Fluoroamines via chiral cyclic sulfamidates

Article abstract of DOI:10.1055/s-2002-25766

N-benzyl [1,2,3]-oxathiazolidine 2,2-dioxides (cyclic sulfamidates) were synthesized from their corresponding β-amino alcohols and used as substrates in fluorination reactions with tetrabutylammonium fluoride (TBAF). After desulfonation of the intermediates, the N-benzyl fluoroamines were debenzylated by transfer hydrogenolysis with Pd/C to yield (S) and (R)-2-amino-1-fluoropropanes (2b and 3b, respectively, both with 95% ee). The reactions were carried out on multi-gram scale without the need for chromatographic purification of the intermediates. In the presence of carbonate, the (S)- and (R)-N-benzylfluoroamines underwent intramolecular cyclizations in which fluoride was displaced to yield cyclic carbamates 13 and 14.

Full text of DOI:10.1055/s-2002-25766

766
PAPER
Fluoroamines via Chiral Cyclic Sulfamidates
F
luoroam
e
s
via
C
h
f
iral Cycl
f
ic Sulfa
m
r
idates ey J. Posakony,a Timothy J. Tewson*b
a
University of Washington, Department of Radiology Imaging Research Laboratory, Rm NW041, Box 356004,
1959 NE Pacific St., Seattle, WA 98195, USA
b
University of Iowa PET Imaging Center, Department of Radiology, 0911Z JPP, 200 Hawkins Drive, Iowa City, Iowa,
52242-1007, USA
Fax (319)3536512; E-mail: timothy-tewson@uiowa.edu
Received 20 April 2001; revised 6 March 2002
Initial investigations focused on the synthesis of 1b as this
likely represents the most challenging transformation
since it requires substitution adjacent to a quaternary car-
bon, similar to that of a neopentyl position, at which sub-
Abstract: N-benzyl [1,2,3]-oxathiazolidine 2,2-dioxides (cyclic
sulfamidates) were synthesized from their corresponding -amino
alcohols and used as substrates in fluorination reactions with tet-
rabutylammonium fluoride (TBAF). After desulfonation of the in-
termediates, the N-benzyl fluoroamines were debenzylated by stitutions occur with difficulty. Our attempts to fluorinate
transfer hydrogenolysis with Pd/C to yield (S) and (R)-2-amino-1-
fluoropropanes (2b and 3b, respectively, both with 95% ee). The re-
actions were carried out on multi-gram scale without the need for
example, treatment of N-(carbamate)-1a with DAST re-
chromatographic purification of the intermediates. In the presence
of carbonate, the (S)- and (R)-N-benzylfluoroamines underwent in-
N-protected (FMOC or BOC) 1a using conventional nu-
cleophilic fluorination strategies were unsuccessful. For
sulted in complex mixtures of products, which were likely
the result of intramolecular cyclization reactions involv-
ing the protecting group and intermolecular reactions of
the required intermediate.7,8 In addition, no fluorination
product was observed when the hydroxyl of the N-protect-
ed 1a was converted to its triflate (OTf) and then treated
with TBAF. We then turned to the cyclic sulfamidates,
[1,2,3]-oxathiazolidine-2,2-dioxides, which are readily
prepared from N-protected amino alcohols. They are
versatile substrates that undergo nucleophilic displace-
ment with carbon (cyanide, and organometallic reagents),
[18 and 19]F-, nitrogen (e.g. azide, thiocyanate, amines, and
pyrazole), oxygen (e.g. MeO , AcO , and ArO ) and RS
nucleophiles.9–14
tramolecular cyclizations in which fluoride was displaced to yield
cyclic carbamates 13 and 14.
Key words: fluoroamines, nucleophilic addition, cyclizations, cy-
clic sulfamidates, beta-adrenergic ligands
As part of an ongoing effort to develop non-invasive, in
vivo imaging of heart receptor populations using positron
emission tomography (PET),1–6 we required a convenient
syntheses of fluoro-tert-butylamine (1b) and enantiomer-
ically pure (S)-and (R)-1-fluoro-2-propylamine (2b and
3b, respectively) in order to synthesize selected -adreno-
ceptor ligands. The -adrenergic receptors are present in
the receptor rich tissues in concentrations of nanomoles
per gram of tissue. In order to achieve specific labeling of
the receptors, the labeled ligands must be delivered to the
receptors at concentrations substantially lower than those
of the receptor but still with sufficient radioactivity to per-
form PET imaging. As such, a specific activity of >1Ci/
micromole of the final ligand is required, which limits the
fluorination reagent to the fluoride anion. Thus, we chose
to develop the synthetic route utilizing a hydroxide to flu-
oride conversion starting from the readily available amino
alcohols (1a 3a; Figure).
We previously reported the fluorination reaction of N-
benzyl sulfamidate (4),6 the precursor to 1b HCl. At near-
ly the same time, Ok, et al. described the synthesis of
1b HCl via 10,15 and as such, the production of 1b and its
precursors will not be further elaborated here. However,
the independently developed conditions described here
are applicable for the synthesis of 1b as well as 2b 3b and
have been applied on a scale of tens of grams without time
consuming chromatographic purification of the interme-
diates. We report the preparation of highly enantiopure
fluoroamines 2b and 3b, which were previously described
as an unresolved enantiomeric mixture.16 Also described
is an unusual intramolecular cyclization reaction in which
fluoride is displaced from the chiral N-benzyl amines 11
and 12. The corresponding chemistry with radiolabeled
fluoride has been developed and will be reported else-
where; subsequent references to fluorine in this paper re-
fer to 19F.
Figure
Preparation of the N-benzyl sulfamidates 9 and 10 was
based on White and Garst’s method17 which involves syn-
thesis of the sulfamidite intermediates 7 8 from thionyl
chloride and the amino alcohols 5 6, followed by RuO4-
oxidation (Scheme 1). After RuO4-oxidation, 9 and 10
were isolated as stable, crystalline products in fair overall
Synthesis 2002, No. 6, 29 04 2002. Article Identifier:
1437-210X,E;2002,0,06,0766,0770,ftx,en;M02401SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

PAPER
Fluoroamines via Chiral Cyclic Sulfamidates
767
yields (~35%) each with >99.5% ee. The yields of 9 and 11 would react with carbonate, which was used to neutral-
10 were somewhat lower than the overall yield of 4 report- ize the acidic hydrolysis solution.
ed by Ok, et al. (64%),15 which was similar to our own re-
sults. In our experience, sterically uncongested
sulfamidates such as 9 and 10 are notably more reactive
than their hindered counterparts and the same may be true
In control reaction (A), the test for pathway (A)
(Scheme 3), carbonate reacted with 9 to form a new prod-
uct, putatively 15, (~90% by HPLC, Table); however, this
yielded 5 (92% isolated yield) after the sulfuric acid hy-
for their sulfamidite precursors, although they generally
drolysis. In control reaction (B), no reaction occurred. In
require more vigorous conditions to react.14 This may ex-
control reaction (C), when the aqueous, acidic (sulfuric
plain, in part, the moderate overall yields obtained for 9
acid) solution of 11 was neutralized with sodium bicar-
and 10. Attempts to synthesize sulfamidates directly via
bonate, 13 began to form (10% yield after 40 min) and its
thionyl chloride- and triethylamine18 or sodium hydride
yield increased when sodium carbonate was added (up to
and sulfonyl diimidazole12,19 yielded, at most, traces of the
80% yield HPLC, 60% isolated yield). Thus, it is highly
likely that 13 and 14 originated from 11 and 12 and car-
desired products and we had no success using unprotected
amino alcohols. In contrast to the procedure described by
bonate from sodium carbonate, in an unusual cyclization
Ok, et al.,15 our procedure does not employ column chro-
step that involves displacement of fluoride. The phase
matography and is thus more amenable to multigram-
transfer catalyst properties of the tetrabutylammonium
scale syntheses. Indeed we have applied our conditions to
cation, present in the synthesis of 11 and 12, would likely
facilitate the formation of 13 and 14 under these condi-
~25 g of 5 with good results.
tions. Thus sodium hydroxide is recommended for neu-
tralization of the hydrolysis solution in the synthesis of 11
and 12. No such cyclization was observed during the
fluorination of hindered sulfamidate 4 when sodium car-
bonate was used to neutralize the hydrolysis solution.
O
O S
O
SOCl2
Et3N
S
RuO4
O
O
NH
R2
Bn
Bn N
R2
Bn N
R2
OH
R1
R1
R1
R1 = H, R2 = CH3 (5)
R1 = CH3, R2 = H (6)
(7) 44%
(8) 69%
(9) 77%
(10) 52%
Control reaction (A)
Scheme 1
O
1) H2SO4
2) NaOH
O S
(Et4N)2CO3
O-
Using conditions described in the literature,17 9 10 react-
ed with TBAF at room temperature and the intermediate
products were subsequently hydrolyzed to yield 11 12
(Scheme 2).
9
5
N
Bn
OCO2-
15
Control reaction (B)
O
O
1) TBAF
O S
Bn N
R2
2) H2SO4
O
C
1) TBAF, H2SO4
2) Na2CO3
O
NH
R2
Bn
3) NaOH
or Na2CO3
Bn N
R2
F
R1
5
No Reaction
R1
R1
R1 = H, R2 = CH3 (9)
R1 = CH3, R2 = H (10)
(11) 77%
(12) 77%
(13)
(14)
Control reaction (C)
1) NaHCO3
2) Na2CO3
Scheme 2
11•HCl
13
in H2SO4(aq.)
In some experiments with 11 and 12, sodium carbonate
was used to neutralize the aqueous acid in the hydrolysis
step and significant amounts (up to 45% yield) of the cy-
clic carbamates 13 and 14 were isolated. We investigated
the origin of 13 and 14 by analyzing control reactions by
HPLC, described here for the S-isomer series. Three pos-
sible origins were considered. In pathway (A), carbonate,
present in the TBAF reagent solutions, would react with 9
to afford 13 upon workup. In pathway (B), TBAF would
promote the formation of 13 from carbonate and 5 (5 be-
ing formed via a possible side reaction involving adventi-
tious H2O in the TBAF solutions and 9). In pathway (C),
Scheme 3
Table Reverse Phase HPLC Retention Times
Compound
Retention Time (min)
5
5.3
14.0
8.6
9
15 (putative)
11
13
10.4
13.6
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768
J. J. Posakony, T. J. Tewson
PAPER
vated, crushed 4 Å molecular sieves. Solid TBAF or a 1.0 M solu-
tion (in THF with 5% H2O) was dried by azeotropic H2O removal
(CH3CN) prior to use. Stable HCl salts were obtained by dissolving
the product in Et2O or Et2O/MeOH and bubbling HCl(g) through the
solutions; the resulting precipitate was collected and washed thor-
oughly with Et2O. The HPLC analyses were performed using Wa-
ters 515 HPLC Pumps controlled by Millenium-32® software and
the detection was performed by monitoring the eluate at 256 nm us-
ing a Waters 2487 dual wavelength absorbance detector. The organ-
ic solvents were HPLC grade and the aq solutions were filtered
through a 0.45 m nylon membrane (Phenomenex) prior to use.
Chiral HPLC was used to determine the enantiomeric purity of
compounds 9 and 10 using a Chiracel® OD column (Chiral Tech-
nologies Incorporated) and isocratic elution (heptane with 0.25%
TFA i-PrOH, 4:1) at 1 mL/min. Reverse phase HPLC was used to
investigate the formation of 13 and 14. The Prodigy ODS (2) col-
umn (5 , 150 4.60 mm, Phenomenex) was eluted using a gradient
elution protocol at 1 mL/min as follows: solvent A (0.1 M NH4OAc)
and solvent B (MeOH); 0 3 min (4:1, A:B); 3 13 min (4:1, A:B
changing to 0:1) and 13 17 min (0:1, A:B).
The hydrogen-transfer debenzylation (Scheme 4) using
formic acid and 10% Pd/C20 cleanly debenzylated 11 and
12 to afford 2b and 3b in high yield (81% and 94%). The
transfer hydrogenolysis described here is much milder
than the H2/Pd/C debenzylations described by Ok, et al.
and may be suitable for the preparation of other com-
pounds with reduction-labile components. The isolated
fluoroamines were then derivatized with (S)-MTPA
1
(quantitative yield) to yield the Mosher amides. By H
NMR, the methoxy and fluoromethyl signals were re-
solved and the integrations demonstrated 95% ee for both
2b and 3b. By, 19F NMR, integrations of the trifluor-
omethane signals indicated 95 % ee and 98% ee for both
2b and 3b.
R1
10% Pd/C
HCOOH
R2
R1
HCl
R2
Bn
F •HCl
F
H2N
HN
N-Benzyl-(S)-2-methyl-aminopropan-1-ol (5) and N-Benzyl-
(R)-2-methyl-aminopropan-1-ol (6)
R
1 = H, R2 = CH3 (11)
R1 = CH3, R2 = H (12)
(2b) 81%
(3b) 94%
A mixture of benzaldehyde (0.262 mol) and the chiral amino alco-
hol (S, or R -isomer, 0.262 mol) in benzene (100 mL) was refluxed
with the azeotropic removal of H2O (4 h). The solvent was reduced
to 50 mL, and the mixture refrigerated. The intermediate, crude imi-
ne crystallized and was subsequently dissolved in MeOH (300 mL).
The soln was cooled to 0 °C under Ar, and then NaBH4 (9.6 g, 0.254
mol) was added in gram-portions. After stirring for 2 h at 0 °C, 6 N
NaOH (60 mL) was added and the solvent was evaporated. The res-
idue was extracted with H2O (250 mL) and Et2O (4 100 mL).
Compounds 5 and 6 were obtained.
Scheme 4
In summary, a useful method for the synthesis of multi-
gram quantities of fluoroamines 2b 3b in high enantio-
meric purity from the corresponding N-benzyl amino
alcohols (5 and 6) via the cyclic sulfamidates (9 and 10)
has been developed. Fluorination of 9 and 10 was facile,
proceeding to completion within a few minutes at room
temperature with ca. 1:1 ratio of sulfamidate TBAF. The
yields are good to moderate and this methodology is ame-
nable to large-scale preparations of 1b 3b. Furthermore,
the fluorination reaction lends itself to the use of short-
The characterization data for 5 (mp 42.5 45.5 °C) match those re-
ported previously.21
6
Mp 41.5 43.5 (lit. 46.5).22
lived [18F]-fluoride. N-benzyl fluoroamines 11 and 12 re- 1H NMR (CDCl3): = 1.07 (d, 3 H, J = 6 Hz, CH3), 2.2 (br s, 2 H,
NH and OH), [2.92 (m, 1 H), 3.27 (dd, 1 H) and 3.57 (dd, 1 H);
acted with carbonate to afford the corresponding cyclic
AMX system JAM = 10.5 Hz, JAX = 7 Hz, JMX = 4 Hz, CHCH2], 3.70
carbamates (13 and 14) in a cyclization reaction in which
and 3.85 (dd, 2 H, AB system, J = 13 Hz, benzyl H), 7.24 7.35 (m,
fluoride is displaced.
5 H, phenyl H).
Melting points were determined using an Electrothermal® melting
point apparatus and are uncorrected. Low resolution mass spec-
trometry was performed on a Micromass Quattro II Tandem Quad-
rupole Mass Spectrometer (electrospray ionization). High
resolution mass spectrometry was performed using a Micromass
70SEQ Tandem Hybrid Mass Spectrometer (FAB) or a PE Biosys-
Cyclic Sulfamidite Formation; General Procedure
We modified the method by White and Garst17 for the synthesis of
compounds 7 and 8. Briefly, a soln of the N-benzyl amino alcohol
(~0.33 M) and Et3N (2.1 equiv) in anhyd CH2Cl2 under Ar was
cooled to –78 °C with stirring. SOCl2 (1.05 equiv, ~1.5 M in anhyd
CH2Cl2) was added dropwise over 45 min. The soln was allowed to
warm to r.t., filtered (Et3N HCl removal), and was washed with H2O
and brine. The organic phase was dried (Na2SO4) and the solvent
was removed to afford an oil. This material was dissolved in a min-
imum of Et2O and filtered through a short plug of silica followed by
continued elution with Et2O until no more sulfamidite eluted. The
crude sulfamidite was used directly in the RuO4-oxidation proce-
dure described below.
1
tems Mariner electrospray (TOF) instrument. H- and 19F NMR
spectra were obtained with a GE Omega 300 MHz spectrometer.
1H-chemical shifts are reported in ppm ( ) and 19F-chemical shifts
are referenced to CFCl3. Coupling constants are rounded to the
nearest 0.5 Hz. Elemental analyses were performed by Galbraith
Laboratories, Knoxville TN. Prior to elemental analysis, samples
were dried under vacuum at 40 50 °C. Optical rotation measure-
ments were made using a Jasco DIP-370 digital polarimeter. Flash
column chromatography was performed using silica gel (Merck,
grade 9385, 230 400 mesh). Analytical TLC and Rf values were
determined using Analtech GF silica gel plates (0.25 mm); prepar-
ative TLC was performed using Analtech GF silica gel plates (1
mm). Unless otherwise noted, reagents were purchased from Al-
drich Chemical Co. Solvents were ACS reagent grade or better. Un-
less otherwise noted, anhyd solvents (Aldrich) were used as
received except for CH2Cl2, which was dried by storing over acti-
RuO4 Oxidation; General Procedure
We adapted White and Garst’s procedure17 for the synthesis of 9
and 10. The conditions described below were based on 0.15 mol of
sulfamidite. Briefly, the sulfamidite was dissolved in CH3CN (300
mL) and the soln cooled to 0 °C. RuCl3 3H2O (10 mg) and then
NaIO4 (1 equiv) were added, followed by distilled H2O (300 mL).
After 10 min, the ice bath was removed and the soln was stirred for
2 h. H2O (250 mL) was added and the mixture was extracted with
Et2O (3 200 mL). The volume of the organic phase was reduced
Synthesis 2002, No. 6, 766–770 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Fluoroamines via Chiral Cyclic Sulfamidates
769
(100 mL) and the crude mixture was filtered through a plug of silica,
which was eluted with additional Et2O. The solvent was removed
and the product was crystallized from CH2Cl2 heptane.
containing unreacted starting material was separated from the aq
phase. The aq phase was adjusted to pH 10 12 using aq NaOH. The
product was extracted into Et2O and subsequently purified by col-
umn chromatography (CH2Cl2 acetone, 20:1, Rf 0.36) to yield 0.16
g of crude 11. The reaction was scaled up to 50 mmol of 9 without
a decrease in yield.
1H NMR (CDCl3): = 1.10 (dd, 3 H, J1 = 7 Hz, J2 = 1.5 Hz, CH3),
1.93 (s, 1 H, NH), 3.79 and 3.88 (2 d, 2 1 H, AB system, J = 13
Hz, benzyl H), {3.02 (m, 1 H), [4.29 (dd) and 4.36 (dd), 2 H total,
each split by JHF = 48 Hz]; ABX pattern JAB = 9 Hz, JAX = 6.5 Hz,
3-Benzyl-(S)-4-methyl-[1,2,3]-oxathiazolidine-2-oxide (7)
Compound 5 (27.0 g, 0.167 mol) afforded 28.3 g of crude 7. A sam-
ple of the crude product (0.50 g) was purified by column chroma-
tography (CH2Cl2 acetone, 20:1, Rf 0.75) to yield 0.27 g of an oil
(1.3 mmol, 44%). Although NMR spectral data can be used to iden-
tify 7, a satisfactory elemental analysis was not obtained.
1H NMR (CDCl3): = 1.21 (d), 1.32 (d), 3.50 (m), 3.78 (m), 3.99
(dd), 4.10 (d), 4.17 (d), 4.26 (d), 4.40 (d), 4.53 (d), 4.85 (dd), 7.28
7.43 (m).
JBX = 6 Hz, CHCH2F}, 7.22 7.36 (m, 5 H, phenyl H).
19F NMR (CDCl3):
=
225.37 (td, J1 = 48 Hz, J2 = 17 Hz, addi-
tional splitting J = 1.5 Hz due to coupling to CH3 group is ob-
MS: m/z = 211.9 (100, M + H), 166.0 (50) 148, 147, 146 cluster
served).
(30).
MS: m/z = 168 (100, M + H).
The product was converted to its HCl salt and recrystallized from
MeOH EtOAc Et2O to yield 0.17 g (76%) of 11 HCl.
Mp 159.5 160.5 °C; [ ]D23 +4.8 (c 0.92, MeOH).
3-Benzyl-(R)-4-methyl-[1,2,3]-oxathiazolidine-2-oxide (8)
Compound 6 (18.5 g, 0.112 mol) afforded 19.2 g of crude 8. A sam-
ple of the crude product (0.50 g) was purified by column chroma-
tography (CH2Cl2 acetone, 20:1, Rf 0.75) to yield 0.42 g of an oil
(69%).
1H NMR (CDCl3): = 1.21 (d), 1.32 (d), 3.50 (m), 3.78 (m), 3.99
(dd), 4.10 (d), 4.17 (d), 4.26 (d), 4.40 (d), 4.53 (d), 4.85 (dd), 7.28
7.43 (m). The NMR spectrum showed very few impurities, but a sat-
isfactory elemental analysis was not obtained.
Anal. Calcd for C10H15ClFN: C, 58.97; H, 7.42; N, 6.87. Found: C,
58.77; H, 7.71; N, 6.81.
3-Benzyl-(S)-4-methyl-oxazolidin-2-one (13)
23
Rf 0.69 (CH2Cl2 acetone, 20:1); [ ]D
23 (c 0.93, MeOH).
1H NMR: = 1.22 (d, 3 H, J = 6 Hz, CH3), [3.7 (m, 1 H), 3.85 (dd,
1 H) and 4.37 (dd, 1 H); AMX system JAM = 8.5 Hz, JAX = 7 Hz,
MS: m/z = 211.9 (10, M + H), 166.0 (100) 148, 147, 146 cluster
(10).
JMX = 8.5 Hz, CHCH2], 4.11 and 4.79 (2 d, 2 1 H, AB system, J
= 15 Hz, benzyl H), 7.25 7.3 (m, 5 H, phenyl H).
3-Benzyl-(S)-4-methyl-[1,2,3]-oxathiazolidine-2,2-dioxide (9)
Crude 7 (27.8 g) afforded 12.2 g of crystalline 9 (33.5% from 5,
77% this step). After removal of the ice bath, the mixture turned
brown/red.
MS: m/z = 192 (100, M + H).
Anal. Calcd for C11H13NO2: C, 69.09; H, 6.85; N, 7.32. Found: C,
69.25; H, 6.95; N, 7.35.
[ ]D23 +25 (c 0.86, MeOH); mp 64.5 66 °C.
Chiral chromatography of 9 on a Chiracel® OD column (Rt 8.60
(R)-N-Benzyl-2-amino-1-fluoropropane (12)
Procedure was identical to that used to synthesize 11.
1H NMR (CDCl3): identical to 11.
19F NMR (CDCl3): 225.22 (td, J1 = 48 Hz, J2 = 17 Hz, additional
splitting J = 1.5 Hz due to coupling to CH3 group is observed).
min) demonstrated >99.5% ee.
1H NMR (CDCl3): =1.21 (d, 3 H, J = 6 Hz, CH3), [3.74 (m, 1 H),
4.13 (dd, 1 H) and 4.57 (dd, 1 H); AMX system JAM = 8 Hz, JAX = 7
Hz, JMX = 6.5 Hz, CHCH2], 4.22 and 4.41 (dd, 2 1 H each, AB sys-
tem, J = 15 Hz, benzyl H), 7.3 7.45 (m, 5 H, phenyl H).
MS: m/z = 168 (40, M + H), 90.9 (100).
12 HCl
MS: m/z = 249.9 (100, M + Na), 227.9 (20, M + H).
23
[ ]D
6.9 (c 0.58, MeOH); mp 160.5 162 °C.
Anal. Calcd for C10H13NO3S: C, 52.84; H, 5.77; N, 6.16. Found: C,
52.82; H, 6.01; N, 6.13.
Anal. Calcd for C10H15ClFN: C, 58.97; H, 7.42; N, 6.87. Found: C,
58.88; H, 7.55; N, 6.70.
3-Benzyl-(R)-4-methyl-[1,2,3]-oxathiazolidine-2,2-dioxide (10)
Crude 8 (18.7 g) afforded 9.05 g of 10 (36.5% from 6, 52% this
step).
3-Benzyl-(R)-4-methyl-oxazolidin-2-one (14)
Rf 0.69 (CH2Cl2 acetone, 20:1); [ ]D23 +19.9 (c 1.23, MeOH).
23
[ ]D
29.3 (c 1.07, MeOH); mp 65 66 °C.
1H NMR (CDCl3): spectrum identical to 13.
Chiral chromatography of 10 on a Chiracel® OD column (Rt 10.73
min) demonstrated >99.5% ee.
1H NMR (CDCl3): spectrum was identical to 9.
MS: m/z = 214.0 (100, M + Na), 192.0 (70, M + H).
HRMS: m/z calcd for C11H14NO2, 192.10245; found, 192.1023.
Anal. Calcd for C11H13NO2: C, 69.09; H, 6.85; N, 7.32. Found: C,
69.09; H, 6.99; N, 7.20.
MS: m/z = 249.9 (10, M + Na).
Anal. Calcd for C10H13NO3S: C, 52.84; H, 5.77; N, 6.16. Found: C,
52.91; H, 6.00; N, 6.14.
Formation of (13) and (14)
Control reactions A, B, and C were monitored by reverse phase
HPLC. In control reaction (A), 9 (0.1 g, 0.44 mmol) and bis(tetra-
ethylammonium)carbonate (0.16 g,.48 mmol) were dissolved in
CH3CN. After hydrolysis and neutralization (Na2CO3), 5 was isolat-
ed (73 mg, 92%). In control reaction (B), standard hydrolysis con-
ditions were applied to amino alcohol 5 in the presence of 1 equiv
TBAF. In control reaction (C), 11 HCl (45 mg, 0.22 mmol) was
treated with the standard hydrolysis conditions. The acid was neu-
tralized using NaHCO3, Na2CO3 was added (to pH 10 12) after 40
(S)-N-Benzyl-2-amino-1-fluoropropane (11)
TBAF (1.2 mL of a 1.0 M soln in THF) was dried and the residue
was dissolved in anhyd CH3CN (5 mL). Compound 9 (0.25 g, 1.1
mmol) was added and the mixture was stirred for 30 min at r.t. TLC
indicated complete conversion of 9 to non-mobile material. After
solvent removal, the formed NSO3 intermediate was hydrolyzed by
treating with 20% H2SO4(aq) Et2O (1:1, 20 mL/g of sulfamidate).
The mixture was stirred for 2 h at r.t. and then the organic phase
Synthesis 2002, No. 6, 766–770 ISSN 0039-7881 © Thieme Stuttgart · New York

770
J. J. Posakony, T. J. Tewson
PAPER
The Mosher amide was prepared in the same manner as for 2b.
1H NMR (CDCl3): = 1.30 (dd, 3 H, J1 = 7 Hz, J2 = 1 Hz, CH3),
3.37 (q, J = 1.5 Hz, OCH3), 4.2 4.6 (m, 3 H, CHCH2F), 6.9 (br s, 1
H, NH), 7.4 and 7.55 (m, 5 H, phenyl H).
min and the mixture stirred for 3 h. The product was extracted into
Et2O (2 10 mL), the solvent was dried (Na2SO4) and the mixture
was chromatographed using CH2Cl2 acetone, 20:1 to afford 13 (25
mg, 60%).
19F NMR (CDCl3):
Hz).
= 69.19 (s), 231.9 (td, J1 = 47 Hz, J2 = 27
(S)-1-Methyl-2-fluoroethylamine HCl salt (2b HCl)
Adapting the conditions described by ElAmin et al.,20 11 (3.5 g, 21
mmol) was treated with 10% Pd/C (0.5 g) and HCOOH (4 mL, 0.11
mol) in MeOH (250 mL). After stirring for 3.5 h at r.t., the reaction
was complete (TLC). The mixture was filtered over celite followed
MS: m/z = 294 (25, M + H), 316 (100, M + Na).
by a MeOH rinse (50 mL). The solvent was removed under reduced Acknowledgement
pressure to yield 2.97 g of crude 2b HCOOH. The crude product
We would like to thank Dr. John Grierson for many useful discus-
sions and the National Institutes of Health for funding: Grants
HL60221 and HL36728.
was dissolved in MeOH (10 mL) and then was treated with HCl(g).
MeOH was repeatedly added and then removed under reduced pres-
sure (5 20 mL); the residual solid was then dissolved in a mini-
mum amount of MeOH and was precipitated by adding EtOAc,
yielding 1.93 g (81%) of 2b HCl. An analytical sample was recrys-
tallized again from MeOH EtOAc.
References
(1) Tewson, T. J.; Kinsey, B. M.; Franceschini, M. P. J.
Labelled Compd. Radiopharm. 1991, 30, 385.
(2) Kinsey, B. M.; Tewson, T. J. J. Labelled Compd.
Radiopharm. 1991, 30, 373.
(3) Kinsey, B. M.; Barber, R.; Tewson, T. J. J. Labelled Compd.
Radiopharm. 1993, 32, 298.
[ ]D 23 = +12.7 (c 1.01, MeOH); mp 127 127.5 °C.
1H NMR (CD3OD): 1.32 (dd, 3 H, J1 = 7 Hz, J2 = 1.5 Hz, CH3),
[3.55 3.70 (m, 1 H), (4.44 (dd) and 4.63 (dd), 2 H total, each split
by JHF = 47 Hz); ABX pattern JAB = 10.5 Hz, JAX = 6.5 Hz, JBX = 3
Hz, CHCH2F].
19F NMR (CD3OD): 230.94 (td, J1 = 47 Hz, J2 = 19 Hz); addition-
al splitting was observed in each of the peaks, J = 1.5 Hz.
(4) Tewson, T. J.; Stekhova, S. J. Labelled Compd.
Radiopharm. 1997, 40, 58.
(5) Tewson, T. J.; Stekhova, S.; Kinsey, B.; Chin, L.; Wiens, L.;
Barber, R. Nucl. Med. Biol. 1999, 26, 891.
(6) Posakony, J. J.; Tewson, T. J. J. Labelled Compd.
Radiopharm. 1999, 42, S527.
MS: m/z = 78 (100, M + H).
Anal. Calcd for C3H9ClFN: C, 31.73; H, 7.99; N, 12.33. Found: C,
31.88; H, 8.04; N, 12.24.
(7) Albert, R.; Dax, K.; Stütz, A. E. Tetrahedron Lett. 1983, 24,
1763.
(8) Torii, T.; Tsuchiya, T.; Umezawa, S. Carbohydr. Res. 1983,
116, 289.
(9) Lyle, T. A.; Magill, C. A.; Pitzenberger, S. M. J. Am. Chem.
Soc. 1987, 109, 7890.
(10) Okuda, M.; Tomioka, K. Tetrahedron Lett. 1994, 35, 4584.
(11) Stiasny, H. C. Synthesis 1996, 259.
(12) Aguilera, B.; Fernandez-Mayoralas, A.; Jaramillo, C.
Tetrahedron 1997, 53, 5863.
(13) Zubovics, A.; Toldy, L.; Varro, A.; Rabloczky, G.; Kürthy,
M.; Dvortsak, P.; Jerkovich, G.; Tomori, E. Eur. J. Med.
Chem. 1986, 21, 370.
(14) Lohray, B. B.; Bhushan, V. In Advances in Heterocyclic
Chemistry, Vol. 68; Katritzky, A. R., Ed.; Academic Press:
San Diego, 1997, 89.
The Mosher amide of 2 was prepared by adding 2 HCl (46 mg, 0.40
mmol) to a soln of (S)-( )- -methoxy- -(trifluoromethyl)pheny-
lacetic acid (0.23 g, 0.925 mmol), benzotriazol-1-yloxy-tris(dime-
thylamino)phosphonium hexafluorophosphate (0.438 g, 0.99
mmol), and diisopropyethylamine (0.28 mL, 1.6 mmol) in DMF (2
mL) at 0 °C in a 5 mL round bottom flask to minimize loss of the
potentially volatile fluoroamine. The soln was stirred for 24 h al-
lowing the soln to gradually warm to r.t., the solvent was removed
and the product isolated by chromatography (EtOAc-hexanes, 1:1,
Rf 0.57) to yield 0.116 mg (quantitative yield).
1H NMR (CDCl3): = 1.26 (dd, 3 H, J1 = 7 Hz, J2 = 1 Hz, CH3),
3.44 (q, J = 1.5 Hz, OCH3), 4.2 4.6 (m, 3 H, CHCH2F), 6.95 (br s,
1 H, NH), 7.4 and 7.55 (m, 5 H, phenyl H).
19F NMR (CDCl3):
Hz).
= 69.10 (s), 232.3 (td, J1 = 47 Hz, J2 = 27
(15) Ok, D.; Fisher, M. H.; Wyvratt, M. J.; Meinke, P. T.
Tetrahedron Lett. 1999, 40, 3831.
MS: m/z = 294 (25, M + H), 316 (100, M + Na).
(16) Abdelkafi, M. M.; Baklouti, A. Bull. Soc. Chim. Fr. 1979,
1044.
(17) White, G. J.; Garst, M. E. J. Org. Chem. 1991, 56, 3177.
(18) Alker, D.; Doyle, K. J.; Harwood, L. M.; McGregor, A.
Tetrahedron: Asymmetry 1990, 1, 877.
(R)-1-Methyl-2-fluoroethylamine HCl salt (3b HCl)
N-Benzylfluoroamine 12 (2.7 g, 16 mmol) was debenzylated via
transfer hydrogenation as for 2b, to afford 1.69 g (94%) of 3b HCl.
An analytical sample was obtained by recrystallization from
MeOH EtOAc.
(19) Lim, J. L.; Zheng, L.; Berridge, M. S.; Tewson, T. J. Nucl.
Med. Biol. 1996, 23, 911.
23
[ ]D
14.9 (c 1.10, MeOH); mp 127 128 °C.
1H NMR (CD3OD): spectrum identical to 2b HCl.
(20) ElAmin, B.; Anantharamaiah, G. M.; Royer, G. P.; Means,
G. E. J. Org. Chem. 1979, 44, 3442.
(21) Leskovsek, V.; Urleb, U. Synth. Commun. 1994, 24, 1415.
(22) Hunt, J. H.; McHale, D. J. Chem. Soc. 1957, 2073.
19F NMR (CD3OD):
= 231.4 (td; identical coupling constants as
observed for 2b HCl).
Anal. Calcd for C3H9ClFN: C, 31.73; H, 7.99; N, 12.33. Found: C,
31.97; H, 8.14; N, 12.26.
Synthesis 2002, No. 6, 766–770 ISSN 0039-7881 © Thieme Stuttgart · New York