γ-Fluorophenyl-GABA derivatives from fluorobenzonitriles in high diastereomeric and enantiomeric excess

Article abstract of DOI:10.1016/j.jfluchem.2008.10.002

An enantioselective synthesis of α-fluoroaryl homoallylic amines in 52-71% yields and 76-93% enantioselectivities has been achieved via the allylboration of the corresponding fluorinated N-aluminobenzaldimines with B-allyldiisopinocampheylborane in the pr

Full text of DOI:10.1016/j.jfluchem.2008.10.002

Journal of Fluorine Chemistry 130 (2009) 204–215
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
g
-Fluorophenyl-GABA derivatives from fluorobenzonitriles in high
diastereomeric and enantiomeric excess
*
P. Veeraraghavan Ramachandran , G. Venkat Reddy, Debanjan Biswas
Department of Chemistry, Purdue University, 560 Oval Drive, West Lafayette, IN 47907-2084, United States
A R T I C L E I N F O
A B S T R A C T
Article history:
An enantioselective synthesis of
a-fluoroaryl homoallylic amines in 52–71% yields and 76–93%
Received 29 July 2008
enantioselectivities has been achieved via the allylboration of the corresponding fluorinated N-
aluminobenzaldimines with B-allyldiisopinocampheylborane in the presence of methanol, followed by
alkaline hydrogen peroxide workup. Crotylboration of these aluminobenzaldimines with potassium B-
Received in revised form 4 October 2008
Accepted 6 October 2008
Available online 17 October 2008
methoxy B-E- or -Z-crotyldiisopinocampheylborinate provided the corresponding
b
-anti- or -syn-methyl
This manuscript is dedicated in honor of
Professor Dennis P. Curran, 2008 ACS
Awardee for Creative Work in Fluorine
Chemistry.
a
-fluoroarylhomoallylamines, respectively in high de and ee. Similarly, alkoxyallylboration with lithium
B-methoxy B-g-OMEMallyldiisopinocampheylborinate provided the corresponding b-syn-alkoxyho-
moallylamines in excellent de and ee. Representatives of these amino alkenes were converted to the
corresponding optically active N-Boc-protected fluorinated amino alcohols via hydroboration-oxidation.
Further chromium-mediated oxidation provided N-Boc-protected
which upon deprotection provided the corresponding -lactams.
ß 2008 Elsevier B.V. All rights reserved.
g-fluorophenyl-g-aminobutyric acids,
Keywords:
g
Fluorine-containing amino acids
GABA
Allylboration
Crotylboration
Alkoxyallylboration
Homoallylamines
Central nervous system
1. Introduction
activitysuchasepilepsy andneuropathicpain[8]. Anumberofdrugs
currentlyavailablefortheirtreatmentincludeGABAanalogs, suchas
Tiagabine (Gabitril1) [9], Gabapentin (Neurontin1) [10], Pregabalin
(Lyrica1) [11], and Vigabatrin (Sabril1) [12]. Though related in
structure, these drugs target several different proteins involved in
modulation of neuronal excitability. For example, Tiagabine inhibits
the re-uptake of GABA from the synaptic cleft by the GABA
transporters (GATs), prolonging the action of endogenously released
GABA. Vigabatrin inhibits the breakdown of endogenous GABA by
inhibiting GABA transaminase. Finally, Gabapentin and Pregabalin
bind to the a2d1 subunit of voltage-dependent Ca2+ channels, and
may inhibit the releaseof excitatory neurotransmitters byinhibiting
Ca2+ current. Interestingly, none of the currently available GABA-
derived drugs is an agonist at the GABA-A receptors. The antispastic
drug baclofen (Lioresal1) is a GABA-B receptor agonist [13]. As part
of our program on the application of organoboranes for biologically
activemolecules[14], wewereinterestedindevelopingagonistsand
antagonists for GABA receptors. Recently, we accomplished the
Appropriate substitution of a hydrogen atom or hydroxyl group
with a fluorine atom is commonplace in medicinal and biological
studies[1]. Synthesisofunnaturalaminoacids and peptidomimetics
are important for biomedical research [2]. Fluorinated amino acids
and peptides often create altered physical, chemical, and biological
properties [3]. Gamma-aminobutyric acid (GABA) is a ubiquitous
neurotransmitter that modulates neuronal activity throughout the
central and peripheral nervous system [4] and GABA-associated
receptors play a vital role in numerous central nervous system (CNS)
disorders [5]. The major effect of GABA is to inhibit neuronal activity
via its action on the GABA-A receptors [6]. A second type of GABA
receptor, GABA-B receptor, a G-protein-coupled receptor, also plays
an important role in the physiological actions of GABA [7]. The
neuro-modulatory role of GABA and GABA-A receptors has led to the
development of drugs designed to enhance the action of GABA for
the treatment of disorders that stem from abnormal neuronal
synthesis ofa series ofb- and g-substituted GABAderivatives via the
‘‘allyl’’ boration of N-metaloimines Scheme 1 [15]. Owing to our
interestin fluoroorganic chemistry [16–18], we turned our attention
to the development of fluorinated analogs of this primary class of
* Corresponding author. Tel.: +1 765 494 5303; fax: +1 765 494 0239.
E-mail address: chandran@purdue.edu (P.V. Ramachandran).
0022-1139/$ – see front matter ß 2008 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2008.10.002

P.V. Ramachandran et al. / Journal of Fluorine Chemistry 130 (2009) 204–215
205
Scheme 4.
Scheme 1.
Alkaline hydrogen peroxide workup provided the corresponding
homoallylamine (4a) in 71% yield. Analysis of the corresponding
methoxy -(trifluoromethyl)phenylacetamides (MTPA-amides,
a-
biomolecules for structure–activity relationship (SAR) studies and
therapy. Although several classes of fluorinated amino acids have
been synthesized [19], the preparation of optically active
fluoroalkyl and -aryl substituted GABA has not been examined
thoroughly [20]. We have recently reported a few fluoroaryl-GABA
via the allylboration of imine–borane complexes (Scheme 2) [21].
We wished to include crotyl- and alkoxyallylboration of fluroar-
a
Mosher amides) [26] using 19F NMR spectroscopy revealed 76%
enantiomeric excess. The racemic homoallylamine was prepared by
the reaction of allyl Grignard reagent with the corresponding
aluminoimine (Scheme 4) for comparison of the MTPA amide and
the determination of the enantiomeric excess. On the basis of our
earlier results from the non-fluorinated benzaldimines, we believe
that we have obtained the S isomer.
g-
ylimines to prepare the
b,g-disubstituted GABA derivatives. For
feasible and cost-effective large-scale synthesis, we now examined
the allyl-, crotyl-, and alkoxyallylboration of the corresponding
fluoroaryl aluminoimines [15]. Our results are summarized herein.
Encouraged by this result, we examined a series of ring-
fluorinated N-alumino-benzaldimines, prepared by the reduction
of the corresponding benzonitriles with DIBAL-H. Accordingly, 3-
fluorobenzonitrile (1b), 4-fluorobenzonitrile (1c), 2,3-difluoro-
(1d), 2,4-difluoro- (1e), 2,5-difluoro- (1f), 2,6-difluoro- (1g), 3,4-
difluoro- (1h) and 3,5-difluorobenzonitrile (1i) were subjected to
DIBAL-H reduction for further allylboration reaction in the
presence of methanol. In all of the cases, the allylboration of the
corresponding N-alumino-fluorobenzaldimines 2b–2i were per-
formed at À78 8C and were complete within 4–5 h. Alkaline
hydrogen peroxide workup provided the corresponding homo-
allylic amines 4b–4i in 52–69% yield and 76–93% ee (Scheme 3,
Table 1). In general, the yields of the fluorinated homoallylic
amines were slightly lower than the corresponding non-fluori-
2. Results and discussion
2.1. Allylboration
Initially, we examined the preparation of the homoallylic amine
from 2-fluorobenzonitrile (1a) via allylboration. The required
fluorinated N-alumino-benzaldimine (2a) was prepared from the
corresponding benzonitrile via the reduction using diisobutylalu-
minumhydride (DIBAL-H) according to the reported procedure[22].
Consistent with our earlier observation in the case of non-
fluorinated N-aluminoimines, treatment of 2a with I, prepared
from(À)-B-methoxydiisopinocampheylboraneandallylmagnesium
bromide [23], in THF failed to react, even at room temperature (RT),
over several days, as revealed by 11B NMR spectroscopy. This was,
however, overcome by the addition of 1 equiv. of water or methanol,
which released the free aldimine, as an allylborane complex [24,25].
The reaction now proceeded within 4–5 h at À78 8C, as was shown
nated derivatives [21]. The
% enantiomeric excesses were
consistently high, as is the norm with the allylborating agent I [23].
2.2. Crotylboration
Having achieved the allylboration of ring-fluorinated benzaldi-
mines, we turned our attention to the crotylboration reaction, with
by the chemical shift in the 11B NMR spectrum (change from
79 ppm for reagent I to 47 ppm for the intermediate 3a, Scheme 3).
d
the aim of preparing
can be further converted to the corresponding
b
-methyl-
a
-fluoroarylhomoallylamines that
-amino alcohols
d
d
Scheme 2.
Scheme 3.

206
P.V. Ramachandran et al. / Journal of Fluorine Chemistry 130 (2009) 204–215
Table 1
Preparation of
a
-fluorophenylhomoallylamines from fluorobenzonitrilesa.
Entry
1
Benzonitrile
Homoallylic amine
Yield, %b
ee, %c
76
#
Structure
#
Structure
1a
4a
71
2
3
1b
1c
4b
4c
63
69
88
90
4
5
1d
1e
4d
4e
55
52
82
80
6
1f
4f
59
76
7
8
9
1g
1h
1i
4g
4h
4i
57
60
62
93
90
89
a
Reactions were carried out in Et2O at À78 8C for 4–5 h.
b
c
Isolated yield after chromatography.
Determined from the 19F NMR spectra of Mosher (MTPA) amides. In all of the cases, we assign the (S)-configuration of homoallylic amines for the major isomer, see text.
and
g
-aminobutyric acids. The crotylborane reagents V and VI
Potassium B-methoxy B-E- or -Z-crotyldiisopinocampheylbor-
inates (II and III) were prepared from E- or Z-2-butenylpotassium
(7 and 8) respectively and (À)-B-methoxydiisopinocampheylbor-
ane as reported earlier [27] and the imine 2a, obtained from 2-
fluorobenzonitrile 1a, was reacted in THF at À78 8C after the
addition of 1 equiv. of methanol. The reaction was complete
within 4–5 h and the usual workup provided the expected
amines 9a and 10a, respectively, in 71% and 73% yields and
very high de and 92% ee. The diastereomeric excess was
determined from the 1H NMR of the crude product. The
were prepared from E- and Z-2-butene (5 and 6) (Scheme 5) and
attempted crotylboration in the presence of methanol gave a
complex mixture of products difficult to separate. Boron trifluoride
diethyl etherate used to free the reagents from the ‘ate’ complexes
II and III was found to be detrimental to the free imine [15].
However, for the non-fluorinated aluminoimines, we had shown
that the reaction proceeded well with II and III. Accordingly, we
extended this reaction to N-aluminofluorobenzaldimines with II
and III (Scheme 6).

P.V. Ramachandran et al. / Journal of Fluorine Chemistry 130 (2009) 204–215
207
Scheme 5.
enantiomeric excess was determined using the 19F NMR of the
MTPA (Mosher) amide.
We then chose II as the representative reagent for the
crotylboration of aluminoimines 2b–2i and the corresponding
of the products was assigned based on analogy of the non-
fluorinated benzaldimines. The racemic products were prepared
by the reaction of corresponding aluminoimines in presence of
methanol with the ‘ate’ complexes obtained from E- or Z-2-
butenylpotassium (7 and 8) and B-methoxy-9-BBN (Scheme 7).
anti-b-methylhomoallylamines were obtained in very high de and
87–98% ee (Scheme 6; Table 2, Entries 3–10). The stereochemistry
2.3. Alkoxyallylboration
Having completed the crotylboration successfully with the ‘ate’
complexes II and III, we now proceeded to the alkoxyallylboration.
As in the case of crotylboration, the reaction gave a mixture of
products with the free reagent VII (Scheme 8). However, the
reaction proceeded well with the ‘ate’ complex. IV. Imine 2a was
mixed with IV [28], followed by the addition of 1 equiv. of
methanol and the reaction was monitored with 11B NMR
spectroscopy. Upon completion (4–5 h), alkaline oxidative workup
Scheme 6.
Table 2
Preparation of
g-fluorophenyl-
b
-methylhomoallylamines from fluorobenzonitrilesa.
Entry
Benzonitrile
Homoallylic amine
Yield, %b
ee, %c
92
de, %d
99
#
Structure
#
Structure
1
2
1a
9a
71
1a
10a
73
92
99
3
4
1b
1c
9b
9c
75
69
92
91
99
99
5
1d
9d
63
88
99

208
P.V. Ramachandran et al. / Journal of Fluorine Chemistry 130 (2009) 204–215
Table 2 (Continued )
Entry
6
Benzonitrile
Homoallylic amine
Yield, %b
ee, %c
de, %d
#
Structure
#
Structure
1e
9e
66
60
90
99
7
1f
9f
87
99
8
1g
1h
1i
9g
9h
9i
54
66
68
88
95
98
99
99
99
9
10
a
Reactions were carried out in THF at À78 8C for 4–5 h.
b
c
Isolated yield after chromatography.
Determined from the 19F NMR spectra of Mosher (MTPA) amides. In all of the cases, we assign the (S)-configuration of homoallylic amines for the major isomer, see text.
Determined by analysis of 1H NMR of crude product.
d
furnished the syn-b-alkoxy homoallylic amine 13a with the results
(51%, 91% ee and 99% de) comparable with those obtained from the
crotylboration (Scheme 9; Table 2, Entry 1). As in the case of the
crotylboration, the de was determined from the 1H NMR of the
crude product mixture and the ee was determined from the 19F
NMR of the MTPA amide. The racemic products were prepared by
Scheme 9.
Scheme 7.
Scheme 8.

P.V. Ramachandran et al. / Journal of Fluorine Chemistry 130 (2009) 204–215
209
Table 3
Preparation of d-amino alcohols, GABA derivatives, and g-lactams.
Entry
Homoallyla-
mines
d
hols
-Amino alco-
g-F-Ph-GABA
g-Lactam
#
F-Ph
#
Yield, %a
#
Yield, %a
#
Yield, %a
1
2
3
4
4a
4b
4g
4i
2-F-Ph
14a
14b
14g
14i
75
78
76
79
15a
15b
15g
15i
78
16a
16b
16g
16i
94
98
95
98
3-F-Ph
84
76
83
2,6-F2-Ph
3,5-F2-Ph
a
Isolated yields of pure products, after chromatography.
Scheme 10.
Table 4
Preparation of
g
-methyl-
d-amino alcohols, b-methyl-GABA derivatives, and b-
the reaction of corresponding aluminoimines in presence of
methanol with the ‘ate’ complex obtained from lithiated Z-
allylOMEM (12) and B-methoxy-9-BBN (Scheme 10). Additional
examples of fluorobenzaldimines were also subjected to alkox-
yallylboration and consistent results (45–61% yields, >98% de, and
89–94% ee) were obtained, which are summarized in Scheme 9.
methyl-g-lactams.
Entry
Homoallyla-
mines
d-Amino alco-
g-F-Ph-GABA
g
-Lactam
hols
#
F-Ph
#
Yield, %a
#
Yield, %a
#
Yield, %a
1
2
3
4
5
9a
9b
9g
9i
2-F-Ph
17a
17b
17g
17i
71
69
78
70
72
18a
18b
18g
18i
77
19a
19b
19g
19i
90
97
89
95
91
3-F-Ph
90
70
81
79
2.4. Preparation of d-amino alcohols and g-lactams
2,6-F2-Ph
3,5-F2-Ph
2-F-Ph
13a
20a
21a
22a
Having achieved the preparation of the homoallylic amines in
very high de and ee, we attempted their conversion to the
a
Isolated yields of pure products, after chromatography.
corresponding amino alcohols, and eventually to the
g-amino
acids. First, we selected four representative examples of fluor-
ophenyl homoallylamines for this purpose. The homoallylic
amines 4a, 4b, 4g, and 4i were protected using di-tert-butyldi-
carbonate and the hydroboration of the alkenes was examined
using various hydroborating agents, such as borane-THF, borane-
methyl sulfide, dicyclohexylborane (Chx2BH), and 9-borabicy-
clo[3.3.1]nonane (9-BBN). Both Chx2BH and 9-BBN were found to
be superior for the hydroboration, which was complete within 24 h
homoallylic alcohols [18b], we believe that there is no loss of
optical activity during the preparation of 14. Further oxidation of
the above N-Boc protected amino alcohols using pyridinium
dichromate (PDC) gave the Boc-protected
g-fluorophenyl GABA
derivatives, 15a, 15b, 15g, and 15i, respectively, in 76–84% yields.
Boc-deprotection using 30% trifluoroacetic acid in dichloro-
methane lactamized the amino acids instantly to provide the
g-
lactams, 16a, 16b, 16g, and 16i, respectively, in 94–98% isolated
yields. All of these results are summarized in Table 3 (Scheme 11).
This methodology was now extended to include representative
at RT (11B NMR
peroxide provided the corresponding Boc-protected
d
80 ppm). Oxidation using alkaline hydrogen
-amino
d
alcohols, 14a, 14b, 14g, and 14i, respectively, in 75–79% yields.
examples of
b-substituted-g-(fluorophenyl)-g-aminobutyric acid.
On the basis of our earlier work on the hydroboration-oxidation of
Thus 9a, 9b, 9g, 9i, and 13a were protected using di-tert-
Scheme 11.
Scheme 12.

210
P.V. Ramachandran et al. / Journal of Fluorine Chemistry 130 (2009) 204–215
butyldicarbonate and subjected to hydroboration with 9-BBN,
followed by alkaline hydrogen peroxide oxidation to obtain the
or a Finnigan mass spectrometer model 4000. The chemical
ionization gas used was isobutene. Flash chromatography was
corresponding
78% yield. Further PDC oxidation of the above N-Boc protected
amino alcohols gave the N-Boc-protected -substituted- -fluor-
ophenyl GABA 18a, 18b, 18g, 18i, and 21a in 70–90% yields. Boc-
deprotection using 30% trifluoroacetic acid in dichloromethane
d
-amino alcohols 17a, 17b, 17g, 17i, and 20a in 69–
performed on 40–63 mm silica gel (230–400 mesh).
Preparation of (1S)-1-(3-fluorophenyl)-but-3-en-1-amine (4b)
is representative for the allylboration reaction. Preparation of
(1S,2S)-1-(3-fluorophenyl)-2-methylbut-3-en-1-amine (9b) is
representative for the crotylboration reaction and the preparation
b
g
lactamized the amino acids instantly to provide the
b
-substituted
of
(1R,2R)-1-(2-fluorophenyl)-2-((2-methoxyethoxy)methoxy)-
g
-lactams, 19a, 19b, 19g, 19i, and 22a in 89–97% isolated yields
but-3-en-1-amine (13a) is representative of the alkoxyallylbora-
tion reaction. The preparation of (S)-tert-butyl-1-(3-fluorophenyl)-
4-hydroxybutylcarbamate (14b), (S)-4-(tert-butoxycarbonyla-
mino)-4-(3-fluorophenyl)butanoic acid (15b), and (S)-5-(3-fluor-
ophenyl)-pyrrolidin-2-one (16b) from 3-fluorobenzonitrile (1b)
are representatives of the protection-hydroboration-oxidation of
the homoallylamine, the oxidation of the amino alcohol, and the
deprotection of the Boc-derivative. The same procedures were
adopted for all of the other fluoro-benzonitriles.
(Table 4, Scheme 12).
3. Conclusion
In summary, we have examined the isopinocampheyl-mediated
enantioselective allyl-, crotyl-, and alkoxyallylboration of N-
alumino fluorobenzaldimines, prepared by the reduction of the
corresponding fluorobenzonitriles with DIBAL-H. The homoallylic
amines were prepared in 52–71% yields and in 76–93% ee for the
allylboration, in 54–75% yields and in 87–98% ee for the
crotylboration, and in 45–61% yields and in 89–94% ee for
the alkoxyallylboration. The diastereoselectivity achieved for
the crotyl- and alkoxy-allylboration was consistently >98%. A
representative series of the fluoroaryl homoallylamines achieved
5. Experimental procedure and analytical data for products
5.1. (1S)-1-(3-fluorophenyl)-but-3-en-1-amine (4b)
DIBAL-H (0.89 mL, 5 mmol) was added to a solution of 3-
fluorobenzonitrile (1b; 0.54 mL, 5.05 mmol) in Et2O (5 mL) cooled
to 0 8C and the mixture was stirred for 1 h to obtain the
corresponding N-aluminoimine (2b). This was transferred via
cannula to a solution of (À)-B-allyldiisopinocampheylborane (I, 1M
in pentane; 7 mL, 7 mmol) diluted with Et2O (7 mL) and cooled to
À78 8C, followed by a slow addition of 0.20 mL (5.0 mmol) of
methanol. The mixture was then stirred for 4 h when the reaction
from the above reactions were converted to
the corresponding -fluorophenyl -amino acids and
well as -substituted -fluorophenyl -amino acids and
substituted -lactams without any loss of optical activity. The
-fluoroaryl GABA derivatives are currently being screened for the
d
-amino alcohols and
g
g
g
-lactams as
b
g
g
b-
g
g
ability to activate ClÀ currents via GABA-A receptors composed of
several different combinations of GABA-A subunits. The results
from this study will be reported in due course.
was complete (11B NMR spectral peak shift from
d 79 ppm to
47 ppm). The mixture was now slowly oxidized with H2O2 (30% in
H2O; 1.5 mL) in presence of aqueous NaOH (3M, 3 mL) and was left
stirring under positive N2 pressure while it slowly warmed to RT.
The product was then extracted with Et2O (3Â 50 mL), treated with
HCl (20% in H2O; 5 mL), and stirred for 0.2 h. Water (50 mL) was
added to the mixture and the organics removed. The aqueous
solution of the homoallylamine hydrochloride was extracted thrice
with ether (3Â 25 mL), and neutralized with NaOH until pH ꢀ8 and
the resulting amine was extracted with Et2O (3Â 50 mL). The
solvent was removed under reduced pressure, and the material
was purified on silica gel (hexanes/ethyl acetate/triethylamine
84.5:15:0.5) to afford the product (1S)-1-(3-fluorophenyl)-but-3-
en-1-amine (4b) (0.52 g, 3.15 mmol, 63%). The Mosher amide of 4b
was made using DCC condensation in the presence of DMAP [26].
Analysis of the 19F NMR spectrum of the MTPA amide revealed an
enantiomeric ratio of 94% and 6% favoring the S-isomer.
4. Experimental
Unless otherwise noted, all manipulations were carried out
under an inert atmosphere using flame-dried glassware. Tetrahy-
drofuran (THF) was freshly distilled before use from sodium
benzophenone ketyl and anhydrous diethyl ether was purchased
from Mallinckrodt Chemicals. The fluorinated benzonitriles, E- and
Z-2-butene, DIBAL-H, 9-borabicyclo-[3.3.1]nonane (9-BBN), B-
methoxydiisopinocampheylborane, B-methoxy-9-BBN, allylmagne-
sium bromide, (R)-(+)-a-methoxy a-(trifluoromethyl)phenylacetic
acid, dicyclohexylcarbodiimide (DCC), N,N-dimethylaminopyridine
(DMAP), pyridinium dichromate (PDC) and trifluoroacetic acid were
purchased from commercial sources and were used without further
purification, unless otherwise noted. (À)-B-allyldiisopinocampheyl-
borane (I) was prepared according to Brown’s procedure by the
treatment of (À)-B-methoxydiisopinocampheylborane with allyl-
magnesium bromide [23]. The ‘ate’ complexes II and III were
prepared by the treatment of (À)-B-methoxydiisopinocampheyl-
borane with E- or Z-2-butenylpotassium, respectively [27] and ‘ate’
complex IV was produced by the treatment of (À)-B-methoxydii-
1H NMR: (300 MHz, CDCl3)
2H), 6.97–6.88 (m, 1H), 5.83–5.63 (m, 1H), 5.16–5.07 (m, 2H), 4.01
d 7.33–7.22 (m, 1H), 7.15–7.04 (m,
(dd, J = 7.6 Hz, J = 5.4 Hz, 1H), 2.57–2.26 (m, 2H), 1.66 (br s, 2H); 19
F
NMR (282 MHz, CDCl3):
CDCl3)
d
À135.4 (s, 1F); 13C NMR: (75 MHz,
d
162.7 (d, JC–F = 240.2 Hz), 148.2, 134.8, 129.9 (d, JC–
sopinocampheylboranewithlithiatedZ-allylOMEM [28]. The 1H, 13
C
F = 8.1 Hz), 122.1, 118.2, 113.9 (d, JC–F = 28.1 Hz), 113.3 (d, JC–
F = 21.3 Hz), 54.9, 43.8; MS (EI): m/z: 146 [MÀF]+, 124; (CI): m/z:
166 [M+H]+, 149 [(M+H)–NH3]+, 124 [M–C3H5]+.
and19Fnuclearmagneticresonance(NMR)spectrawereplottedona
Varian Gemini-300 spectrometer (300, 75 and 282 MHz, respec-
tively) with a Nalorac-quad probe. 1H NMR spectra were obtained
using CDCl3 as the solvent with either tetramethylsilane (TMS:
0 ppm) or chloroform (CHCl3: 7.2 ppm) as the internal standard.
19F NMR spectra were recorded in CDCl3 using CFCl3 as the internal
standard. 1H NMR data are reported as chemical shifts (
, ppm),
multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet),
coupling constant (Hz), and integration. Enantiomeric excesses (%
ee) were measured using 19F NMR spectroscopy of the correspond-
ing Mosher amides. Mass spectra were recorded using a Hewlett
Packard 5989Bmass spectrometer/5890 seriesIIgaschromatograph
d
5.2. (1S)-1-(2-fluorophenyl)-but-3-en-1-amine (4a)
d
1H NMR (300 MHz, CDCl3):
1H), 5.14–5.07 (m, 2H), 4.29 (dd, J = 7.3 Hz, J = 5.9 Hz, 1H), 2.54–
2.35 (m, 2H), 1.74 (br s, 2H); 19F NMR (282 MHz, CDCl3):
À133.1
(s, 1F); 13C NMR (75 MHz, CDCl3):
160.8 (d, JC–F = 258.0 Hz),
d 7.43–6.98 (m, 4H), 5.81–5.69 (m,
d
d
d
135.2, 128.7, 128.3, 127.6 (d, JC–F = 21.0 Hz), 124.2, 117.9, 115.4 (d,
JC–F = 21.0 Hz), 49.2, 42.7; MS (EI): m/z: 146 [MÀF]+, 124; (CI): m/z:
166 [M+H]+, 149 [(M+H)–NH3]+, 124 [M–C3H5]+.

P.V. Ramachandran et al. / Journal of Fluorine Chemistry 130 (2009) 204–215
211
5.3. (1S)-1-(4-fluorophenyl)-but-3-en-1-amine (4c)
1H NMR: (300 MHz, CDCl3)
7.33–7.26 (m, 2H), 7.0 (t, J = 8.6 Hz,
118.2, 117.1 (d, JC–F = 11.1 Hz), 115.0 (d, JC–F = 18.9 Hz), 54.4, 44.2;
MS (EI): m/z: 164 [MÀF]+, 142; (CI): m/z: 184 [M+H]+, 167 [(M+H)–
NH3]+, 142 [M–C3H5]+.
d
2H), 5.83–5.62 (m, 1H), 5.15–5.06 (m, 2H), 3.99 (dd, J = 7.5 Hz,
J = 5.7 Hz, 1H), 2.47–2.25 (m, 2H), 1.61 (br s, 2H); 19F NMR
5.9. (S)-1-(3,5-difluorophenyl)but-3-en-1-amine (4i)
(282 MHz, CDCl3):
d
À134.2 (s, 1F); 13C NMR: (75 MHz, CDCl3)
d
161.8 (d, JC–F = 242.1 Hz), 141.6, 135.2, 127.8 (d, JC–F = 8.5 Hz),
117.8, 115.1 (d, JC–F = 21 Hz), 54.7, 44.4; MS (EI): m/z: 146 [M–F]+,
124; (CI): m/z: 166 [M + H]+, 149 [(M+H)–NH3]+, 124 [M–C3H5]+.
1HNMR(300 MHz,CDCl3):
5.78–5.64 (m, 1H), 5.15–5.05 (m, 2H), 3.99 (dd, J = 7.7 Hz, J = 7.6 Hz,
d6.90–6.87(m,2H),6.70–6.63(m,1H),
1H), 2.27–2.48 (m, 2H), 1.95 (br s, 2H), 19F NMR (282 MHz, CDCl3):
d
À123.5(s, 2F);13CNMR(75 MHz, CDCl3):
d163.1(dd,JC–F = 246.5 Hz,
5.4. (S)-1-(2,3-difluorophenyl)but-3-en-1-amine (4d)
JC–F = 12.7 Hz), 149.6, 134.4, 118.5, 109.2 (d, JC–F = 24.5 Hz), 102.4 (t,
JC–F = 25.4 Hz), 54.8, 43.8; MS (EI): m/z: 164 [M-F]+, 142; (CI): m/z:
184 [M+H]+, 167 [(M+H)-NH3]+, 142 [M–C3H5]+.
1H NMR (300 MHz, CDCl3):
d 7.18–7.15 (m, 1H), 7.06–7.02 (m,
2H), 5.79–5.67 (m, 1H), 5.14–5.08 (m, 2H), 4.32 (dd, J = 7.6 Hz,
J = 5.8 Hz, 1H), 2.54–2.34 (m, 2H), 1.69 (br s, 2H); 19F NMR
5.10. (1S,2S)-1-(3-fluorophenyl)-2-methylbut-3-en-1-amine (9b)
(282 MHz, CDCl3):
d
À152.4 (m, 1F), À158.4 (d, J = 21 Hz, 1F); 13C
NMR (75 MHz, CDCl3):
d
162.7 (dd, JC–F = 247.5 Hz, JC–F = 13.9 Hz),
Trans-butene (5, 1 mL, 10 mmol) and n-butyllithium (2.5 M in
hexanes; 2.8 mL, 7.0 mmol) were added to potassium tert-
butoxide (1 M in THF; 7 mL, 7 mmol) diluted with 7 ml of THF
and cooled to À78 8C. The mixture was stirred for 0.1 h at À78 8C,
followed by 0.3 h at À55 8C, and cooled again to À78 8C, when a
solution of (À)-B-methoxydiisopinocampheylborane (2.36 g,
7.4 mmol) in 8 mL THF was added and the reaction mixture was
stirred for 1 h at À78 8C. To thus generated II was added via
cannula a solution of 2b [prepared as follows: to a solution of 3-
fluorobenzonitrile (1b; 0.54 mL, 5.05 mmol) in 5 mL THF cooled to
0 8C was added DIBAL-H (0.89 mL, 5 mmol) and the mixture was
stirred for 1 h], followed by slow addition of methanol (0.20 mL,
5 mmol) and the mixture was stirred for 4 h at À78 8C when it was
slowly oxidized with H2O2 (30% in H2O; 1.5 mL) in presence of
aqueous NaOH (3 M; 3 mL) and was left stirring under positive N2
pressure while it slowly warmed to RT. The product was extracted
with Et2O (3Â 50 mL) after the acid–base manipulation, the solvent
was removed under reduced pressure, and the crude material was
purified on silica gel (hexanes/ethyl acetate/triethylamine
84.5:15:0.5) to afford (1S,2S)-1-(3-fluorophenyl)-2-methylbut-3-
en-1-amine (9b) (0.68 g, 3.9 mmol, 68%) in >98% de as determined
by 1H NMR analysis of the crude product. The Mosher amide of 9b
was made using DCC condensation in the presence of DMAP [26].
Analysis of the 19F NMR spectrum of the MTPA amide revealed an
enantiomeric ratio of 96% and 4%.
146.5 (dd, JC–F = 246.5 Hz, JC–F = 10.4 Hz), 134.5, 128.1, 118.4, 109.3
(d, JC–F = 7.3 Hz), 109.0 (d, JC–F = 7.7 Hz), 102.3 (t, JC–F = 25.1 Hz),
54.8, 34.9; MS (EI): m/z: 164 [MÀF]+, 142; (CI): m/z: 184 [M+H]+,
167 [(M+H)–NH3]+, 142 [M–C3H5]+.
5.5. (S)-1-(2,4-difluorophenyl)but-3-en-1-amine (4e)
1H NMR (300 MHz, CDCl3):
2H), 5.78–5.69 (m, 1H), 5.13–5.07 (m, 2H), 4.28 (m, 1H), 2.51–2.37
d 7.44–7.36 (m, 1H), 6.88–6.74 (m,
(m, 2H), 1.98 (br s, 2H); 19F NMR (282 MHz, CDCl3):
d
À126.3 (s,
1F), À129.1 (s, 1F); 13C NMR (75 MHz, CDCl3):
d 161.8 (dd, JC–
F = 246.4 Hz, JC–F = 12.7 Hz), 160.3 (dd, JC–F = 246.5 Hz, JC–
F = 12.7 Hz), 134.9, 128.3 (d, JC–F = 8.4 Hz); 118.1, 111.2 (t, JC–
F = 12.6 Hz), 103.9 (d, JC–F = 25.2 Hz), 103.3 (d, JC–F = 25.3 Hz), 48.6,
42.9; MS (EI): m/z: 164 [MÀF]+, 142; (CI): m/z: 184 [M + H]+, 167
[(M + H)–NH3]+, 142 [M–C3H5]+.
5.6. (S)-1-(2,5-difluorophenyl)but-3-en-1-amine (4f)
1H NMR (300 MHz, CDCl3):
d 7.14–7.09 (m, 1H), 6.91–6.82 (m,
2H), 5.77–5.63 (s, 1H), 5.09–5.03 (m, 2H), 4.24 (dd, J = 6.8 Hz,
J = 6.0 Hz, 1H), 2.48–2.24 (m, 2H), 1.55 (br s, 2H); 19F NMR
(282 MHz, CDCl3):
(75 MHz, CDCl3):
d
À139.1 (m, 1F), À132.2 (m, 1F) 13C NMR
d
158.9 (dd, JC–F = 240.3 Hz, JC–F = 14.7 Hz), 156.1
(dd, JC–F = 239.4 Hz, JC–F = 2.1 Hz), 134.6, 118.1, 116.3 (d, JC–
F = 8.3 Hz), 116.0 (d, JC–F = 8.6 Hz), 114.4 (d, JC–F = 23.6 Hz), 114.0
(d, JC–F = 19.2 Hz), 48.6, 42.5; MS (EI): m/z: 164 [MÀF]+, 142; (CI):
m/z: 184 [M+H]+, 167 [(M+H)–NH3]+, 142 [M–C3H5]+.
1H NMR (300 MHz, CDCl3):
d 7.26–7.21 (m, 1H), 7.06–7.0 (m,
2H), 6.92–6.86 (m, 1H), 5.74–5.62 (m, 1H), 5.14–5.06 (m, 2H), 3.6
(d, J = 8.1 Hz, 1H), 2.30 (q, J = 7.6 Hz, 1H), 1.52 (br s, 2H), 0.80 (d,
J = 6.7 Hz, 3H); 19F NMR (282 MHz, CDCl3):
d
À127.0 (s, 1F); 13C
NMR (75 MHz, CDCl3):
d 160.9 (d, JC–F = 210 Hz), 141.3, 131.8,
5.7. (S)-1-(2,6-difluorophenyl)but-3-en-1-amine (4g)
128.4 (d, JC–F = 4.8 Hz), 128.2 (d, JC–F = 8.4 Hz), 124.1 (d, JC–F = 3.2),
116.1, 115.3 (d, JC–F = 22.5 Hz), 53.9, 45.6, 17.5; MS (EI): 163 [M–
NH2]+, 124; (CI): 180 [M+H]+, 163 [(M+H)–NH2]+, 124 [M–C4H7]+.
1H NMR: (300 MHz, CDCl3)
2H), 5.79–5.66 (m, 1H), 5.08–4.99 (m, 2H), 4.30 (t, J = 7.4 Hz, 1H),
d 7.17–7.09 (m, 1H), 6.89–6.78 (m,
2.59–2.51 (m, 2H), 1.77 (br s, 2H); 19F NMR (282 MHz, CDCl3):
d
5.11. (1S,2S)-1-(2-fluorophenyl)-2-methylbut-3-en-1-amine (9a)
À128.6 (m, 2F); 13C NMR: (75 MHz, CDCl3)
d 161.1 (dd, JC–
F = 245.1 Hz, JC–F = 9.1 Hz), 135.1, 128.3 (d, JC–F = 10.4 Hz), 117.6,
111.7 (d, JC–F = 17.7 Hz), 111.5 (d, JC–F = 17.8 Hz), 47.2, 42.1; MS
(EI): m/z: 164 [MÀF]+, 142; (CI): m/z: 184 [M+H]+, 167 [(M+H)–
NH3]+, 142 [M–C3H5]+.
1HNMR(300 MHz,CDCl3):
d7.39–7.34(m,1H),7.20–7.08(m,2H),
7.0–6.94 (m, 1H), 5.78–5.66 (m, 1H), 5.14–5.07 (m, 2H), 3.95 (d,
J = 8.3 Hz, 1H), 2.4(q, J = 7.4 Hz, 1H), 1.56(br s, 2H), 0.85(d, J = 6.7 Hz,
3H); 19F NMR (282 MHz, CDCl3):
CDCl3)d160.7(d, JC–F = 248 Hz), 141.3, 131.5(d, JC–F = 13.2 Hz), 128.4
d
À132.3 (s, 1F); 13C NMR: (75 MHz,
5.8. (S)-1-(3,4-difluorophenyl)but-3-en-1-amine (4h)
(d, JC–F = 14.6 Hz), 128.1 (d, JC–F = 15.0 Hz), 124.1, 116.0, 115.2 (d, JC–
F = 22.7 Hz), 53.8, 45.6, 17.5; MS (EI): 163 [M–NH2]+, 124; (CI): 180
[M+H]+, 163 [(M+H)–NH2]+, 124 [M–C4H7]+.
1H NMR: (300 MHz, CDCl3)
1H), 5.06–4.99 (m, 2H), 3.90 (dd, J = 5.4 Hz, J = 8.4 Hz, 1H), 2.36–
d 7.17–6.96 (m, 3H), 5.71–5.58 (m,
2.15 (m, 2H), 1.53 (br s, 2H); 19F NMR (282 MHz, CDCl3):
d
À138.0
5.12. (1S,2R)-1-(2-fluorophenyl)-2-methylbut-3-en-1-amine (10a)
(m, 1F), À140.9 (m, 1F); 13C NMR: (75 MHz, CDCl3)
d 150.0 (dd, JC–
F = 246.0 Hz, JC–F = 12.6 Hz), 149.3 (dd, JC–F = 245.1 Hz, JC–
F = 12.6 Hz), 142.9 (t, JC–F = 4.1 Hz), 134.8, 122.2 (d, JC–F = 9.5 Hz),
1H NMR (300 MHz, CDCl3):
2H), 6.92–6.86 (m, 1H), 5.74–5.62 (m, 1H), 5.14–5.06 (m, 2H), 3.61
d 7.26–7.19 (m, 1H), 7.06–7.01 (m,

212
P.V. Ramachandran et al. / Journal of Fluorine Chemistry 130 (2009) 204–215
(d, J = 8.13 Hz, 1H), 2.29 (q, J = 7.4 Hz, 1H), 1.52 (br s, 2H), 0.80 (d,
5.18. (1S,2S)-1-(3,4-difluorophenyl)-2-methylbut-3-en-1-amine (9h)
1H NMR (300 MHz, CDCl3):
7.18–6.97 (m, 3H), 5.71–5.60 (m,
J = 7.9 Hz, 3H); 19F NMR (282 MHz, CDCl3):
NMR (75 MHz, CDCl3):
d
À134.6 (s, 1F); 13C
d
162.9 (d, JC–F = 242.0 Hz), 147.2, 141.2,
d
129.5 (d, JC–F = 8.1 Hz), 123.0 (d, JC–F = 2.6 Hz), 116.1, 114.1 (d, JC–
F = 21.1), 113.8 (d, JC–F = 15.0 Hz), 60.3, 46.3, 17.5; MS (EI): 163 [M–
NH2]+, 124; (CI): 180 [M+H]+, 163 [(M+H)–NH2]+, 124 [M–C4H7]+.
1H), 5.14–5.06 (m, 2H), 3.6 (d, J = 8.1 Hz, 1H), 2.24 (q, J = 7.2 Hz,
1H), 1.5 (br s, 2H), 0.78 (d, J = 6.7 Hz, 3H); 19F NMR (282 MHz,
CDCl3):
CDCl3):
d
d
À154.1 (m, 1F), À151.7 (m, 1F); 13C NMR (75 MHz,
150.2 (dd, JC–F = 246.0 Hz, JC–F = 12.6 Hz), 149.3 (dd, JC–
5.13. (1S,2S)-1-(4-fluorophenyl)-2-methylbut-3-en-1-amine (9c)
F = 245.0 Hz, JC–F = 12.5 Hz), 141.8, 141.6 (d, JC–F = 4.12 Hz), 123.2
(d, JC–F = 3.5 Hz), 116.7 (d, JC–F = 17.1 Hz), 116.3, 115.9 (d, JC–
F = 17.0 Hz), 59.8, 46.3, 17.4; MS (EI): 180 [M–NH3]+, 142; (CI): 198
[M+H]+, 181 [(M+H)–NH3]+, 142 [M–C4H7]+.
1HNMR(300 MHz,CDCl3):
d7.38–7.33(m,2H),7.10–7.05(m,2H),
5.85–5.73 (m, 1H), 5.20–5.16 (m, 2H), 3.7 (d, J = 8.1 Hz, 1H), 2.38 (q,
J = 6.9 Hz, 1H), 1.76 (br s, 2H), 0.87 (d, J = 6.6 Hz, 3H); 19F NMR
(282 MHz,CDCl3):
d
À131.9(s, 1F);13CNMR(75 MHz,CDCl3):
d
162.1
5.19. (1S,2S)-1-(3,5-difluorophenyl)-2-methylbut-3-en-1-amine (9i)
(d, JC–F = 248.0 Hz), 141.6, 140.2, 128.7 (d, JC–F = 8.4 Hz), 116.1, 115.0
(d, JC–F = 21.0 Hz), 60.0, 46.4, 17.6; MS (EI): 163 [M–NH2]+, 124; (CI):
180 [M+H]+, 163 [(M+H)–NH2]+, 124 [M–C4H7]+.
1H NMR (300 MHz, CDCl3):
d 6.85 (d, J = 6.5 1H), 6.69–6.63 (m,
2H), 5.73–5.61 (m, 1H), 5.16–5.09 (m, 2H), 3.64 (d, J = 7.8 Hz, 1H),
2.30 (q, J = 7.2 Hz, 1H), 1.63 (br s, 2H), 0.84 (d, J = 6.7 Hz, 3H); 19F
5.14. (1S,2S)-1-(2,3-difluorophenyl)-2-methylbut-3-en-1-amine
NMR (282 MHz, CDCl3):
CDCl3): d 163.0 (dd, JC–F = 246.5 Hz, JC–F = 12.5 Hz), 148.9, 140.7,
d
À123.9 (s, 2F); 13C NMR (75 MHz,
(9d)
116.5, 110.1 (d, JC–F = 9.4 Hz), 102.4 (t, JC–F = 25.2 Hz), 60.1, 46.1,
17.4; MS (EI): 180 [M–NH3]+, 142; (CI): 198 [M+H]+, 181 [(M+H)–
NH3]+, 142 [M–C4H7]+.
1H NMR (300 MHz, CDCl3):
2H), 5.77–5.65 (m, 1H), 5.15–5.09 (m, 2H), 3.9 (d, J = 8.4 Hz, 1H),
2.38 (q, J = 7.5 Hz, 1H), 1.58 (br s, 2H), 0.86 (d, J = 6.7 Hz, 3H); 19F
d 7.16–7.11 (m, 1H), 7.04–6.99 (m,
NMR (282 MHz, CDCl3):
d
À157.6 (d, J = 21.3 Hz, 1F), À152.4 (m,
150.4 (dd, JC–F = 255.0 Hz, JC–
5.20. (1R,2R)-1-(2-fluorophenyl)-2-((2-
1F); 13C NMR (75 MHz, CDCl3):
d
methoxyethoxy)methoxy)but-3-en-1-amine (13a)
F = 14.1 Hz), 148.8 (dd, JC–F = 195.0 Hz, JC–F = 13.2 Hz), 140.9, 134.0
(d, JC–F = 10.4 Hz), 123.9 (d, JC–F = 4.6 Hz), 123.0 (d, JC–F = 3.5 Hz),
116.4, 115.4 (d, JC–F = 17.2 Hz), 53.6, 45.6, 17.4; MS (EI): 180 [M–
NH3]+, 142; (CI): 198 [M+H]+, 181 [(M+H)–NH3]+, 142 [M–C4H7]+.
sec-Butyllithium (1.4 M in cyclohexane; 5.4 mL, 7.5 mmol) was
added to 3-[(2-methoxyethoxy)-methoxy]prop-1-ene (11; 1.10 g,
7.6 mmol) diluted with THF (8 mL) and cooled to À78 8C and the
mixture was stirred for 0.5 h at À78 8C. Then, a solution of (À)-B-
methoxydiisopinocampheylborane (2.84 g, 9.0 mmol) in THF
(10 mL) was added and the mixture was stirred for 1 h. To thus
generated IV was added via cannula a solution of 2a [prepared as
5.15. (1S,2S)-1-(2,4-difluorophenyl)-2-methylbut-3-en-1-amine (9e)
1H NMR (300 MHz, CDCl3):
d 7.41–7.33 (m, 1H), 6.87–6.71 (m,
2H), 5.77–5.66 (m, 1H), 5.15–5.09 (m, 2H), 3.95 (d, J = 8.3 Hz, 1H),
2.37 (q, J = 7.3 Hz, 1H), 1.49 (br s, 2H), 0.87 (d, J = 6.7 Hz, 3H); 19F
follows: to a solution of 2-fluorobenzonitrile (1a; 0.55 mL,
5.05 mmol) in 5 mL THF and cooled to 0 8C was added DIBAL-H
(0.89 mL, 5 mmol) and the mixture was stirred for 1 h], followed by
methanol(0.20 mL, 5 mmol). Thereactionmixturewasstirredfor4 h
at À78 8C and was slowly oxidized with H2O2 (30% in H2O; 1.5 mL) in
presence of aqueous NaOH (3M; 3 mL) and was left stirring under
positive N2 pressure while it slowly warmed to RT. The product was
extractedwithEt2O(3Â50 mL)aftertheacid–basemanipulation,the
solventwasremovedunderreducedpressure,andthecrudematerial
was purified on silica gel (hexanes/ethyl acetate/triethylamine
84.5:15:0.5) to afford (1R,2R)-1-(2-fluorophenyl)-2-((2-methox-
yethoxy)methoxy)but-3-en-1-amine (13a) (0.69 g, 2.57 mmol,
51%) in 99% de as determined by 1H NMR analysis of the crude
product.TheMosheramideof13awasmadeusingDCCcondensation
inthepresenceofDMAP[25].Analysisofthe19FNMRspectrumofthe
MTPA amide revealed an enantiomeric ratio of 95.5% and 4.5%.
NMR (282 MHz, CDCl3):
(75 MHz, CDCl3):
d
À128.5 (m, 1F), À126.3 (m, 1F); 13C NMR
d
161.7 (dd, JC–F = 255 Hz, JC–F = 12.1 Hz), 160.7
(dd, JC–F = 225.0 Hz, JC–F = 11.1 Hz), 141.1, 129.2 (d, JC–F = 16.1 Hz),
127.4 (d, JC–F = 10.1 Hz), 116.3, 111.2 (d, JC–F = 17.3 Hz), 103.5 (t, JC–
F = 25.8 Hz), 53.2, 45.7, 17.4; MS (EI): 180 [M–NH3]+, 142; (CI): 198
[M+H]+, 181 [(M+H)–NH3]+, 142 [M–C4H7]+.
5.16. (1S,2S)-1-(2,5-difluorophenyl)-2-methylbut-3-en-1-amine (9f)
1H NMR (300 MHz, CDCl3):
d 7.14–7.08 (m, 1H), 6.98–6.83 (m,
2H), 5.76–5.64 (m, 1H), 5.14–5.08 (m, 2H), 3.96 (d, J = 8.1 Hz, 1H),
2.35 (q, J = 7.4 Hz, 1H), 1.66 (br s, 2H), 0.87 (d, J = 6.7 Hz, 3H); 19F
NMR (282 MHz, CDCl3):
(75 MHz, CDCl3):
d
À138.3 (m, 1F), À132.2 (m, 1F); 13C NMR
d
158.9 (dd, JC–F = 240.4 Hz, JC–F = 4.2 Hz), 156.5
(dd, JC–F = 239.2 Hz, JC–F = 5.1 Hz), 140.7, 133.7 (dd, JC–F = 15.8 Hz,
JC–F = 6.6 Hz), 116.4, 116.3, 116.0 (d, JC–F = 8.7 Hz), 114.2 (t, JC–
F = 22.2 Hz), 53.4, 45.5, 17.3; MS (EI): 180 [M–NH3]+, 142; (CI): 198
[M+H]+, 181 [(M+H)–NH3]+, 142 [M–C4H7]+.
1H NMR (300 MHz, CDCl3):
d 7.40–7.36 (m, 1H), 7.14–7.10 (m,
1H), 7.06–7.0 (m, 1H), 6.95–6.89 (m, 1H), 5.71–5.60 (m, 1H), 5.13–
5.07 (m, 2H), 4.23–4.13 (m, 2H), 4.66 (d, J = 7.0 Hz, 1H), 4.53 (d,
J = 6.9 Hz, 1H), 4.23–4.16 (m, 2H), 3.39–3.30 (m, 4H), 3.26 (s, 3H),
1.71 (br s, 2H); 19F NMR (282 MHz, CDCl3):
NMR (75 MHz, CDCl3): d 160.3 (d, JC–F = 243.7 Hz), 135.3, 129.6 (d,
d
À131.6 (s, 1F); 13C
5.17. (1S,2S)-1-(2,6-difluorophenyl)-2-methylbut-3-en-1-amine
(9g)
JC–F = 13.1 Hz), 128.7 (d, JC–F = 4.6 Hz), 128.4 (d, JC–F = 8.3 Hz), 123.8
(d, JC–F = 3.3 Hz), 118.9, 115.1 (d, JC–F = 22.1 Hz), 92.8, 80.7, 71.6,
66.8, 58.8, 53.1; MS (EI): 194 [M–OCH2CH2OCH3]+, 124; (CI): 270
[M+H]+, 194 [M+H–CH2OCH2CH2OH]+, 124.
1H NMR (300 MHz, CDCl3):
2H), 5.81–5.69 (m, 1H), 5.16–5.08 (m, 2H), 3.93 (d, J = 9.6 Hz, 1H),
2.54 (q, J = 7.4 Hz, 1H), 1.7 (br s, 2H), 0.81 (d, J = 6.7 Hz, 3H); 19F
NMR (282 MHz, CDCl3):
CDCl3):
d 7.16–7.08 (m, 1H), 6.84–6.78 (m,
d
À127.5 (s, 2F); 13C NMR (75 MHz,
5.21. (1R,2R)-1-(3-fluorophenyl)-2-((2-
d
161.3 (dd, JC–F = 245.3 Hz, JC–F = 9.0 Hz), 141.9, 128.3 (t,
methoxyethoxy)methoxy)but-3-en-1-amine (13b)
JC–F = 10.8 Hz), 119.6 (t, JC–F = 13.1 Hz), 116.1, 111.4 (dd, JC–
F = 20.7 Hz, JC–F = 11.9 Hz)), 51.9, 45.2, 17.9; MS (EI): 180 [M–
NH3]+, 142; (CI): 198 [M+H]+, 181 [(M+H)–NH3]+, 142 [M–C4H7]+.
1H NMR (300 MHz, CDCl3):
2H), 6.92–6.85 (m, 1H), 5.66–5.55 (m, 1H), 5.18–5.10 (m, 2H), 4.70
d 7.26–7.19 (m, 1H), 7.09–7.04 (m,

P.V. Ramachandran et al. / Journal of Fluorine Chemistry 130 (2009) 204–215
213
(d, J = 6.8 Hz, 1H), 4.57 (d, J = 6.9 Hz, 1H), 4.13 (t, J = 6.4 Hz, 1H),
2H), 1.45 (m, 9H); 19F NMR (282 MHz, CDCl3):
NMR (75 MHz, CDCl3): d 160.6 (d, JC–F = 244.0 Hz), 155.5, 129.7 (d,
JC–F = 12.8 Hz), 128.5 (d, JC–F = 21.1 Hz), 127.5 (d, JC–F = 23.1 Hz),
124.3, 115.8 (d, JC–F = 21.1 Hz), 79.6, 61.9, 50.7, 32.5, 29.2 and 28.4.
d
À134.3 (s, 1F); 13
C
3.94 (d, J = 5.8 Hz, 1H), 3.47–3.36 (m, 4H), 3.31 (s, 3H), 1.76 (br s,
2H); 19F NMR (282 MHz, CDCl3):
(75 MHz, CDCl3):
d
À127.1 (s, 1F); 13C NMR
d
162.8 (d, JC–F = 243.8 Hz), 145.3 (d, JC–
F = 6.7 Hz), 135.1, 129.4 (d, JC–F = 8.2 Hz), 123.2, 119.1, 114.4 (d,
JC–F = 21.3 Hz), 113.9 (d, JC–F = 20.9 Hz), 92.8, 81.4, 71.6, 67.0, 59.3,
58.9; MS (EI): 194 [M–OCH2CH2OCH3]+, 124; (CI): 270 [M+H]+, 194
[M+H–CH2OCH2CH2OH]+, 124.
5.26. (S)-tert-butyl-1-(2,6-difluorophenyl)-4-
hydroxybutylcarbamate (14g)
1H NMR (300 MHz, CDCl3):
d 7.27–7.17 (m, 1H), 6.93–6.85 (m,
5.22. (1R,2R)-1-(3,4-difluorophenyl)-2-((2-
2H), 5.40 (d, J = 9.9 Hz, 1H), 5.19 (q, J = 7.5 Hz, 1H), 3.65 (t,
J = 5.7 Hz, 2H), 2.86 (br s, 1H), 2.01–1.79 (m, 2H), 1.69–1.49 (m,
methoxyethoxy)methoxy)but-3-en-1-amine (13h)
2H), 1.44 (s, 9H); 19F NMR (282 MHz, CDCl3):
d
À114.8 (s, 1F); 13
C
1H NMR (300 MHz, CDCl3):
d
7.21–7.0 (m, 3H), 5.63–5.51 (m,
NMR (75 MHz, CDCl3): d 160.9 (dd, JC–F = 246.3 Hz, JC–F = 8.4 Hz),
1H), 5.18–5.09 (m, 2H), 4.71 (d, J = 6.8 Hz, 1H), 4.59 (d, J = 6.8 Hz,
1H), 4.08 (t, J = 6.7 Hz, 1H), 3.92 (d, J = 6.1 Hz, 1H), 3.53–3.40 (m,
155.4, 128.8 (t, JC–F = 10.5 Hz), 118.4 (t, JC–F = 13.4 Hz), 111.7 (d, JC–
F = 25.3 Hz), 79.9, 61.9, 45.7, 31.9, 29.3 and 28.4.
4H), 3.34 (s, 3H), 1.77 (br s, 2H); 19F NMR (282 MHz, CDCl3):
d
À153.8 (s, 1F), À151.7 (s, 1F); 13C NMR (75 MHz, CDCl3):
d
150.2
5.27. (S)-tert-butyl-1-(3,5-difluorophenyl)-4-
(dd, JC–F = 246.2 Hz, JC–F = 12.7 Hz), 149.5 (dd, JC–F = 245.4 Hz, JC–
F = 12.8 Hz), 139.6 (q, JC–F = 4.3 Hz), 134.8, 123.4 (d, JC–F = 6.1 Hz),
120.3, 119.5, 116.5 (t, JC–F = 17.7 Hz), 92.9, 81.5, 71.6, 67.1, 58.9,
58.8; MS (EI): 194 [M–OCH2CH2OCH3]+, 124; (CI): 270 [M+H]+, 194
[M+H–CH2OCH2CH2OH]+, 124.
hydroxybutylcarbamate (14i)
1H NMR (300 MHz, CDCl3):
d 7.13–7.0 (m, 3H), 5.58 (d,
J = 5.1 Hz, 1H), 4.56 (d, J = 6.0 Hz, 1H), 3.59 (t, J = 5.1 Hz, 2H),
2.01 (br s, 1H), 1.83–1.70 (m, 2H), 1.63–1.46 (m, 2H), 1.39 (s, 9H);
19F NMR (282 MHz, CDCl3):
CDCl3): d 150.3 (dd, JC–F = 246.3 Hz, JC–F = 12.6 Hz), 147.5, 140.6,
d
À123.1 (s, 2F); 13C NMR (75 MHz,
5.23. (1R,2R)-1-(3,5-difluorophenyl)-2-((2-
methoxyethoxy)methoxy)but-3-en-1-amine (13i)
117.0 (d, JC–F = 16.8 Hz), 115.1 (d, JC–F = 16.3 Hz), 79.6, 61.6, 53.9,
33.1, 29.0, 28.3.
1H NMR (300 MHz, CDCl3):
d 6.90–6.81 (m, 2H), 6.69–6.61 (m,
1H), 5.66–5.55 (m, 1H), 5.22–5.13 (m, 2H), 4.70 (d, J = 7.0 Hz, 1H),
4.58 (d, J = 6.9 Hz, 1H), 4.12 (t, J = 6.7 Hz, 1H), 3.93 (d, J = 5.7 Hz,
1H), 3.50–3.39 (m, 4H), 3.33 (s, 3H), 1.67 (br s, 2H); 19F NMR
5.28. tert-Butyl-1-(1S,2S)-1-(3-fluorophenyl)-4-hydroxy-2-
methylbutylcarbamate (17b)
(282 MHz, CDCl3):
d
À123.8 (s, 2F); 13C NMR (75 MHz, CDCl3):
1H NMR (300 MHz, CDCl3):
d 7.36–7.29 (m, 1H), 7.08–6.95 (m,
3H), 5.49 (d, J = 7.8 Hz, 1H), 4.53 (t, J = 7.2 Hz, 1H), 3.83–3.61 (m,
2H), 2.61 (br s, 1H), 2.21–2.01 (m, 1H), 1.98–1.89 (m, 1H), 1.73–
1.62 (m, 1H), 1.46 (s, 9H), 0.90 (d, J = 7.2 Hz, 3H); 19F NMR
d
= 162.7 (dd, JC–F = 246.5 Hz, JC–F = 13.1 Hz), 146.9, 134.8, 119.5,
110.4 (d, JC–F = 16.9 Hz), 102.4 (t, JC–F = 25.3 Hz), 92.8, 81.1, 71.6,
67.1, 56.1, 58.9; MS (EI): 194 [M–OCH2CH2OCH3]+, 124; (CI): 270
[M+H]+, 194 [M+H–CH2OCH2CH2OH]+.
(282 MHz, CDCl3):
d
À113.05 (s, 1F); 13C NMR (75 MHz, CDCl3):
d
162.9 (d, JC–F = 246.9 Hz), 155.8, 144.8, 129.8, 122.5 (d, JC–
F = 27.3 Hz), 113.9 (d, JC–F = 21.1 Hz), 113.4 (JC–F = 16.8 Hz), 79.8,
60.4, 59.3, 36.3, 35.2, 28.4 and 16.6.
5.24. (S)-tert-butyl-1-(3-fluorophenyl)-4-hydroxybutylcarbamate
(14b)
Di-tert-butyl dicarbonate (0.68 g, 3.1 mmol) was added to the
above (1S)-1-(3-fluorophenyl)-but-3-en-1-amine (4b; 0.46 g,
2.8 mmol) dissolved in Et2O (30 mL) and the reaction was stirred
for 6 h at RT, after which time the solvent was removed under
reduced pressure. The crude material was dissolved in THF (7 mL)
and treated with 9-BBN (0.5 M in THF; 13 mL, 6.5 mmol) for 24 h at
RT, followed by oxidation with sodium acetate (20% in H2O, 20 mL)
and, slowly, H2O2 (30% in H2O; 6 mL) for 5 h at RT. The product was
extracted with Et2O (3Â 30 mL), and after evaporation of the
solvents purified on silica gel (hexanes/ethyl acetate 2:1) to furnish
(S)-tert-butyl-1-(3-fluorophenyl)-4-hydroxybutylcarbamate (14b)
(0.60 g, 2.13 mmol, 76%).
5.29. (S)-4-(tert-butoxycarbonylamino)-4-(3-fluorophenyl)butanoic
acid (15b)
The above N-Boc protected alcohol (14b; 0.23 g, 0.8 mmol) in
DMF (10 mL) was added to a stirring solution of pyridinium
dichromate (1.13 g, 3.0 mmol) in DMF (20 mL) and the mixture
was stirred for 18 h at RT. The reaction was quenched with H2O
(5 mL), the product was extracted with Et2O (3Â 50 mL), the
combined ether layers were washed with H2O (3Â 50 mL), the
solvent was removed and the obtained material was purified on
silica gel (flash; hexanes/ethyl acetate 2:1) to afford (S)-4-(tert-
butoxycarbonylamino)-4-(3-fluorophenyl)butanoic acid (15b)
(0.19 g, 0.64 mmol, 80%).
1H NMR (300 MHz, CDCl3):
d 7.28–7.21 (m, 1H), 7.04–6.87 (m,
3H), 5.18 (br s, 1H), 4.62 (br s, 1H), 3.61 (t, J = 6.9 Hz, 2H), 2.53 (br s,
1H), 1.86–1.77 (m, 1H), 1.58–1.47 (m, 3H), 1.39 (s, 9H); 19F NMR
1H NMR (300 MHz, CDCl3):
d 7.33–7.26 (m, 1H), 6.98–6.87 (m,
3H), 5.10 (t, J = 3.7 Hz, 1H), 2.66–2.42 (m, 2H), 1.87–1.80 (m, 1H),
(282 MHz, CDCl3):
d
À169.2 (s, 1F); 13C NMR (75 MHz, CDCl3):
d
1.25 (s, 9H); 19F NMR (282 MHz, CDCl3):
(75 MHz, CDCl3): d 174.5, 163.2 (d, JC–F = 226.7 Hz), 149.4, 145.2 (d,
d
À125.9 (s, 1F); 13C NMR
162.9 (d, JC–F = 244.2 Hz), 155.6, 145.6, 130.1 (d, JC–F = 6.2 Hz),
122.1, 114.0 (d, JC–F = 21.2 Hz), 113.2 (d, JC–F = 21.8 Hz), 79.8, 62.1,
54.2, 33.1, 28.9 and 28.4.
JC–F = 6.8 Hz), 130.4 (d, JC–F = 8.2 Hz), 120.6 (d, JC–F = 2.8 Hz), 114.4
(d, JC–F = 21.1 Hz), 112.1 (d, JC–F = 22.1 Hz), 83.1, 61.1, 31.2, 27.7
and 27.2.
5.25. (S)-tert-butyl-1-(2-fluorophenyl)-4-hydroxybutylcarbamate
(14a)
5.30. (S)-4-(tert-butoxycarbonylamino)-4-(2-fluorophenyl)butanoic
acid (15a)
1H NMR (300 MHz, CDCl3):
d 7.34–7.21 (m, 2H), 7.14–7.02 (m,
2H), 5.42 (d, J = 8.1 Hz, 1H), 4.85 (d, J = 7.5 Hz, 1H), 3.64 (t,
J = 6.6 Hz, 2H), 3.06 (br s, 1H), 1.91–1.79 (m, 2H), 1.65–1.51 (m,
1H NMR (300 MHz, CDCl3):
J = 6.4 Hz, J = 8.3 Hz, 1H), 2.67–2.44 (m, 3H), 1.93–1.86 (m, 1H),
d 7.29–7.02 (m, 4H), 5.43 (dd,

214
P.V. Ramachandran et al. / Journal of Fluorine Chemistry 130 (2009) 204–215
1.26 (s, 9H); 19F NMR (282 MHz, CDCl3):
NMR (75 MHz, CDCl3):
129.4 (d, JC–F = 13.1 Hz), 129.2 (d, JC–F = 8.3 Hz), 125.9 (d, JC–
F = 3.8 Hz), 124.3, 115.7 (d, JC–F = 21.2 Hz), 83.0, 55.5, 31.2, 27.7
and 25.9.
d
À133.4 (s, 1F); 13C
5.36. (S)-5-(2,6-difluorophenyl)pyrrolidin-2-one (16g)
d
174.7, 159.7 (d, JC–F = 244.7 Hz), 149.3,
1H NMR (300 MHz, CDCl3):
2H), 6.66 (br s, 1H), 5.17 (dd, J = 4.8 Hz, J = 8.1 Hz, 1H), 2.66–2.37
(m, 3H), 2.26–2.16 (m, 1H); 19F NMR (282 MHz, CDCl3):
À128.5
(s, 2F); 13C NMR (75 MHz, CDCl3):
178.5, 161.1 (dd, JC–
d 7.29–7.19 (m, 1H), 6.91–6.83 (m,
d
d
5.31. (S)-4-(tert-butoxycarbonylamino)-4-(2,6-
F = 255.9 Hz, JC–F = 14.6 Hz), 129.7 (t, JC–F = 10.7 Hz), 117.7, 111.9
(d, JC–F = 17.6 Hz), 47.9, 29.9, 27.3; MS (EI): 197 [M]+, 177, 142 (CI):
198 [M+H]+.
difluorophenyl)butanoic acid (15g)
1H NMR (300 MHz, CDCl3):
(m, 2H), 5.52 (dd, J = 4.0 Hz, J = 9.3 Hz, 1H), 2.88–2.43 (m, 3H),
d 7.29–7.20 (m, 1H), 6.91–6.85
5.37. (S)-5-(3,5-difluorophenyl)pyrrolidin-2-one (16i)
2.07–1.97 (m, 1H), 1.29 (s, 9H); 19F NMR (282 MHz, CDCl3):
d
À128.9 (s, 2F); 13C NMR (75 MHz, CDCl3):
d
174.5, 160.7 (dd, JC–
1H NMR (300 MHz, CDCl3):
d 7.17 (br s, 1H), 6.84–6.69 (m, 3H),
F = 247.1 Hz, JC–F = 10.9 Hz), 149.2, 129.4 (d, JC–F = 10.9 Hz), 118.6
(d, JC–F = 7.2 Hz), 111.7 (d, JC–F = 17.6 Hz), 83.0, 51.9, 31.6, 27.7
and 23.9.
4.73 (t, J = 6.9 Hz, 1H), 2.61–2.35 (m, 3H), 1.98–1.89 (m, 1H); 19F
NMR (282 MHz, CDCl3):
CDCl3):
d
À122.0 (s, 2F); 13C NMR (75 MHz,
d
178.9, 163.4 (dd, JC–F = 248.3 Hz, JC–F = 11.1 Hz), 146.9,
108.5 (d, JC–F = 17.2 Hz), 103.3 (d, JC–F = 25.4 Hz), 57.5, 30.9, 30.0;
5.32. (S)-4-(tert-butoxycarbonylamino)-4-(3,5-
MS (EI): 197 [M]+, 177, 142 (CI): 198 [M+H]+.
difluorophenyl)butanoic acid (15i)
5.38. (4S,5S)-5-(3-fluorophenyl)-4-methylpyrrolidin-2-one (19b)
1H NMR (300 MHz, CDCl3):
d 6.89–6.62 (m, 3H), 5.08 (dd,
J = 3.8 Hz, J = 7.5 Hz, 1H), 2.62–2.42 (m, 3H), 1.94–1.78 (m, 1H),
1H NMR (300 MHz, CDCl3):
d 7.38–7.31 (m, 1H), 7.11–6.99
(m, 3H), 6.10 (br s, 1H), 4.22 (d, J = 7.1 Hz, 1H), 2.65–2.57 (m,
1H), 2.30–2.08 (m, 2H), 1.17 (d, J = 6.5, 3H); 19F NMR (282 MHz,
1.27 (s, 9H); 19F NMR (282 MHz, CDCl3):
(75 MHz, CDCl3):
d
À122.1 (s, 2F); 13C NMR
d
= 174.2, 163.4 (dd, JC–F = 248.3 Hz, JC–
F = 12.4 Hz), 149.3, 1146.8, 108.1 (d, JC–F = 9.2 Hz), 103.0 (t, JC–
F = 25.1 Hz), 83.4, 60.8, 31.0, 27.7 and 26.9.
CDCl3): d À125.6 (s, 1F); 13C NMR (75 MHz, CDCl3):
d 177.7,
162.9 (d, JC–F = 240.5 Hz), 143.7 (d, JC–F = 6.5 Hz), 130.4 (d, JC–
F = 8.3 Hz), 121.8, 115.1 (d, JC–F = 20.9 Hz), 113.1 (d, JC–
F = 21.9 Hz), 65.5, 40.3, 38.9, 17.8; MS (EI): 193 [M]+, 173,
149; (CI): 194 [M+H]+.
5.33. (3S,4S)-4-(tert-butoxycarbonylamino)-4-(3-fluorophenyl)-3-
methylbutanoic acid (18b)
1H NMR (300 MHz, CDCl3):
d
7.34–7.28 (m, 1H), 7.01–6.81
Acknowledgement
(m, 3H), 5.09 (d, J = 8.1 Hz, 1H), 2.78–2.68 (m, 1H), 2.59–2.51 (m,
1H), 2.36–2.1 (m, 1H), 1.25 (s, 9H), 0.67 (d, J = 6.9 Hz, 3H); 19F
We gratefully acknowledge the Herbert C. Brown Center for
Borane Research for support of this research.
NMR (282 MHz, CDCl3):
CDCl3):
d
À112.5 (m, 1F); 13C NMR (75 MHz,
d
174.2, 162.9 (d, JC–F = 246.3 Hz), 149.3, 140.0 (d, JC–
References
F = 6.3 Hz), 130.2 (d, JC–F = 16.9 Hz), 121.0, 114.5 (d, JC–
F = 18.9 Hz), 113.4 (d, JC–F = 23.2 Hz), 82.8, 65.1, 38.7, 30.1,
27.6 and 15.7.
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5.34. (S)-5-(3-fluorophenyl)-pyrrolidin-2-one (16b)
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dissolved in CH2Cl2 (3 mL) was treated with CF3COOH (0.1 mL) for
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obtain (S)-5-(3-fluorophenyl)-pyrrolidin-2-one (16b) (0.09 g,
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1H NMR (300 MHz, CDCl3):
d 7.35–7.26 (m, 2H), 7.22 (br s, 1H),
7.07–6.93 (m, 2H), 4.74 (t, J = 6.9 Hz, 1H), 2.59–2.36 (m, 3H), 1.98–
1.89 (m, 1H); 19F NMR (282 MHz, CDCl3):
(75 MHz, CDCl3):
d
À125.7 (s, 1F); 13C NMR
d
179.0, 163.2 (d, JC–F = 245.5 Hz), 145.3 (d, JC–
F = 6.5 Hz), 130.4 (d, JC–F = 8.1 Hz), 121.1 (d, JC–F = 2.6 Hz), 114.7 (d,
JC–F = 20.9 Hz), 112.5 (d, JC–F = 22.2 Hz), 57.7, 31.1, 30.4; MS (EI):
179 [M]+, 159, 135; (CI): 180 [M+H]+.
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5.35. (S)-5-(2-fluorophenyl)pyrrolidin-2-one (16a)
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.
1H NMR (300 MHz, CDCl3):
d 7.37–7.23 (m, 2H), 7.17–7.12 (m,
(b) Pfizer tradename for pregabalin: Lyrica1
.
1H), 7.08–7.01 (m, 1H), 6.92 (br s, 1H), 5.06 (t, J = 6.5 Hz, 1H), 2.69–
2.58 (m, 1H), 2.48–2.38 (m, 2H), 2.04–1.93 (m, 1H); 19F NMR
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(282 MHz, CDCl3):
d
À133.0 (s, 1F); 13C NMR (75 MHz, CDCl3):
d
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179.0, 160.0 (d, JC–F = 257.4 Hz), 129.6 (d, JC–F = 12.8 Hz), 129.3 (d,
JC–F = 8.2 Hz), 126.2 (d, JC–F = 4.1 Hz), 124.5 (d, JC–F = 3.3 Hz), 115.6
(d, JC–F = 21.1 Hz), 51.9, 29.9, 29.5; MS (EI): 179 [M]+, 159, 135; (CI):
180 [M+H]+.
.
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