min, (S)-5h: 29.8 min.
lene)]2,47,48 were prepared as described previously. (R)-2-(4-
Nitrophenyl)oxirane, (S,S)-TsDPEN and phthalimide were from
Aldrich. 1-(4-Nitrophenyl)ethanone, 4-acetylbenzonitrile, DEAD
(40% solution in toluene) and Silica 60 were from Fluka. Triphe-
nylphosphine was from SigmaeAldrich.
C. antarctica lipase B (Novozym 435), C. antarctica lipase A
(Novozym 735) and Rhizomucor miehei lipase (Lipozyme RM-IM)
were kind gifts from Novozymes. Pseudomonas cepacia, Aspergillus
niger, Aspergillus oryzae, Candida rugosa, C. rugosa IM, Thermomyces
lanuginosa, P. fluorescens were from Aldrich. The enzymatic resolu-
tions were performed in an Infors-HT Minitron type AY70 incubator.
4.3. General procedures
4.2. Analyses
4.3.1. Preparation of 2aeh. The following procedure is
representative:
1H and 13C NMR spectra were recorded with Bruker Avance 400
spectrometer operating at 400 MHz and 100 MHz, respectively. 19F
NMR was performed on a Bruker Avance 500 operating at 470 MHz.
For 1H and 13C NMR chemicalshifts are inparts per million rel toTMS,
while for 19F NMR the shift values are relative to hexafluorobenzene.
Coupling constants are in hertz. HPLC was performed using an
1-(4-Bromophenyl)-2-fluoroethanone (1e) (4.36 g, 20.1 mmol)
and titanium isopropoxide (12.0 mL,e40.0 mmol) were dissolved in
an ethanol/ammonia solution (2 M, 50 mL) and stirred under argon
atmosphere at room temperature for 24 h. Upon full conversion as
detected by 1H NMR spectroscopy, NaBH4 (1.13 g, 30.30 mmol) was

6738
T.H.K. Thvedt et al. / Tetrahedron 66 (2010) 6733e6743
added, and the reaction mixture was stirred under argon atmo-
sphere at room temperature for 24 h. The reaction mixture was
made acidic (pH¼2) using HCl (6 M), and washed with tert-butyl
methyl ether (TBME) (3ꢁ20 mL). The mixture was made alkaline
with NaOH pellets (pH¼10), saturated with sodium chloride and
extracted with TBME (5ꢁ30 mL). The organic phase was dried over
Na2SO4, and the solvent was evaporated under reduced pressure.
Purification using silica-gel column chromatography (EtOAc/MeOH,
4/1, Rf 0.45), gave 3.11 g (14.3 mmol, 71%) of a colourless oil.
in THF, 25 mmol) was added. The mixture was stirred at room
temperature until all the starting material had been consumed
(TLC) (2e10 h.). Then HCl (2 M, 10 mL) was added and the reaction
was stirred at room temperature overnight. Water (40 mL) was
added and the mixture extracted with Et2O (50 mL). The water
phase was made alkaline with NaOH (2 M, 30 mL) and extracted
with Et2O (3ꢁ50 mL). The combined organic phases were washed
with brine (30 mL), dried over MgSO4 and evaporated under re-
duced pressure. The products, (S)-1aeh were purified by silica-gel
column chromatography (EtOAc/MeOH, 9/1).
4.3.2. Small-scale enzymatic resolution. The racemic 1-aryl-2-fluo-
roethylamines, 2aeh, (0.04 mmol), ethyl methoxyacetate
(1e4 mol equiv) and Novozym 435 (1 equiv wt) were mixed in the
specified solvent (3 mL) and agitated in an incubator at 300 rpm at
4.4. Racemic 1-aryl-2-fluoroethylamines (2aeh)
4.4.1. 2-Fluoro-1-(4-methoxyphenyl)ethylamine (2a). The synthesis
was performed as described for 2e (Section 4.3.1) starting with 2-
fluoro-1-(4-methoxyphenyl)ethanone (1a) (2.18 g 12.94 mmol).
This gave 1.96 g (11.58 mmol, 89%) of a colourless oil. Rf (EtOAc/
the specified temperature. Samples (150 mL) were withdrawn after
1, 2 and 6 h. The samples were analysed for ee of the product and
remaining substrate. The water content of hexane was varied by
equilibrating on the presence of saturated salt solutions:
MgCl2$7H2O (aw¼0.33), LiCl (aw¼0.12) and dried over molecular
sieves 4 Å (aw¼w0).50
MeOH, 4/1) 0.47. 1H NMR (CDCl3)
d
: 1.70 (s, 2H, eNH2), 3.80 (s, 3H,
eOCH3), 4.22e4.53 (m, 3H, eCHCH2F), 6.89 (m, 2H, eC6H4e), 7.30
(m, 2H, eC6H4e). 13C NMR (CDCl3)
d
: 55.0 (d, J¼19.4), 55.6, 88.3 (d,
J¼174.5), 114.1 (2C), 128.0 (2C), 132.2 (d, J¼8.5), 159.2. 19F NMR
4.3.3. Preparative scale enzymatic resolution. The racemic amines
2beg (2.5 mmol), ethyl methoxyacetate (295 mg, 2.5 mmol) and
Novozym 435 (1 equiv wt) were diluted with dry hexane (12 mL)
and stirred in an incubator at 300 rpm at 60 ꢀC. When 50% con-
version was reached, the reaction mixture was diluted with TBME
(20 mL) and extracted with water containing acetic acid (1 M,
5ꢁ15 mL). The combined water phases were washed with TBME
(2ꢁ15 mL). The organic phase was dried over Na2SO4, and the
solvent evaporated under reduced pressure, yielding the
methoxyacetamides (S)-3beg, which were purified by silica-gel
column chromatography (EtOAc/MeOH, 4/1). The water phase was
made alkaline with NaOH (pellets), saturated with sodium chloride
and extracted with TBME (5ꢁ15 mL). The organic phase was dried
over Na2SO4, and the solvent was evaporated under reduced
pressure, yielding the amines (R)-2beg, which were purified by
silica-gel column chromatography (EtOAc/MeOH, 4/1).
(CDCl3)
d
: ꢂ219.15 (m). IR (neat, cmꢂ1): 3381, 3315, 2954, 2904,
2838, 1611, 1513, 1463, 1249, 1179, 1032, 995, 833. HRMS (ESI):
169.0907 (calcd 169.0903, [Mþ]).
4.4.2. 1-(4-(Benzyloxy)phenyl)-2-fluoroethylamine (2b). The syn-
thesis was performed as described for 2e (Section 4.3.1) starting with
1-(4-benzyloxyphenyl)-2-fluoroethanone (1b) (0.76 g, 3.10 mmol).
This gave 0.64 g (2.61 mmol, 84%) of a white solid, mp 42e43 ꢀC, Rf
(EtOAc/MeOH, 4/1) 0.45. 1H NMR (CDCl3)
d: 1.68 (s, 2H, eNH2),
4.22e4.54 (m, 3H, eCHCH2F), 5.07 (s, 2H, CH2Ph), 6.97 (m, 2H,
eC6H4e), 7.29 (m, 2H, eC6H4e), 7.30e7.34 (m, 5H, eC6H5). 13C NMR
(CDCl3)
d
: 55.0 (d, J¼19.0), 70.0, 88.3 (d, J¼174.5), 115.0 (2C), 127.0,
127.4 (2C), 128.0 (2C), 128.5 (2C), 132.5 (d, J¼8.5), 136.9, 158.5. 19F
NMR (CDCl3)
d
: ꢂ219.20 (m). IR (KBr, cmꢂ1): 3381, 3279, 3033, 2947,
2872, 1611, 1513, 1242, 1174, 1014, 839, 745, 697. HRMS (ESI):
245.1215 (calcd 245.1216, [Mþ]).
4.3.4. Asymmetric transfer hydrogenation28 of 1aee and 1geh. A
suspension of the [RuCl2(mesitylene)]2 (23 mg, 0.04 mmol) and (S,
S)-TsDPEN (44 mg, 0.12 mmol) in CH2Cl2 (8 mL) were stirred at 20 ꢀC
4.4.3. 2-Fluoro-1-phenylethylamine (2c). The synthesis was per-
formed as described for 2e (Section 4.3.1) starting with 2-fluoro-1-
phenylethanone (1c) (0.49 g, 3.55 mmol). This gave 0.46 g
(3.28 mmol, 92%) of a colourless oil, Rf (EtOAc/MeOH, 4/1) 0.46. 1H
for 30 min. After removal of CH2Cl2, the
a-fluoroacetophenone
(4.0 mmol) in a mixture of HCO2H/Et3N (5/2 mol ratio, 10 mL) was
added. The reaction mixture was stirred vigorously at 40 ꢀC for the
specified number of hours before it was quenched with water
(10 mL) and extracted with CH2Cl2 (3ꢁ15 mL). The organic phase
was then washed with brine (20 mL) and dried over Na2SO4 before
the solvent was removed under reduced pressure. Purification is
described for each individual compound.
NMR (CDCl3)
d: 1.72 (s, 2H, eNH2), 4.28e4.57 (m, 3H, eCHCH2F),
7.23 (m, 2H, Ph), 7.37 (m, 2H, Ph), 7.36 (m, 1H, Ph). 13C NMR (CDCl3)
d
: 55.6 (d, J¼19.4), 88.2 (d, J¼174.1), 126.9 (2C), 127.9, 128.6 (2C),
140.2 (d, J¼8.1). 19F NMR (CDCl3)
d
: ꢂ219.85 (m). IR (neat, cmꢂ1):
3384, 3314, 3063, 3030, 2950, 2890, 1604, 1493, 1454, 997, 861, 760,
701. HRMS (ESI): 139.0799 (calcd 139.0797, [Mþ]).
4.4.4. 2-Fluoro-1-(4-fluorophenyl)ethylamine (2d). The synthesis
was performed as described for 2e (Section 4.3.1) starting with 2-
fluoro-1-(4-fluorophenyl)ethanone (1d) (0.41 g, 2.61 mmol). This
gave 0.39 g (2.48 mmol, 95%) of a colourless oil. Rf (EtOAc/MeOH,
4.3.5. Mitsunobu inversion (S)-5aeh from (R)-4aeh. Under an N2-
atmosphere PPh3 (859 mg, 3.3 mmol) and phthalimide (487 mg,
3.3 mmol) were dissolved in THF (20 mL). To this mixture was
added the 1-aryl-2-fluoroethanol, (R)-4aeh, (3.0 mmol) dissolved
in THF (5 mL), followed by the DEAD solution (40% in toluene,
1.36 mL, 3.6 mmol). The mixture was stirred overnight at room
temperature, before the solvent was removed under reduced
pressure. The reaction mixture was then re-dissolved in CH2Cl2
(2 mL), K2CO3 (0.02 M,10 mL) added and the mixture stirred for 1 h.
The mixture was extracted with CH2Cl2 (3ꢁ15 mL) and the organic
phase washed with brine (20 mL) and dried over MgSO4. The sol-
vent was removed under reduced pressure and the crude product
was purified by silica-gel column chromatography.
4/1) 0.46. 1H NMR (CDCl3)
d
: 1.68 (s, 2H, eNH2), 4.25e4.50 (m, 3H,
eCHCH2F), 7.04 (m, 2H, eC6H4e), 7.35 (m, 2H, eC6H4e). 13C NMR
(CDCl3)
: 55.0 (d, J¼19.4), 88.0 (dd, J¼174.5, 1.4), 115.4 (d, J¼21.2,
d
2C), 128.5 (dd, J¼8.1, 0.7, 2C), 135.9 (dd, J¼8.1, 2.8), 162.3 (d,
J¼246.2). 19F NMR (CDCl3)
: ꢂ115.14 (m), ꢂ219.87 (m.). IR (neat,
d
cmꢂ1): 3388, 3321, 3044, 2952, 2891, 1734, 1605, 1510, 1229, 1158,
1093, 1003, 846. HRMS (ESI): 157.0706 (calcd 157.0703, [Mþ]).
4.4.5. 1-(4-Bromophenyl)-2-fluoroethylamine (2e). The synthesis is
described in Section 4.3.1. 1H NMR (CDCl3)
d: 1.68 (s, 2H, eNH2),
4.22e4.52 (m, 3H, eCHCH2F), 7.27 (m, 2H, eC6H4e), 7.47 (m, 2H,
4.3.6. Hydrazinolysis of (S)-5aeh. The N-substituted phthalimides
5aeh (2.5 mmol) were dissolved in MeOH (40 mL) and N2H4 (1.0 M
eC6H4e). 13C NMR (CDCl3)
d
: 55.1 (d, J¼19.8), 87.8 (d, J¼174.5),
121.7, 128.6 (d, J¼0.7, 2C), 131.7 (2C), 139.3 (d, J¼7.8). 19F NMR

T.H.K. Thvedt et al. / Tetrahedron 66 (2010) 6733e6743
6739
(CDCl3)
d
: ꢂ220.34 (m). IR (neat, cmꢂ1): 3383, 3330, 2950, 2890,
gel column chromatography 126 mg (0.91 mmol, 36%) of (R)-2c as
20
1590, 1488, 1406, 1073, 1004, 830. HRMS (ESI): 216.9904 (calcd
colourless oil, ee >99.5%, [
a
]
D
ꢂ40.5 (c 0.60, CHCl3).
216.9902, [(79Br)Mþ]).
4.5.4. (R)-Fluoro-1-(4-fluorophenyl)ethylamine ((R)-2d). The reso-
lution was performed as described in Section 4.3.3, starting with 2d
(393 mg, 2.49 mmol). Reaction time was 6 h. This gave after silica-
gel column chromatography 169 mg (1.08 mmol, 43%) of (R)-2d as
4.4.6. 2-Fluoro-1-(4-(trifluoromethyl)phenyl)ethylamine (2f). The
synthesis was performed as described for 2e (Section 4.3.1) starting
with 2-fluoro-1-(4-(trifluoromethyl)phenyl)ethanone (1f) (0.91 g,
4.40 mmol). This gave 0.62 g (2.99 mmol, 68%) of a colourless oil, Rf
a colourless oil, ee >99.5%, [
a
]
20 ꢂ39.7 (c 0.71, CHCl3).
D
(EtOAc/MeOH, 4/1) 0.49. 1H NMR (CDCl3)
d
: 1.71 (s, 2H, eNH2),
4.27e4.56 (m, 3H, eCHCH2F), 7.52 (m, 2H, eC6H4e), 7.57 (m, 2H,
eC6H4e). 13C NMR (CDCl3)
: 55.4 (d, J¼19.8), 87.7 (d, J¼175.2),
4.5.5. (R)-1-(4-Bromophenyl)-2-fluoroethylamine ((R)-2e). The res-
olution was performed as described in Section 4.3.3, starting with
2e (545 mg, 2.50 mmol). Reaction time was 6 h. This gave after
silica-gel column chromatography 213 mg (0.98 mmol, 39%) of (R)-
d
124.0 (q, J¼272.0), 125.5 (q, J¼3.8, 2C), 127.3 (d, J¼0.7, 2C), 130.1 (q,
J¼32.5), 144.4 (dq, J¼7.6, 1.3). 19F NMR (CDCl3)
: ꢂ63.18 (s, 3F),
d
ꢂ221.06 (m). IR (neat, cmꢂ1): 3392, 3330, 2954, 2895, 1621, 1420,
1326, 1160, 1120, 1068, 1017, 842, 606. HRMS (ESI): 207.0668 (calcd
207.0671, [Mþ]).
2e as a colourless oil, ee >99.5%, [
a]
20 ꢂ28.5 (c 0.68, CHCl3).
D
4.5.6. (R)-2-Fluoro-1-(4-(trifluoromethyl)phenyl)ethylamine
((R)-
2f). The resolution was performed as described in Section 4.3.3,
starting with 2f (518 mg, 2.50 mmol). Reaction time was 6 h. This
4.4.7. 4-(1-Amino-2-fluoroethyl)benzonitrile (2g). The synthesis
was performed as described for 2e (Section 4.3.1) starting with 1-
(4-cyanophenyl)-2-fluoroethanone (1g) (1.03 g, 6.34 mmol). This
gave 0.84 g (5.13 mmol, 81%) of a white solid, mp 48e49 ꢀC, Rf
gave after silica-gel column chromatography 195 mg (0.94 mmol,
20
38%) of (R)-2f as a colourless oil, ee >99.5%, [
CHCl3).
a
]
ꢂ27.4 (c 0.61,
D
(EtOAc/MeOH, 4/1) 0.42. 1H NMR (CDCl3)
d: 1.70 (s, 2H, eNH2),
4.27e4.55 (m, 3H, eCHCH2F), 7.53 (m, 2H, eC6H4e), 7.65 (m, 2H,
4.5.7. (R)-4-(1-Amino-2-fluoroethyl)benzonitrile ((R)-2g). The res-
olution was performed as described in Section 4.3.3, starting with
2g (411 mg, 2.50 mmol). Reaction time was 24 h. This gave after
silica-gel column chromatography 150 mg (0.91 mmol, 37%) of (R)-
eC6H4e). 13C NMR (CDCl3)
d
: 55.4 (d, J¼19.8), 87.3 (d, J¼175.6),
111.8, 118.6, 127.8 (d, J¼0.7, 2C), 132.4 (2C), 145.8 (d, J¼7.0). 19F NMR
(CDCl3)
d
: ꢂ221.61 (m). IR (KBr, cmꢂ1): 3381, 3317, 2954, 2863, 2227,
1609, 1502, 1412, 1359, 1099, 1050, 992, 832, 564. HRMS (ESI):
2g as a white solid, mp 46.5e47.0 ꢀC, ee¼99.0%, [
a]
20 ꢂ32.0 (c 0.56,
D
164.0750 (calcd 164.0750, [Mþ]).
CHCl3).
4.4.8. 2-Fluoro-1-(4-nitrophenyl)ethylamine (2h). The synthesis
was performed as described for 2e (Section 4.3.1) starting with 2-
fluoro-1-(4-nitrophenyl)ethanone (1h) (1.15 g, 6.26 mmol). This
gave 0.91 g (4.95 mmol, 79%) of a white solid, mp 52e53 ꢀC, Rf
4.5.8. (R)-2-Fluoro-1-(4-nitrophenyl)ethylamine ((R)-2h). The res-
olution was performed as described in Section 4.3.3, starting with
2h (460 mg, 2.50 mmol), but with toluene (12 mL) as solvent. Re-
action time was 48 h. This gave after silica-gel column chroma-
(EtOAc/MeOH, 4/1) 0.40. 1H NMR (CDCl3)
d
: 1.72 (br s, 2H, eNH2),
tography 200 mg (1.09 mmol, 43%) of (R)-2h as a pale yellow solid,
20
4.28e4.60 (m, 3H, CHCH2F), 7.58e7.62 (m, 2H, eC6H4e), 8.21e8.24
mp 53.0e53.5 ꢀC, ee >99.5%, [
a]
ꢂ20.1 (c 0.71, CHCl3).
D
(m, 2H, eC6H4e). 13C NMR (CDCl3)
d
: 55.3 (d, J¼20.1), 87.3 (d,
J¼175.6), 123.8 (2C), 128.0 (d, J¼0.7, 2C), 147.7, 147.8, (d, J¼7.1). 19F
4.6. (S)-1-Aryl-2-fluoroethylamines ((S)-2aeh)
NMR (CDCl3)
d
: ꢂ221.78 (m). IR (neat, cmꢂ1): 3379, 3113, 2952,
2852, 1599, 1510, 1346, 995, 855. HRMS (ESI): 185.0726 (calcd
Compounds (S)-2aeh were obtained from the alcohols (R)-
4aeh by the Mitsunobu inversion described in Sections 4.3.4e4.3.6.
The NMR spectroscopic properties corresponded with that repor-
ted for the corresponding racemate.
185.0726, [MþHþ]).
4.5. (R)-1-Aryl-2-fluoroethylamines ((R)-2aeg)
4.6.1. (S)-2-Fluoro-1-(4-methoxyphenyl)ethylamine ((S)-2a)10. The
Compounds (R)-2aeh were obtained by lipase-catalysed reso-
lution as described in Section 4.3.3. The NMR spectroscopic prop-
erties corresponded with that reported for the corresponding
racemates.
hydrazinolysis was performed as described in Section 4.3.6 starting
with (S)-5a (200 mg, 0.67 mmol). This gave 83 mg (0.49 mmol,
20
73%) of (S)-2a as a pale yellow oil, ee¼53.5%, [
a]
þ20.9 (c 0.54,
D
CHCl3), Rf (EtOAc/MeOH, 9/1) 0.37.
The hydrochloride salt of (S)-2a was obtained by treatment with
HCl saturated ether (5 mL) under stirring for 20 min. The solvent
was then evaporated under reduced pressure and the product
isolated as a white powder, which decomposed on melting. The 1H
4.5.1. (R)-2-Fluoro-1-(4-methoxyphenyl)ethylamine ((R)-2a). The
resolution was performed as described in Section 4.3.3, starting
with 2a (423 mg, 2.50 mmol), but with hexane (24 mL) and
Novozym 435 (846 mg). Reaction time was 24 h. This gave after
silica-gel column chromatography 180 mg (1.06 mmol, 43%) of (R)-
NMR data corresponded with that reported.10 1H NMR (CD3OD)
d:
3.82 (s, 3H, eOCH3), 4.59e4.69 (m, 2H, eCH2F), 4.81e8.83 (m, 1H,
eCHCH2F), 7.00e7.05 (m, 2H, eC6H4e), 7.38e7.43 (m, 2H, eC6H4e).
2a as a colourless oil, ee¼97.0%, [
a
]
20 ꢂ37.4 (c 0.55, CHCl3).
D
[a
]
20 þ17.7 (c 0.66, MeOH), lit.10 þ31.5 (c 0.66, MeOH).
D
4.5.2. (R)-1-(4-(Benzyloxy)phenyl)-2-fluoroethylamine ((S)-2b). The
resolution was performed as described in Section 4.3.3, starting
with 2b (613 mg, 2.50 mmol). Reaction time was 24 h. This gave
4.6.2. (S)-1-(4-(Benzyloxy)phenyl)-2-fluoroethylamine ((S)-2b). The
hydrazinolysis was performed as described in Section 4.3.6 starting
with (S)-5b (205 mg, 0.55 mmol). This gave 97 mg (0.40 mmol,
after silica-gel column chromatography 211 mg (0.86 mmol, 34%) of
20
(R)-2b as a white solid, mp 41.5e42 ꢀC, ee¼96.0%, [
a
]
ꢂ29.1 (c
72%) of (S)-2b as a white solid, mp 42e43 ꢀC, ee¼60.0%, [
(c 0.52, CHCl3), Rf (EtOAc/MeOH, 9/1) 0.40.
a]
20 þ16.0
D
D
0.50, CHCl3).
4.5.3. (R)-2-Fluoro-1-phenylethylamine ((R)-2c)7. The resolution
was performed as described in Section 4.3.3, starting with 2c
(348 mg, 2.50 mmol). Reaction time was 24 h. This gave after silica-
4.6.3. (S)-2-Fluoro-1-phenylethylamine ((S)-2c)9e11. The hydrazi-
nolysis was performed as described in Section 4.3.6 starting with
(S)-5c (672 mg, 2.50 mmol). This gave 228 mg (1.64 mmol, 66%) of

6740
T.H.K. Thvedt et al. / Tetrahedron 66 (2010) 6733e6743
20
(S)-2c as a colourless oil, ee¼98.5%, [
a
]
D
þ44.0 (c 0.60, CHCl3), Rf
eCH2eC6H5).13C NMR (CDCl3)
d
: 51.8 (d, J¼19.3), 59.1, 70.0, 71.9, 84.7
(EtOAc/MeOH, 9/1) 0.40.
(d, J¼175.8), 115.1 (2C), 127.4 (2C), 128.0, 128.2 (d, J¼1.1, 2C), 128.6
The hydrochloride salt of (S)-2c was obtained by treatment with
HCl saturated ether (5 mL) under stirring for 20 min. The solvent
was then evaporated under reduced pressure and the product
isolated as a white powder, which decomposed on melting. The 1H
(2C),129.9 (d, J¼3.4), 136.8, 158.6, 169.1. 19F NMR (CDCl3)
: ꢂ229.60
d
(td, J¼47.3, 24.0). IR (neat, cmꢂ1): 3294, 1650, 1532, 1116, 1003, 829,
542. HRMS (ESI): 317.1430 (calcd 317.1427, [Mþ]).
NMR data corresponded with that reported.10 1H NMR (CD3OD)
d:
4.7.3. (S)-N-(2-Fluoro-1-phenylethyl)-2-methoxyacetamide
((S)-
4,67e4.76 (m, 2H, eCH2F), 4.84 (m, 1H, eCHCH2F), 7.48e7.51 (m,
3c). The compound was prepared as described in Section 4.3.3. This
5H, Ph). [
a
]
20 þ29.4 (c 0.53, MeOH), lit.10 þ29.1 (c 0.57, MeOH).
gave 170 mg (0.80 mmol, 32%) of a white solid, mp 111e112 ꢀC, ee
D
20
>99.5%, [
a
]
þ58.4 (c 0.46, CHCl3), Rf (EtOAc/MeOH, 4/1) 0.62. 1H
D
4.6.4. (S)-2-Fluoro-1-(4-fluorophenyl)ethylamine ((S)-2d). The hyd-
razinolysis was performed as described in Section 4.3.6 starting
NMR (CDCl3)
d
: 3.44 (s, 3H, eCH2OCH3), 3.94 (d, J¼15.1,1H, eCH2Oe),
3.96 (d, J¼15.1, 1H, eCH2Oe), 4.66 (ddd, J¼47.5, 9.5, 4.7, 1H, eCH2F),
with (S)-5d (760 mg, 2.65 mmol). This gave 311 mg (1.98 mmol,
4.70 (ddd, J¼47.5, 9.5, 4.3,1H, eCH2F), 5.32 (m,1H, eCHCH2F), 7.12 (d,
20
75%) of (S)-2c as a pale yellow oil, ee¼92.5%, [
a]
þ36.4 (c 0.67,
J¼5.1,1H, eNHe), 7.29e7.41 (m, 5H, eC6H5). 13C NMR (CDCl3)
d: 52.3
D
CHCl3), Rf (EtOAc/MeOH, 9/1) 0.43.
(d, J¼19.2), 59.2, 71.9, 84.7 (d, J¼175.9), 126.9 (d, J¼1.1, 2C), 128.1,
128.8 (2C), 137.5 (d, J¼3.4), 169.2. 19F NMR (CDCl3)
: ꢂ229.87 (td,
d
4.6.5. (S)-1-(4-Bromophenyl)-2-fluoroethylamine ((S)-2e). The hyd-
razinolysis was performed as described in Section 4.3.6 starting
with (S)-5e (836 mg, 2.40 mmol). This gave 436 mg (2.00 mmol,
83%) of (S)-2e as a pale yellow oil, which solidified at 0 ꢀC,
J¼47.7, 24.3). IR (neat, cmꢂ1): 3301,1650,1532,1371,1217,1117,1005,
847, 588. HRMS (ESI): 211.1015 (calcd 211.1009, [Mþ]).
4.7.4. (S)-N-(2-Fluoro-1-(4-fluorophenyl)ethyl)-2-methoxy-
acetamide ((S)-3d). The compound was prepared as described in
Section 4.3.3. Purification gave 228 mg (0.99 mmol, 40%) of a white
ee¼90.5%, [
a]
20 þ27.4 (c 0.66, CHCl3), Rf (EtOAc/MeOH, 9/1) 0.40.
D
4.6.6. (S)-2-Fluoro-1-(4-(trifluoromethyl)phenyl)ethylamine
((S)-
solid, mp 79e80 ꢀC, ee >99.5%, [
a
d
]
20 þ61.1 (c 0.5, CHCl3), Rf (EtOAc/
D
2f). The hydrazinolysis was performed as described in Section 4.3.6
starting with (S)-5f (840 mg, 2.49 mmol). This gave 366 mg
MeOH, 4/1) 0.65. 1H NMR (CDCl3)
: 3.44 (s, 3H, eCH2OCH3), 3.93 (d,
J¼15.1,1H, eCH2Oe), 3.95 (d, J¼15.1,1H, eCH2Oe), 4.64 (ddd, J¼47.5,
9.5, 4.6, 1H, eCH2F), 4.69 (ddd, J¼47.5, 9.5, 4.1, 1H eCH2F), 5.29 (m, ,
1H, eCHCH2F), 7.03e7.09 (m, 2H, eC6H4e), 7.10 (d, J¼7.1,1H, eNHe),
(1.77 mmol, 71%) of (S)-2f as a colourless oil, ee¼91.5%, [
a]
20 þ25.7
D
(c 0.61, CHCl3), Rf (EtOAc/MeOH, 9/1) 0.45.
7.31e7.36 (m, 2H, eC6H4e). 13C NMR (CDCl3)
d
: 51.7 (d, J¼19.3), 59.2,
4.6.7. (S)-4-(1-Amino-2-fluoroethyl)benzonitrile ((S)-2g). The hyd-
razinolysis was performed as described in Section 4.3.6 starting
71.8, 84.6 (d, J¼175.9), 115.7 (d, J¼21.6, 2C),128.7 (dd, J¼1.2, 8.2, 2C),
133.4 (d, J¼3.2),162.4 (d, J¼246.5),169.1.19F NMR (CDCl3)
: ꢂ230.38
d
with (S)-5g (609 mg, 2.07 mmol). This gave 256 mg (1.56 mmol,
(td, J¼47.6, 25.4), ꢂ117.17 (s). IR (neat, cmꢂ1): 3308, 1656, 1511, 1217,
20
75%) of (S)-2g as a solid, mp 47e49 ꢀC, ee¼87.5%, [
0.54, CHCl3), Rf (EtOAc/MeOH, 9/1) 0.40.
a]
þ28.5 (c
1112, 984, 834, 604. HRMS (ESI): 229.0917 (calcd 229.0914, [Mþ]).
D
4.7.5. (S)-N-(1-(4-Bromophenyl)-2-fluoroethyl)-2-methoxy-
acetamide ((S)-3e). The compound was prepared as described in
4.6.8. (S)-2-Fluoro-1-(4-nitrophenyl)ethylamine ((S)-2h). The hydra-
zinolysis was performed as described in Section 4.3.6 starting with
(S)-5h (310 mg, 0.99 mmol). This gave 145 mg (0.79 mmol, 80%) of
Section 4.4.3. Purification gave 305 mg (1.05 mmol, 42%) of a white
20
solid, mp 111e112 ꢀC, ee >99.5%, [
a
]
þ63.9 (c 0.57, CHCl3). Rf
D
(S)-2h as a white solid, mp 52e53 ꢀC, ee¼84.0%, [
CHCl3), Rf (EtOAc/MeOH, 9/1) 0.34.
a
]
D
20 þ15.9 (c 0.69
(EtOAc/MeOH, 4/1) 0.66. 1H NMR (CDCl3)
d: 3.44 (s, 3H, eCH2OCH3),
3.93 (d, J¼15.2, 1H, eCH2Oe), 3.96 (d, J¼15.2, 1H, eCH2Oe), 4.64
(ddd, J¼47.5, 9.5, 4.5, 1H, eCH2F), 4.68 (ddd, J¼47.5, 9.5, 4.3, 1H,
eCH2F), 5.26 (m,1H, eCHCH2F), 7.12 (d, J¼7.5,1H, eNHe), 7.21e7.25
4.7. (S)-N-(2-Fluoro-1-arylethyl)-2-methoxyacetamides
((S)-3aeh)
(m, 2H, eC6H4e), 7.48e7.52 (m, 2H, eC6H4e). 13C NMR (CDCl3)
d:
52.0 (d, J¼19.1), 59.2, 71.8, 84.5 (d, J¼176.3), 122.1, 128.7 (d, J¼1.1,
4.7.1. (S)-N-(2-Fluoro-1-(4-methoxyphenyl)ethyl)-2-methoxy-
acetamide ((S)-3a). The compound was prepared as described in
Section 4.3.3. This gave 210 mg (0.87 mmol, 35%) of awhite solid, mp
2C), 132.0 (2C), 136.7 (d, J¼3.2), 169.2. 19F NMR (CDCl3)
: ꢂ230.60
d
(td, J¼47.2, 25.8). IR (neat, cmꢂ1): 3290, 1653, 1527, 1368,1228,1112,
1008, 821, 594. HRMS (ESI): 289.0111 (calcd 289.0114, [Mþ]).
94e95 ꢀC, ee >99.5%, [
a
]
20 þ77.1 (c 0.58, CHCl3), Rf (EtOAc/MeOH, 4/
D
1) 0.63. 1H NMR (CDCl3)
d: 3.43 (s, 3H, eCH2OCH3), 3.80 (s, 3H,
4.7.6. (S)-N-(2-Fluoro-1-(4-(trifluoromethyl)phenyl)ethyl)-2-me-
thoxyacetamide ((S)-3f). The compound was prepared as described
eOCH3), 3.92 (d, J¼15.1, 1H, eCH2Oe), 3.95 (d, J¼15.1, 1H, eCH2Oe),
4.63 (ddd, J¼47.5, 9.5, 4.3, eCH2F), 4.67 (ddd, J¼47.5, 9.5, 4.8, eCH2F),
5.27 (m, 1H, eCHCH2F), 6.88e6.92 (m, 2H, eC6H4e), 7.04 (d, J¼7.7,
in Section 4.4.3. Purification gave 245 mg (0.87 mmol, 35%) of
20
a white solid, mp 108e109 ꢀC, ee >99.5%, [
a]
þ47.5 (c 0.58,
D
1H, eNHe), 7.25e7.30 (m, 2H, eC6H4e). 13C NMR (CDCl3)
d: 51.8 (d,
CHCl3), Rf (EtOAc/MeOH, 4/1) 0.66. 1H NMR (CDCl3)
d: 3.46 (s, 3H,
J¼19.4), 55.3, 59.1, 71.9, 84.7 (d, J¼175.7), 114.2 (2C), 128.2 (d, J¼1.2,
eCH2OCH3), 3.94 (d, J¼15.2, 1H, eCH2Oe), 3.97 (d, J¼15.2, 1H,
eCH2Oe), 4.68 (ddd, J¼47.5, 9.6, 4.3, 1H, eCH2F), 4.73 (ddd, J¼47.5,
9.6, 4.0, 1H, eCH2F), 5.35 (m, 1H, eCHCH2F), 7.21 (d, J¼7.2, 1H,
2C), 129.6 (d, J¼3.4), 159.4, 169.1. 19F NMR (CDCl3)
: ꢂ229.56 (td,
d
J¼47.2, 23.8). IR (neat, cmꢂ1): 3319,1655,1518,1367,1207,1111,1005,
833, 586. HRMS (ESI): 241.1122 (calcd 241.1114, [Mþ]).
eNHe), 7.43e7.50 (m, 2H, eC6H4e), 7.60e7.66 (m, 2H, eC6H4e). 13
C
NMR (CDCl3)
d
: 52.1 (d, J¼19.0), 59.2, 71.8, 84.5 (d, J¼176.2), 123.9
4.7.2. (S)-N-(1-(4-(Benzyloxy)phenyl)-2-fluoroethyl)-2-methoxy-
acetamide ((S)-3b). The compound was prepared as described in
Section 4.3.3. This gave 246 mg (0.77 mmol, 31%) of awhite solid, mp
(q, J¼272.1), 125.8 (q, J¼3.8, 2C), 127.4 (d, J¼1.2, 2C), 130.4 (q,
J¼32.6), 141.6 (m), 169.3. 19F NMR (CDCl3)
: ꢂ230.98 (td, J¼46.4,
d
28.3), ꢂ65.86 (s, 3F). IR (neat, cmꢂ1): 3292, 1658, 1532, 1375, 1228,
109e110 ꢀC, ee >99.5%, [
a
]
d
20 þ66.5 (c 0.53, CHCl3), Rf (EtOAc/MeOH,
1116, 1011, 838, 606. HRMS (ESI): 279.0895 (calcd 279.0882, [Mþ]).
D
4/1) 0.66. 1H NMR (CDCl3)
: 3.43 (s, 3H, eCH2OCH3), 3.92 (d, J¼15.1,
1H, eCH2Oe), 3.94 (d, J¼15.1, 1H, eCH2Oe), 4.63 (ddd, J¼47.5, 9.5,
4.8, 1H, eCH2F), 4.67 (ddd, J¼47.5, 9.5, 4.3, 1H, eCH2F), 5.01 (s, 2H,
eOCH2Ph), 5.26 (m, 1H, eCHCH2F), 6.95e6.99 (m, 2H, eC6H4), 7.00
(d, J¼7.9, 1H, eNH), 7.25e7.29 (m, 2H, eC6H4), 7.30e7.44 (m, 5H,
4.7.7. (S)-N-(1-(4-Cyanophenyl)-2-fluoroethyl)-2-methoxy-
acetamide ((S)-3g). The compound was prepared as described in
Section 4.4.3. Purification gave 249 mg (1.05 mmol, 42%) of a white
20
solid, mp 76.5e77.0 ꢀC, ee >99.5%, [
a]
þ82.8 (c 0.53, CHCl3), Rf
D

T.H.K. Thvedt et al. / Tetrahedron 66 (2010) 6733e6743
6741
(EtOAc/MeOH, 4/1) 0.63. 1H NMR (CDCl3)
d
: 3.46 (s, 3H, eCH2OCH3),
Purification
by
bulb-to-bulb
distillation
(35e40 ꢀC
at
3.94 (d, J¼15.3, 1H, eCH2Oe), 3.98 (d, J¼15.3, 1H, eCH2Oe), 4.68
(ddd, J¼47.4, 9.7, 4.1, 1H, eCH2F), 4.72 (ddd, J¼47.4, 9.7, 3.8, 1H,
eCH2F), 5.34 (m,1H, eCHCH2F), 7.24 (d, J¼7.7,1H, eNHe), 7.46e7.50
3.0ꢁ10ꢂ3 mbar) gave 603 mg (3.81 mmol, 79%) of a colourless oil,
20
20
ee¼93.0%, [
a
]
ꢂ51.9 (c 0.59, CHCl3), corr. ref. ee¼99.0%, [
a]
D
D
ꢂ60.8 (c 0.60, CHCl3). 1H NMR (CDCl3)
d: 2.63 (br, 1H, eOH), 4.37
(m, 2H, eC6H4e), 7.65e7.69 (m, 2H, eC6H4e). 13C NMR (CDCl3)
d:
(ddd, J¼48.4, 9.6, 8.2, 1H, eCH2F), 4.48 (ddd, J¼46.7, 9.6, 3.3, 1H,
eCH2F), 5.03 (ddd, J¼13.9, 8.2, 3.3, 1H, eCHCH2F), 7.01e7.08 (m, 2H,
eC6H4e), 7.32e7.36 (m, 2H, eC6H4e).
59.2, 71.7, 84.4 (d, J¼176.4),112.1,118.4,127.8 (d, J¼1.1, 2C),132.6 (2C),
143.0 (d, J¼3.0), 169.3. 19F NMR (CDCl3)
: ꢂ231.46 (td, J¼46.4, 27.9).
d
IR (neat, cmꢂ1): 3310, 2232, 1655, 1532, 1372, 1226, 1117, 1014, 841,
563. HRMS (ESI): 236.0963 (calcd 236.0961, [Mþ]).
4.8.5. (R)-1-(4-Bromophenyl)-2-fluoroethanol ((R)-4e)49. The re-
action was performed as described in Section 4.3.4 starting with
1-(4-bromophenyl)-2-fluoroethanol (1e) (868 mg, 4.00 mmol). Pu-
rification by bulb-to-bulb distillation (60e65 ꢀC at 1.1ꢁ10ꢂ2 mbar)
gave 688 mg (3.14 mmol, 79%) of a white solid, mp 41e42 ꢀC,
4.7.8. (S)-N-(2-Fluoro-1-(4-nitrophenyl)ethyl)-2-methoxyacetamide
((S)-3h). The compound was prepared as described in Section
4.4.3. Purification by silica-gel column chromatography (EtOAc/
MeOH, 4/1) gave 217 mg (0.90 mmol, 36%) of a white solid, mp
ee¼91.0%, [
a
]
D
20 ꢂ33.4 (c 0.90, CHCl3), corr. ref. ee¼98.5%, [
a]
20 ꢂ35.9
D
20
95.0e95.5 ꢀC, ee >99.5%, [
a
]
þ70.8 (c¼0.69, CHCl3), Rf (EtOAc/
(c 0.90, CHCl3). 1H NMR (CDCl3)
d: 2.43 (dd, J¼1.1, 3.1, 1H, eOH), 4.36
D
MeOH, 4/1) 0.62. 1H NMR (CDCl3)
d
: 3.47 (s, 3H, eCH2OCH3), 3.95 (d,
(ddd, J¼48.1, 9.6, 8.2, 1H, eCH2F), 4.49 (ddd, J¼46.6, 9.6, 3.3, 1H,
eCH2F), 4.97 (m, 1H, eCHCH2F), 7.28e7.30 (m, 2H, eC6H4e),
7.45e7.53 (m, 2H, eC6H4e).
J¼15.3, 1H, eCH2Oe), 3.98 (d, J¼15.3, 1H, eCH2Oe), 4.71 (ddd,
J¼47.4, 9.7, 4.0, 1H, eCH2F), 4.75 (ddd, J¼47.4, 9.7, 4.0, 1H, eCH2F),
5.39 (m, 1H, eCHCH2F), 7.28 (d, J¼7.2, 1H, eNHe), 7.52e7.56 (m, 2H,
eC6H4e), 8.21e8.26 (m, 2H, eC6H4e). 13C NMR (CDCl3)
d: 52.1 (d,
4.8.6. (R)-2-Fluoro-1-(4-(trifluoromethyl)phenyl) ethanol ((R)-4f)49. A
suspension of [RuCl2(mesitylene)]2 (23 mg, 0.04 mmol) and the (S,
S)-TsDPEN (44 mg, 0.12 mmol) in H2O (20 mL) were stirred at 40 ꢀC
for 1 h. Sodium formate (1.36 g, 20.0 mmol) and 2-fluoro-1-(4-tri-
fluoromethylphenyl)ethanone (1f) (825 mg, 4.0 mmol) were added
and the mixture was stirred vigorously at 40 ꢀC for 10 h before it
was cooled to room temperature and extracted with CH2Cl2
(3ꢁ20 mL). The organic phase was then washed with brine (20 mL),
filtered through a plug of silica gel and dried over Na2SO4. The
solvent was removed under reduced pressure and the crude
product was purified by bulb-to-bulb distillation (40e45 ꢀC at
1.0ꢁ10ꢂ2 mbar). This gave 429 mg (2.06 mmol, 52%) of a colourless
J¼19.1), 59.3, 71.8, 84.4 (d, J¼176.6), 124.0 (2C), 128.0 (d, J¼1.0, 2C),
145.0 (d, J¼2.8), 147.7, 169.4. 19F NMR (CDCl3)
: ꢂ231.62 (td, J¼46.4,
d
28.3). IR (neat, cmꢂ1): 3273, 2970, 1650, 1516, 1348, 1110, 1012, 851,
697. HRMS (ESI): 256.0860 (calcd 256.0859, [Mþ]).
4.8. (R)-1-Aryl-2-fluoroethanols ((R)-4aeh)
In the course of this work, calculation errors in the optical ro-
tations data for (R)-4aeh in our previous study were discovered.49
Corrected values for these data are therefore included.
20
20
4.8.1. (R)-2-Fluoro-1-(4-methoxyphenyl)ethanol ((R)-4a)49. The re-
action was performed as described in Section 4.3.4 starting with 2-
fluoro-1-(4-methoxyphenyl)ethanone (1a) (673 mg, 4.00 mmol).
Purification by silica-gel column chromatography (CH2Cl2/MeOH,
99/1, Rf 0.47) gave 515 mg (3.03 mmol, 76%) of a colourless oil,
oil, ee¼92.5%, [
a]
ꢂ27.4 (c 0.69, CHCl3), corr. ref. ee¼93.0, [
a]
D
D
ꢂ28.6 (c 0.70, CHCl3). 1H NMR (CDCl3)
: 2.55 (d, J¼3.1, 1H, eOH),
d
4.42 (ddd J¼48.0, 9.6, 8.1, 1H, eCH2F), 4.55 (ddd, J¼46.7, 9.6, 3.4, 1H,
eCH2F), 5.11 (m, 1H, eCHCH2F), 7.50e7.53 (m, 2H, eC6H4e),
7.63e7.69 (m, 2H, eC6H4e).
20
20
ee¼96.0%, [
a
]
ꢂ47.1 (c 0.69, CHCl3), corr. ref. ee¼99.5%, [
a]
D
D
ꢂ55.0 (c 0.70, CHCl3). 1H NMR (CDCl3)
d
: 2.41 (br, 1H, eOH), 3.81 (s,
4.8.7. 4-((R)-2-Fluoro-1-hydroxyethyl)benzonitrile ((R)-4g)49. The
reaction was performed as described in Section 4.3.4 starting with
1-(4-cyanophenyl)-2-fluoroethanone (1g) (653 mg, 4.00 mmol).
Purification by silica-gel column chromatography (CH2Cl2/MeOH,
99.5/0.5, Rf 0.43) gave 563 mg (3.41 mmol, 85%) of a white solid, mp
3H, eOCH3), 4.38 (ddd, J¼48.5, 9.5, 8.3, 1H, eCH2F), 4.49 (ddd,
J¼46.8, 9.5, 3.3, 1H, eCH2F), 4.97 (ddd, J¼13.2, 8.3, 3.3, 1H,
eCHCH2F), 6.87e6.91 (m, 2H, eC6H4e), 7.29e7.33 (m, 2H, eC6H4e).
4.8.2. (R)-1-(4-(Benzyloxy)phenyl)-2-fluoroethanol ((R)-4b)49. The
reactionwas performed as described in Section 4.3.4 starting with 1-
(4-benzyloxyphenyl)-2-fluoroethanone (1b) (733 mg, 3.00 mmol).
Purification by silica-gel chromatography (CH2Cl2/MeOH, 99/1, Rf
0.26) gave 450 mg (1.83 mmol, 61%) of a white solid, mp 70e71 ꢀC,
59e60 ꢀC, ee¼87.0%, [
a
]
20 ꢂ35.6 (c 0.70, CHCl3), corr. ref. ee¼91.5%,
D
20
[a
]
ꢂ38.7 (c 0.70, CHCl3). 1H NMR (CDCl3)
d
: 2.62 (d, J¼3.3, 1H,
D
eOH), 4.40 (ddd, J¼48.0, 9.5, 8.0, 1H, eCH2F), 4.55 (ddd, J¼46.7, 9.5,
3.4,1H, eCH2F), 5.09 (m,1H, eCHCH2F), 7.46e7.56 (m, 2H, eC6H4e),
7.65e7.71 (m, 2H, eC6H4e).
ee¼99.5%, [
a
]
20 ꢂ38.3 (c 0.59, CHCl3), corr. ref. ee¼97.0%, [
a]
20 ꢂ33.2
D
D
(c 0.60, CHCl3). 1H NMR (CDCl3)
d
: 2.39 (dd, J¼2.9,1.1,1H, eOH), 4.40
4.8.8. (R)-2-Fluoro-1-(4-nitrophenyl)ethanol ((R)-4h)49. The reaction
was performed as described in Section 4.3.4 starting with 2-fluoro-
1-(4-nitrophenyl)ethanone (1h) (733 mg, 4.00 mmol). Purification
by silica-gel chromatography (CH2Cl2/MeOH, 95/5, Rf 0.52) gave
673 mg (3.63 mmol, 91%) of a white solid, mp 98e99 ꢀC, ee¼85.0%,
(ddd, J¼48.5, 9.5, 8.3, 1H, eCH2F), 4.48 (ddd, J¼46.8, 9.5, 3.4, 1H,
eCH2F), 4.97 (m, 1H, eCHCH2F), 5.09 (s, 2H, eOCH2Ph), 6.95e7.01
(m, 2H, eC6H4e), 7.30e7.47 (m, 7H, Ar).
4.8.3. (R)-2-Fluoro-1-phenylethanol ((R)-4c)49. The reaction was
performed as described in Section 4.3.4 starting with 2-fluoro-1-
phenylethanone (1c) (553 mg, 4.00 mmol). Purification by bulb-to-
[a
]
ꢂ24.7 (c 0.70, CHCl3), corr. ref. ee¼92.5%, [
a]
ꢂ25.3 (c 0.70,
20
20
D
D
CHCl3). 1H NMR (CDCl3)
d: 2.65 (br, 1H, eOH), 4.42 (ddd J¼47.9, 9.6,
7.8, 1H, eCH2F), 4.56 (ddd, J¼46.5, 9.6, 3.4, 1H, eCH2F), 5.16 (ddd,
J¼3.4, 7.8, 14.5, 1H, eCHCH2F), 7.59e7.65 (m, 2H, eC6H4e),
8.22e8.28 (m, 2H, eC6H4e).
bulb distillation (35e40 ꢀC at 5.0ꢁ10ꢂ3 mbar) gave 480 mg
20
(3.42 mmol, 86%) of a colourless oil, ee¼98.0%, [
a
]
ꢂ56.8 (c 1.20,
D
20
CHCl3), corr. ref. ee¼96.5%, [
a
]
ꢂ53.7 (c 1.20, CHCl3). 1H NMR
D
(CDCl3)
d
: 2.51 (br, 1H, eOH), 4.40 (ddd, J¼48.5, 9.5, 8.3, 1H, eCH2F),
4.9. N-Substituted phthalimides (S)-5aeh
4.51 (ddd, J¼46.8, 9.5, 3.3, 1H, eCH2F), 5.04 (ddd, J¼14.0, 8.3, 3.3,
1H, eCHCH2F), 7.33e7.36 (m, 5H, eC6H5).
4.9.1. (S)-2-(2-Fluoro-1-(4-methoxyphenyl)ethyl)isoindoline-1,3-di-
one ((S)-5a). The synthesis was performed as described in Section
4.3.5 starting with (R)-4a (420 mg, 2.47 mmol), and reacting for
10 h prior to addition of HCl. Purification by silica-gel column
chromatography eluting with CH2Cl2/MeOH (99.5/0.5, Rf 0.54)
4.8.4. (R)-2-Fluoro-1-(4-fluorophenyl)ethanol ((R)-4d)49. The re-
action was performed as described in Section 4.3.4 starting with 2-
fluoro-1-(4-fluorophenyl)ethanone (1d) (752 mg, 4.82 mmol).

6742
T.H.K. Thvedt et al. / Tetrahedron 66 (2010) 6733e6743
followed by i-Pr2O/pentane (7/3, Rf 0.28), gave 235 mg (0.79 mmol,
to addition of HCl. Purification by silica-gel column chromatogra-
phy (CH2Cl2/MeOH, 99/1, Rf 0.65) gave 871 mg (2.50 mmol, 83%) of
20
32%) of white solid, mp 75e76 ꢀC, ee¼53.0%, [
a
]
ꢂ15.8 (c 0.50,
D
20
EtOAc), CD (MeCN): D3¼ꢂ1.3 (232 nm). 1H NMR (CDCl3)
d
: 3.78 (s,
a white solid, mp 66e67 ꢀC, ee¼90.0%, [
a
]
D
ꢂ19.8 (c 0.60, EtOAc),
3H, eOCH3), 4.90 (ddd, J¼45.7, 9.6, 5.3, 1H, eCH2F), 5.52 (app. dt.
J¼47.0, 9.6, 1H, eCH2F), 5.63 (ddd, J¼12.1, 9.6, 5.3, 1H, eCHCH2F),
6.86e6.89 (m, 2H, eC6H4OMe), 7.43e7.47 (m, 2H, eC6H4OMe),
7.68e7.73 (m, 2H, phthal.), 7.81e7.86 (m, 2H, phthal.). 13C NMR
CD (MeCN): D3¼ꢂ3.9 (230 nm). 1H NMR (CDCl3)
d: 4.95 (ddd,
J¼45.8, 9.4, 5.8, 1H, eCH2F), 5.46 (app. dt, J¼47.0, 9.4, 1H, eCH2F),
5.64 (ddd, J¼12.1, 9.4, 5.8,1H, eCHCH2F), 7.37e7.40 (m, 2H, C6H4Br),
7.47e7.50 (m, 2H, C6H4Br), 7.71e7.75 (m, 2H, phthal.), 7.82e7.87 (m,
(CDCl3)
d
: 54.3 (d, J¼21.2), 55.3, 80.8 (d, J¼175.2), 114.2 (2C), 123.4
2H, phthal.). 13C NMR (CDCl3)
d
: 54.1 (d, J¼22.6), 80.5 (d, J¼175.6),
(2C), 127.2 (d, J¼7.8), 129.6 (2C), 131.9 (2C), 134.1 (2C), 159.8, 168.3
122.9, 123.5 (2C), 129.9 (2C), 131.7 (2C), 132.1 (2C), 134.2 (d, J¼6.7),
(2C). 19F NMR (CDCl3)
d
: ꢂ220.30 (td, J¼46.9, 12.1). IR (neat, cmꢂ1):
134.3 (2C), 168.1 (2C). 19F NMR (CDCl3)
d
: ꢂ220.87 (td, J¼46.3, 11.9).
1773,1706, 1610, 1514, 1363, 1238, 1087, 1001. HRMS (ESI): 322.0836
IR (neat, cmꢂ1): 1770, 1708, 1591, 1491, 1385, 1355, 1077, 999. HRMS
(calcd 322.0850 [MþNaþ]).
(ESI): 369.9853 (calcd 369.9849, [MþNaþ]).
4.9.2. (S)-2-(1-(4-(Benzyloxy)phenyl)-2-fluoroethyl)isoindoline-1,3-
dione ((S)-5b). The synthesis was performed as described in Section
4.3.5 starting with (R)-4b (452 mg, 1.84 mmol), and reacting for 8 h
prior to addition of HCl. Purification by silica-gel column chroma-
tography (CH2Cl2, Rf 0.55) gave 255 mg (0.68 mmol, 37%) of a white
4.9.6. (S)-2-(2-Fluoro-1-(4-(trifluoromethyl)phenyl)ethyl)isoindo-
line-1,3-dione ((S)-4f). The synthesis was performed as described in
Section 4.3.5 starting with (R)-3f (717 mg, 3.45 mmol), and reacting
for 4 h prior to addition of HCl. Purification by silica-gel column
chromatography (CH2Cl2, Rf 0.63) gave 905 mg (2.68 mmol, 78%) of
20
solid, mp 82e83 ꢀC, ee¼60.0%, [
a]
D
20 ꢂ11.1 (c 0.47, EtOAc), CD (MeCN):
a colourless oil (solidified at 0 ꢀC), ee¼92.0%, [
a]
ꢂ32.4 (c 0.54,
D
D3¼ꢂ3.8 (234 nm). 1H NMR (CDCl3)
d
: 4.89 (ddd, J¼45.7, 9.6, 5.3, 1H,
EtOAc), CD (MeCN): D3¼ꢂ4.8 (225 nm).1H NMR (CDCl3)
d: 5.02 (ddd,
eCH2F), 5.04 (s, 2H, eOCH2Ph), 5.52 (app. dt. J¼47.0, 9.6, 1H, eCH2F),
5.62 (ddd, J¼12.1, 9.6, 5.3, 1H, eCHCH2F), 6.92e6.96 (m, 2H,
eC6H4OBn), 7.29e7.41 (m, 5H, eCH2C6H5), 7.42e7.46 (m, 2H,
J¼45.8, 9.4, 6.1,1H, eCH2F), 5.48 (app. dt, J¼46.7, 9.4,1H, eCH2F), 5.74
(ddd, J¼12.1, 9.4, 6.1, 1H, eCHCH2F), 7.59e7.65 (m, 4H, eC6H4CF3),
7.72e7.77 (m, 2H, phthal.), 7.84e7.88 (m, 2H, phthal.). 13C NMR
eC6H4OBn), 7.68e7.73 (m, 2H, phthal.), 7.81e7.85 (m, 2H, phthal.).13
C
(CDCl3)
d
: 54.1 (d, J¼23.0), 80.5 (d, J¼175.6),123.7,123.8 (q, J¼272.3),
NMR(CDCl3)
d
:54.3(d, J¼21.5), 70.0,80.8(d,J¼175.2),115.2(2C),123.4
125.9 (q, J¼3.9),128.6,130.9 (d, J¼32.9),131.7,134.4,139.1 (dq, J¼6.7,
(2C),127.4 (2C),127.5(d, J¼7.8),128.0,128.6 (2C),129.7 (2C),131.8 (2C),
1.4), 168.0 (2C). 19F NMR (CDCl3)
d
: ꢂ63.40 (s, 3F), ꢂ220.22 (td,
134.1 (2C), 136.7, 159.0, 168.2 (2C). 19F NMR (CDCl3)
d: ꢂ220.29 (td,
J¼46.1,11.8). IR (neat, cmꢂ1): 1777,1710,1620,1469,1385,1322,1067,
1013. HRMS (ESI): 360.0617 (calcd 360.0618, [MþNaþ]).
J¼46.2,11.9). IR (neat, cmꢂ1): 1771, 1708, 1608,1508,1359,1242,1083,
997. HRMS (ESI): 398.1148 (calcd 398.1163, [MþNaþ]).
4.9.7. (S)-4-(1-(1,3-Dioxoisoindolin-2-yl)-2-fluoroethyl)benzonitrile
((S)-5g). The synthesis was performed as described in Section 4.3.5
starting with (R)-4g (547 mg, 3.31 mmol), and reacting for 3 h prior
to addition of HCl. Purification by silica-gel column chromatogra-
phy (pentane/acetone, 8/2, Rf 0.52) gave 647 mg (2.20 mmol, 66%)
4.9.3. (S)-2-(2-Fluoro-1-phenylethyl)isoindoline-1,3-dione ((S)-5c). The
synthesis was performed as described in Section 4.3.5 starting with
(R)-4c (460 mg, 3.28 mmol), and reacting for 2 h prior to addition of
HCl. Purification by silica-gel chromatography (CH2Cl2/MeOH, 99/1,
Rf 0.73) gave 681 mg (2.53 mmol, 77%) of a white solid, mp
of a white solid, mp 89e91 ꢀC, ee¼87.5%, [
a
]
D
20 ꢂ24.4 (c 0.52, EtOAc),
20
69e70 ꢀC, ee¼99.0%, [
a]
ꢂ49.0 (c 0.61, EtOAc), CD (MeCN):
CD (MeCN): D3¼ꢂ2.7 (238 nm). 1H NMR (CDCl3)
d: 5.04 (ddd,
D
D3¼ꢂ3.5 (223 nm). 1H NMR (CDCl3)
d
: 4.95 (ddd, J¼45.7, 9.1, 5.6,1H,
J¼45.7, 9.4, 6.3, 1H, eCH2F), 5.40 (app. dt, J¼46.7, 9.4, 1H, eCH2F),
5.72 (ddd, J¼12.4, 9.1, 6.3, 1H, eCHCH2F), 7.61e7.68 (m, 4H,
eC6H4CN), 7.73e7.78 (m, 2H, phthal.), 7.85e7.89 (m, 2H, phthal.).
eCH2F), 5.55 (app. dt. J¼47.2, 9.1, 1H, eCH2F), 5.69 (ddd, J¼12.4, 9.1,
5.3, 1H, eCHCH2F), 7.29e7.38 (m, 3H, eC6H5), 7.48e7.51 (m, 2H,
eC6H5), 7.69e7.74 (m, 2H, phthal.), 7.82e7.87 (m, 2H, phthal.). 13
C
13C NMR (CDCl3)
d
: 54.0 (d, J¼23.3), 80.3 (d, J¼175.9), 112.7, 118.2,
NMR (CDCl3)
d
: 54.8 (d, J¼21.6), 80.8 (d, J¼174.8), 123.4 (2C), 128.2
123.7 (2C), 128.9 (2C), 131.5 (2C), 132.7 (2C), 134.5 (2C), 140.3 (d,
(2C), 128.7, 128.9 (2C), 131.8 (2C), 134.2 (2C), 135.1 (d, J¼7.4), 168.2
J¼6.0), 167.9 (2C). 19F NMR (CDCl3)
: ꢂ220.36 (td, J¼46.1, 12.2). IR
d
(2C). 19F NMR (CDCl3)
d
: ꢂ219.83 (td, J¼46.2, 11.9). IR (neat, cmꢂ1):
(neat, cmꢂ1): 2227, 1777, 1706, 1610, 1465, 1361, 1334, 1088, 999.
1770,1704,1611,1493,1385,1357,1086,1000. HRMS (ESI): 292.0735
HRMS (ESI): 317.0694 (calcd 317.0697, [MþNaþ]).
(calcd 292.0744, [MþNaþ]).
4.9.8. (S)-2-(2-Fluoro-1-(4-nitrophenyl)ethyl)isoindoline-1,3-dione
((S)-5h). The synthesis was performed as described in Section 4.3.5
starting with (R)-4h (648 mg, 3.50 mmol), and reacting for 3 h prior
to addition of HCl. Purification by silica-gel column chromatogra-
phy using CH2Cl2/MeOH (99.5/0.5, Rf 0.49) followed by pentane/
4.9.4. (S)-2-(2-Fluoro-1-(4-fluorophenyl)ethyl)isoindoline-1,3-dione
((S)-5d). The synthesis was performed as described in Section 4.3.5
starting with (R)-4d (583 mg, 3.69 mmol), and reacting for 4 h prior
to addition of HCl. Purification by silica-gel column chromatogra-
phy (CH2Cl2/MeOH, 99/1, Rf 0.62) gave 815 mg (2.84 mmol, 77%) of
acetone (8/2, Rf 0.50) gave 374 mg (1.19 mmol, 34%) of a white solid,
20
a white solid, mp 58e59 ꢀC, ee¼92.5% (analysed as 2d), [
a]
20 ꢂ36.8
mp 92e94 ꢀC, ee¼84.0%, [
a]
ꢂ6.5 (c 1.05, CHCl3), CD (MeCN):
D
D
(c 0.73, EtOAc), CD (MeCN): D3¼ꢂ1.6 (223 nm). 1H NMR (CDCl3)
d:
D3¼ꢂ1.4 (228 nm). 1H NMR (CDCl3)
: 5.08 (ddd, J¼45.5, 9.3, 6.3,
d
4.93 (ddd, J¼45.5, 9.4, 5.8, 1H, eCH2F), 5.49 (app. dt, J¼47.0, 9.4, 1H,
eCH2F), 5.66 (ddd, J¼12.1, 9.4, 5.8, 1H, eCHCH2F), 7.01e7.07 (m, 2H,
eC6H4F), 7.48e7.53 (m, 2H, eC6H4F), 7.70e7.75 (m, 2H, phthal.),
1H, eCH2F), 5.43 (app. dt, J¼46.5, 9.1, 1H, eCH2F), 5.78 (ddd, J¼12.4,
9.1, 6.3, 1H, eCHCH2F), 7.67e7.70 (m, 2H, eC6H4NO2), 7.74e7.79 (m,
2H, phthal.), 7.85e7.90 (m, 2H, phthal.), 8.21e8.24 (m, 2H,
7.82e7.87 (m, 2H, phthal.). 13C NMR (CDCl3)
d
: 54.0 (d, J¼22.3), 80.6
eC6H4NO2). 13C NMR (CDCl3)
d
: 53.7 (d, J¼23.3), 80.4 (d, J¼176.3),
(d, J¼175.6), 115.9 (d, J¼21.6), 123.5, 130.2 (d, J¼4.1), 131.1 (dd, J¼4.1,
123.7 (2C), 124.1 (2C), 129.2 (2C), 131.5 (2C), 134.6 (2C), 142.2 (d,
3.5), 131.7, 134.3, 162.8 (d, J¼248.3), 168.1 (2C). 19F NMR (CDCl3)
d:
J¼6.0),148.0,167.9 (2C). 19F NMR (CDCl3)
: ꢂ221.22 (td,¼12.1, 46.0).
d
ꢂ113.33 (s), ꢂ219.63 (td, J¼46.2, 11.8). IR (neat, cmꢂ1): 1774, 1707,
1605, 1511, 1389, 1223, 1100, 1000. HRMS (ESI): 288.0838 (calcd
288.0831, [MþHþ]).
IR (neat, cmꢂ1): 1776, 1712, 1606, 1521, 1386, 1347, 1087, 999. HRMS
(ESI): 337.0605 (calcd 337.0595, [MþNaþ]).
4.9.5. (S)-2-(1-(4-bromophenyl)-2-fluoroethyl)isoindoline-1,3-dione
((S)-5e). The synthesis was performed as described in Section 4.3.5
starting with (R)-4e (657 mg, 3.00 mmol), and reacting for 2 h prior
Acknowledgements
NTNU and HIST are acknowledged for PhD grants.

T.H.K. Thvedt et al. / Tetrahedron 66 (2010) 6733e6743
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