Convenient synthesis of enantiopure (R-) and (S-)-3-fluoro-3- aminomethylpyrrolidines

Article abstract of DOI:10.1016/j.tet.2014.03.002

(R-)- and (S-)-3-fluoro-3-aminomethylpyrrolidines were synthesized from methyl α-fluoroacrylate in eight steps. α-Phenylethylamine was used as a chiral auxiliary to separate the racemic mixture. The overall synthesis yield was 31%.

Full text of DOI:10.1016/j.tet.2014.03.002

Tetrahedron xxx (2014) 1e7
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Convenient synthesis of enantiopure (R-) and (S-)-3-fluoro-3-
aminomethylpyrrolidines
,
,
,b,
*
Vladimir S. Yarmolchuk a b, Vladimir L. Mykhalchuk a b, Pavel K. Mykhailiuk a
a Enamine Ltd, Vul. Oleksandra Matrosova 23, 01103 Kyiv, Ukraine
b Department of Chemistry, Kyiv National Taras Shevchenko University, Vul. Volodymyrska 64, 01033 Kyiv, Ukraine
a r t i c l e i n f o
a b s t r a c t
Article history:
(R-)- and (S-)-3-fluoro-3-aminomethylpyrrolidines were synthesized from methyl
eight steps. -Phenylethylamine was used as a chiral auxiliary to separate the racemic mixture. The
overall synthesis yield was 31%.
a-fluoroacrylate in
Received 17 December 2013
Received in revised form 17 February 2014
Accepted 3 March 2014
Available online xxx
a
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Diamines
Fluorine
Pyrrolidine
Cycloaddition
[3þ2]
Drug design
1. Introduction
Therefore, to synthesize diamine 1, we decided to take advan-
tage of this strategy and to use similar transformations7,8 to con-
struct the needed 3-fluoropyrrolidine skeleton. On the other hand,
to obtain the individual enantiomers of 1, we planned to use a chiral
Fluorinated pyrrolidines play a role in medicinal chemistry as
components of bioactive compounds.1 Replacing Fluorine for Hy-
drogen in organic molecules can alter their biological activity due to
the changes in conformation, acidity/basicity of the neighboring
functional groups and enhanced metabolic stability.2,3 Recently,
auxiliaryda-phenylethylamine, which might enable separation of
the corresponding diastereomeric mixtures. Several strategies to
synthesize the target compounds R-(1) and S-(1) were suggested
(Scheme 2).
a
fragment of 3-fluoro-3-aminomethylpyrrolidine (1) was
employed in several medicinal projects, however, in the form of
a racemic mixture (Fig. 1, a).4 To the best of our knowledge the
individual enantiomers of 1 still remain unknown. In this context,
our motivation in this work was to develop a practical synthetic
approach to isomers (R)-1 and (S)-1 (Fig. 1, b).
2.2. Synthesis
Having the retrosynthetic principles described above in mind
we started the synthesis of the target molecules.
2. Results and discussion
2.1. Retrosynthetic analysis
2.2.1. Strategy A. This approach commenced from fluo-
ropyrrolidine 4, which was obtained by [3þ2]-cycloaddition of
compound 29 with alkene 3 in dichloromethane in the presence of
trifluoroacetic acid (Scheme 1).6 Basic hydrolysis of the ester group
in 4 gave acid 5 in 75% yield. Finally, crystallization of racemic acid 5
b
-Substituted pyrrolidines can be efficiently obtained by [3þ2]
cycloaddition between electron-deficient alkenes and azomethine
ylides.5 In particular, recently we reported acid-catalyzed reaction
of 2 with methyl 2-fluoroacrylate (3) to afford pyrrolidine 4 in 95%
yield (Scheme 1).6
with (R)-a-phenylethylamine was attempted following the litera-
ture protocol, described previously to resolve similar substrates.10
Unfortunately, this method did not work out for salt 6, which was
obtained as a stoichiometric mixture of isomers (Scheme 3).
Next, we decided to make the nitrogen atom in 5 non-basic by
protecting it with a carbamate moiety (Boc, Cbz).11 Hydrogenation
of N-benzyl group in 5 using 10% Pd/C gave amino acid 7.6
* Corresponding author. E-mail addresses: Pavel.Mykhailiuk@gmail.com, Pavel.
Mykhailiuk@mail.enamine.net (P.K. Mykhailiuk).
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.03.002
Please cite this article in press as: Yarmolchuk, V. S.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.03.002

2
V.S. Yarmolchuk et al. / Tetrahedron xxx (2014) 1e7
(a)
(b)
Fig. 1. (a) Bioactive derivatives of racemic 3-fluoro-3-aminomethylpyrrolidine (1).4 (b) Individual enantiomers R-(1) and S-(1).
7 by Cbz-moiety (10) followed by crystallization with (R)-a-phen-
ylethylamine was not effective either to afford a mixture of isomers
11. At this point, we decided to stop our efforts on strategy A and to
challenge strategy B.
2.2.2. Strategy B. The synthesis started from compound 12 that
was obtained from (R)-
a-phenylethylamine following the literature
Scheme 1. Literature synthesis of compound 4 (our results described in Ref. 6).
protocol.12 In fact, addition of trifluoroacetic acid to a solution of
Scheme 2. Retrosynthetic analysis of enantiomerically pure diamine 1.
Ph
-
CO2Me
CO2H
F
CO2
F
Ph
+H3N
H2N
NaOH
F
MeOH
H2O
N
N
THF
quant.
N
75%
Ref. 6
Ph
Ph
Ph
4
5
6
Scheme 3. Synthesis of salt 6.
Treatment of 7 with Boc2O under basic conditions provided N-Boc
amino acid 8. Crystallization of racemic acid 8 with (R)- -phenyl-
ethylamine was performed, again providing salt 9 as a stoichio-
compound 12 and ester 3 afforded pyrrolidine 13 in 92% yield
(Scheme 5). No chiral induction was observed in the reaction: the
product was obtained as 1/1 mixture of diastereomers. Separation
of isomers by column chromatography was not possible at this step.
a
metric isomeric mixture (Scheme 4). Protection of nitrogen atom in
Please cite this article in press as: Yarmolchuk, V. S.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.03.002

V.S. Yarmolchuk et al. / Tetrahedron xxx (2014) 1e7
3
Scheme 4. Synthesis of salts 9 and 11.
CO2Me
CO2Me
F
CO2H
CONH2
F
SiMe3
Ph
MeO
*
*
*
F
3
NaOH
CDI, (NH4)2CO3
F
N
TFA [cat.]
CH2Cl2
N
N
MeOH/H2O
95%
N
THF
96%
Ph
Ph
Ph
92 %
12
13
15
16
LiAlH4
OR
BH3*Me2S
LiAlH4
THF
88 %
OH
F
NH2
F
*
*
N
N
Ph
14
Ph
17
Scheme 5. Synthesis of diastereomic mixtures 13, 14, 16.
Next, reduction of ester 13 with LiAlH4 smoothly provided alcohol
14. Separation of diastereomers of 14 by column chromatography
was not effective, however. Therefore, we performed basic hydro-
lysis of the ester group in 13 to afford acid 15. The carboxylic
function in 15 was then converted into eCO2NH2 one (16), again
with no success at the separation of diastereomers by column
chromatography. Unexpectedly, reduction of amide 16 into amine
17 with either BH3*Me2S or LiAlH4 led to complex mixtures that did
not have fluorine atom according to 19F NMR. Therefore, we made
a decision to stop our efforts on strategy B and to test strategy C.
separated by column chromatography on a small scale. The ster-
eoconfiguration of obtained compounds was determined by crys-
tallographic analysis of isomer 18a (Fig. 2).13 We mentioned that
even though the compound 18a was crystalline, its isomer 18b was
an oil. Therefore, we came up with an idea to separate the isomers
by crystallization that is useful when working on a large scale. In
fact, crystallization of the mixture 18a/18b¼50/50 from diethyl
ether gave the crystalline material 18a/18b¼95/5 (Supplementary
data). The second crystallization of this batch provided the pure
isomer 18a (18a/18b>98/2). Using this strategy, we were able to
easily obtain 7 g of pure isomer 18a from 20 g of the mixture 18a/
18b by double crystallization. The other isomer 18b was obtained
by column chromatography of the mother liquor.
2.2.3. Strategy C. For coupling of (R)-a-phenylethylamine we used
first the N-Boc protected acid 8. The reaction was performed in the
presence of CDI as an activation agent to give product 18 in 80%
yield (Scheme 6). Stereoisomers 18a/18b were subsequently
Reduction of the amide bond in 18a by BH3*Me2S gave amine
19a in 97% yield. Finally, cleavage of N-phenylethyl residue by
Scheme 6. Synthesis of individual isomers 18a and 18b.
Please cite this article in press as: Yarmolchuk, V. S.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.03.002

4
V.S. Yarmolchuk et al. / Tetrahedron xxx (2014) 1e7
downfield from TMS (1H, 13C) or C6F6 (19F) as external standards. MS
analyses were done on an LCMS instrument with chemical ioniza-
tion (CI) or GCeMS instrument with electron impact ionization (EI).
4.1. (1S)-1-Phenylethanaminium 1-benzyl-3-fluoropyrrolidine-
3-carboxylate (6)
A solution of (R)-a-phenylethylamine (0.65 g, 5.405 mmol,
1.0 equiv) in dry THF (15 mL) was slowly added to a stirred so-
lution of 5 (1.20 g, 5.405 mmol, 1.0 equiv) in dry THF (15 mL) at
0
ꢀC. Then reaction mixture was stirred for an additional 1 h at
room temperature. The solvent was evaporated under vacuum to
afford the pure salt 6 (1.85 g, 5.405 mmol, 100% yield) as a color-
less oil.
Fig. 2. X-ray crystal structures of compound 18a.
1H NMR (500 MHz; D2O, Me4Si; 2 diastereoisomers are present)
hydrogenolysis of 19a at 60 ꢀC under 30 atm over 10% Pd/C as
a catalyst afforded the target N-protected diamine Boc-(R)-1 in 90%
yield (Scheme 7). Isomer Boc-(S)-1 was similarly synthesized from
compound 18b in 87% over two steps. The both isomers Boc-(R)-1
and Boc-(S)-1 had >95% ee as determined by Mosher reagent.14
d: 1.50 (s, 3H, CH3), 2.35 (m, 1H), 2.53 (m, 1H), 3.49e3.59 (m, 4H),
4.29 (m, 2H), 4.42 (m, 1H, CHCH3), 7.27e7.41 (10H, 2C6H5).
13C NMR (125 MHz; D2O; Me4Si; 2 diastereoisomers are pres-
ent),
d
: 19.1 (s, CH3), 35.5 (d, J¼27 Hz), 52.9 (s), 58.8 (s), 61.9 (d,
Ph
O
Ph
NH
NH2
NH
H2/Pd
BH3*Me2S
F
F
F
THF
MeOH
N
N
N
97%
90%
Boc
Boc
Boc
Boc-(R)-1
18a
19a
F
F
F
H
H
NH2
H2/Pd
Ph
N
Ph
N
BH3*Me2S
MeOH
90%
THF
96%
N
O
N
N
Boc
Boc
Boc
18b
Boc-(S)-1
19b
Scheme 7. Synthesis of optically active diamines Boc-(R)-1 and Boc-(S)-1.
3. Summary
J¼39 Hz), 79.6 (d, J¼39 Hz), 101.2 (m, CF), 125.9 (s, C6H5), 126.8 (s,
C6H5), 127.5 (s, C6H5), 128.1 (s, C6H5), 128.9 (s, C6H5), 128.6 (s, C6H5),
133.7 (s, C6H5), 142.1 (s, C6H5), 173.5 (m, COꢁ2 ).
We have developed a practical route to the novel enantiopure
diamines Boc-(R)-1 and Boc-(S)-1. The synthesis was performed in
eight steps in 31% overall yield. The key reaction was [3þ2]-
cycloaddition between N-benzyl azomethine ylide and methyl 2-
fluoroacrylate (3). Separation of diastereomeric mixture 18a/18b
was effectively performed by crystallization. The obtained com-
pounds are expected to be interesting for medicinal chemistry
(modules for quinolone antibiotics),8c,d agrochemistry and orga-
nocatalysis (to study the role of fluorine gauche effects).15
19F NMR (477 MHz; D2O; C6F6; 2 diastereoisomers are present)
d
: ꢁ150.0 (m).
[
a
]
D
20ꢁ9.88ꢀ (c 0.920 g/100 mL, MeOH).
4.2. (1S)-1-Phenylethanaminium 1-(tert-butoxycarbonyl)-3-
fluoropyrrolidine-3-carboxylate (9)
A solution of (R)-a-phenylethylamine (0.62 g, 5.125 mmol,
1.0 equiv) in dry THF (15 mL) was slowly added to a stirred so-
4. Experimental part
lution of 8 (1.21 g, 5.125 mmol, 1.0 equiv) in dry THF (15 mL) at
0
ꢀC. Then reaction mixture was stirred for an additional 1 h at
Solvents were purified according to the standard procedures. All
reactions were performed in argon atmosphere. Compounds 4, 5, 7,
8 were synthesized according to our preliminary communication.6
All the other reagents were provided by Enamine LTD. Column
chromatography was performed using Kieselgel Merck 60
(230e400 mesh) as the stationary phase. 1H-, 19F-, 13C NMR spectra
were recorded on Bruker Avance 500 spectrometer (at 499.9 MHz,
470.3 MHz, and 124.9 MHz). Chemical shifts are reported in ppm
room temperature. The solvent was evaporated under vacuum to
afford the pure salt 9 (1.82 g, 5.125 mmol, 100% yield) as a white
oil.
1H NMR (500 MHz; D2O, Me4Si; 2 diastereoisomers are present)
d: 1.33 (s, 9H, C(CH3)3), 1.55 (s, 3H, CH3), 2.20 (m, 2H), 3.32 (m, 1H),
3.58 (m, 3H), 4.42 (m, 1H, CHCH3), 7.37 (5H, C6H5).
13C NMR (125 MHz; D2O; Me4Si; 2 diastereoisomers are pres-
ent), d: 18.9 (s, CH3), 27.3 (s, C(CH3)3), 34.5 (m), 44.2 (2m), 50.6 (s),
Please cite this article in press as: Yarmolchuk, V. S.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.03.002

V.S. Yarmolchuk et al. / Tetrahedron xxx (2014) 1e7
5
54.7 (s), 81.3 (s), 100.7 (m, CF), 126.0 (s, C6H5), 128.8 (s, C6H5), 137.3
(s, C6H5), 144.2 (s, C6H5), 155.7 (s, COC]O), 174.9 (m, CO-2).
19F NMR (477 MHz; D2O; C6F6; 2 diastereoisomers are present)
organic phase was washed with saturated solution of NaCl
(250ꢂ3 mL), separated and dried over anhydrous Na2SO4. The
solvent was removed under reduced pressure on a rotary evapo-
rator. The residue was purified by column chromatography using
hexane/EtOAc¼3/1 mixture as eluent to give the pure product 13
(35.3 g, 0.14 mol, 92% yield) as a colorless oil. Rf¼0.5.
d
: ꢁ149.7 (m).
MS (CI, m/z): uninformative.
[
a]
20 ꢁ10.08ꢀ (c 1.003 g/100 mL, MeOH).
D
1H NMR (500 MHz; CDCl3, Me4Si; 2 diastereoisomers are present)
4.3. 1-[(Benzyloxy)carbonyl]-3-fluoropyrrolidine-3-carboxylic
d: 1.37e1.40 (m, 3H, CHCH3), 2.12e2.28 (m, 1H), 2.33e2.51 (m, 2H),
acid (10)
2.68e2.79 (m, 1H), 2.83e3.02 (m, 1H), 3.05e3.12 (m, 1H), 3.28e3.37
(m, 1H), 3.76e3.79 (m, 3H, OCH3), 7.20e7.33 (m, 5H, C6H5).
13C NMR (125 MHz; CDCl3; Me4Si; 2 diastereoisomers are
Triethylamine (8.70 g, 0.086 mol, 2.3 equiv) and a solution of
benzyl chloroformate (7.1 g, 0.041 mol, 1.1 equiv) in THF (25 mL)
were consequentially added dropwise to an ice-cold suspension of
7 (5.0 g, 0.037 mol,1 equiv) in anhydrous THF (75 mL). The obtained
mixture was stirred for 5 h at room temperature. Then the reaction
mixture was diluted with saturated solution of NaHCO3 (100 mL)
and extracted with EtOAc (3ꢂ50 mL). The organic phase was
washed with water (50 mL) and saturated solution of NaCl
(3ꢂ50 mL), then separated and dried over anhydrous Na2SO4. After
that, the solvent was removed under reduced pressure to afford the
pure compound 10 (7.30 g, 0.027 mol, 73% yield) as a yellow solid.
present),
d: 23.0 (CH3), 36.9, 51.6, 52.8, 62.6, 65.0, 99.9 (m,
JCF¼193 Hz, CF), 127.0 (s, C6H5), 127.2 (s, C6H5), 128.4 (s, C6H5), 144.7
(s, C6H5), 171.4 (s, C]O).
19F NMR (477 MHz; CDCl3; C6F6; 2 diastereoisomers are present)
d
: ꢁ148.2 (ꢁ147.6) (m, J¼26 Hz).
Anal. Calcd for C14H18FNO2: C, 66.91; H, 7.22; N, 5.57. Found: C,
66.84; H, 7.35; N, 5.42.
LCeMS: 252 (Mþ).
[a
]
20 þ17.03ꢀ (c 0.702 g/100 mL, MeOH).
D
Mp¼99e100 ꢀ
.
4.6. {3-Fluoro-1-[(1R)-1-phenylethyl]pyrrolidin-3-yl}metha-
nol (14)
1H NMR (500 MHz; CDCl3, Me4Si; 2 conformers are present)
d:
2.36e2.56 (m, 2H), 3.64 (m, 1H), 3.81e3.98 (m, 3H), 5.17 (s, 2H,
CH2O), 7.27e7.37 (m, 5H, Ph), 8.45 (br s, 1H, OH).
In a two-necked flask were charged 150 mL of freshly distilled
THF and LiAlH4 (3.1 g, 0.082 mol, 1.1 equiv). The reaction mixture
was cooled to 0 ꢀC and the solution of 13 (19.0 g, 0.075 mol, 1 equiv)
in THF (150 mL) was carefully added dropwise. Then the reaction
mixture was warmed to room temperature and stirred for an ad-
ditional 4 h. After that the reaction mixture was cooled to 0 ꢀC and
20 mL of THF/water¼9/1 was carefully added. After stirring for
10 min the mixture was filtered through a Buchner funnel and the
solid was washed twice with 150 mL of CH2Cl2. The combined or-
ganic phase was dried over Na2SO4 and evaporated under vacuum
to give 14 (14.8 g, 0.066 mol, 88% yield) as a yellow oil.
13C NMR (125 MHz; CDCl3; Me4Si; 2 conformers are present),
d:
35.3 (dd, 1J¼89 Hz, 2J¼23 Hz), 44.7 (d, J¼39 Hz), 55.1 (q, J¼27 Hz)
67.7 (s, CH2O), 98.2 (q, JCF¼100 Hz), 128.0 (s, C6H5), 128.3 (s, C6H5),
128.6 (s, C6H5), 136.0 (s, C6H5), 154.9 (2s, OCOBn), 171.7 (m, COOH).
19F NMR (477 MHz; CDCl3; C6F6; 2 conformers are present)
d:
ꢁ159.5 (ꢁ159) (2m).
Anal. Calcd for C13H14FNO4: C, 58.42; H, 5.28; N, 5.24. Found: C,
58.54; H, 5.33; N, 5.38.
LC-MS: 266 (Mꢁ1ꢁ).
4.4. (1S)-1-Phenylethanaminium 1-[(benzyloxy)carbonyl]-3-
fluoropyrrolidine-3-carboxylate (11)
1H NMR (500 MHz; CDCl3, Me4Si; 2 diastereoisomers are pres-
ent) d: 1.38e1.41 (m, 3H, CHCH3), 1.70 (br s, 1H), 1.95e2.14 (m, 3H),
2.65e2.87 (m, 3H), 3.26e3.32 (m, 1H), 3.65e3.75 (m, 2H),
7.24e7.35 (m, 5H, C6H5).
A
solution of (R)-a-phenylethylamine (0.49 g, 4.1 mmol,
1.0 equiv) in dry THF (15 mL) was slowly added to a stirred solution
of 10 (1.1 g, 4.1 mmol, 1.0 equiv) in dry THF (15 mL) at 0 ꢀC. The
reaction mixture was stirred for an additional 1 h at room tem-
perature. The solvent was evaporated under vacuum to afford the
pure salt 9 (1.59 g, 4.1 mmol, 100% yield) as a white oil.
13C NMR (125 MHz; CDCl3; Me4Si; 2 diastereoisomers are
present),
d
: 22.7, 33.8 (d, J¼9 Hz), 51.3, 60.6, 65.4 (s), 66.9 (d,
J¼10 Hz), 103.8 (d, JCF¼178 Hz, CF), 127.13 (s, C6H5), 127.17 (s, C6H5),
128.4 (s, C6H5), 144.6 (C6H5).
19F NMR (477 MHz; C6F6; Me4Si; 2 diastereoisomers are present)
1H NMR (500 MHz; D2O, Me4Si; 2 diastereoisomers are present)
d
: ꢁ150.5 (ꢁ149.8) (m, J¼23 Hz).
d
: 1.53 (s, 3H, CH3), 2.14e2.35 (m, 2H), 3.41 (m, 1H), 3.65 (m, 3H),
Anal. Calcd for C13H18FNO: C, 69.93; H, 8.13; N, 6.27. Found: C,
4.42 (m, 1H, CHCH3), 5.02 (s, 2H, CH2Ph), 7.29e7.38 (10H, 2C6H5).
69.88; H, 8.19; N, 6.32.
13C NMR (125 MHz; D2O; Me4Si; 2 diastereoisomers are pres-
LCeMS: 224 (Mþ).
ent), d: 19.1 (s, CH3), 34.5 (m), 44.2 (2m), 50.5 (s), 54.9 (s), 66.8 (s),
[a
]
20 þ12.52ꢀ (c 0.78 g/100 mL, MeOH).
D
100.7 (m, CF), 126.0 (s, C6H5), 127.2 (s, C6H5), 127.8 (s, C6H5), 128.2 (s,
C6H5), 128.5 (s, C6H5), 128.7 (s, C6H5), 135.7 (s, C6H5), 144.3 (s, C6H5),
155.4 (s, COC]O), 174.5 (m, COꢁ2 ).
4.7. 3-Fluoro-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic
acid (15)
19F NMR (477 MHz; D2O; C6F6; 2 diastereoisomers are present)
d
: ꢁ149.8 (m).
[
a]
20 ꢁ10.08ꢀ (c 1.003 g/100 mL, MeOH).
A solution of NaOH (1.2 g, 0.03 mol, 1.07 equiv) in H2O (50 mL)
was added dropwise over a period of 15 min to a stirred solution of
13 (7.0 g, 0.028 mol,1 equiv) in MeOH (100 mL)/H2O (50 mL) at 0 ꢀC.
After the addition was complete the reaction mixture was stirred at
room temperature for 7 h. MeOH was evaporated under vacuum,
and the aqueous phase was extracted with Et2O (3 x 100 mL). The
aqueous phase was acidified with 6 N HCl at 5 ꢀC to adjust the pH of
the reaction mixture to pH 3. Saturated aq NH3 solution (100 mL)
was added and the aqueous phase was extracted with EtOAc
(3ꢂ100 mL). The combined organic phase was dried over Na2SO4
and evaporated under vacuum to give acid 15 (6.28 g, 0.026 mol,
95% yield) as a white semisolid.
D
4.5. Methyl 3-fluoro-1-[(1R)-1-phenylethyl]pyrrolidine-3-
carboxylate (13)
A solution of TFA (1.8 g, 0.015 mol, 0.1 equiv) in dry CH2Cl2
(150 mL) was slowly added to a stirred solution of (R)-12 (40.0 g,
0.159 mol, 1.03 equiv) and methyl 2-fluoroacrylate 3 (16.0 g,
0.153 mol, 1 equiv) in dry CH2Cl2 (250 mL) at 0 ꢀC. (CAUTION:
exothermic reaction!) The reaction mixture was stirred for an ad-
ditional 5 h at room temperature. The reaction mixture was neu-
tralized by adding a saturated aqueous solution of NaHCO3. The
Please cite this article in press as: Yarmolchuk, V. S.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.03.002

6
V.S. Yarmolchuk et al. / Tetrahedron xxx (2014) 1e7
1H NMR (500 MHz; D2O, Me4Si; 2 diastereoisomers are present)
: 1.62 (m, 3H, CHCH3), 2.26e2.56 (m, 2H), 3.27e2.42 (m, 2H), 3.53
13C NMR (125 MHz; CDCl3; Me4Si; 2 conformers are present),
d:
d
21.9(s, CH3), 28.5(s, C(CH3)3), 35.0 (m), 44.5 (2s), 49.0 (s), 55.2 (s), 79.9
(s, C(CH3)3), 101.7 (d, JCF¼193 Hz, CF), 126.0 (s, C6H5), 127.7 (s, C6H5),
128.8 (s, C6H5), 142.4 (s, C6H5), 154.1 (s, HNC]O), 167.5 (m, CONCH2).
(m, 1H), 3.69 (m, 1H), 4.32 (m, 1H), 7.40e7.44 (m, 5H, C6H5).
13C NMR (125 MHz; D2O; Me4Si; 2 diastereoisomers are pres-
ent),
d
: 17.8 (d, J¼12 Hz), 35.0 (d, J¼25 Hz), 51.8 (s), 60.8 (m), 65.8
19F NMR (477 MHz; CDCl3; C6F6; 2 conformers are present)
d:
2
(s), 98.5 (dd, 1JCF¼194 Hz, JCF¼19 Hz, CF), 127.5 (s, C6H5), 129.1 (s,
ꢁ158.1 (ꢁ158.7) (2m).
C6H5), 129.5 (s, C6H5), 135.9 (s, C6H5), 173.3 (m, C]O).
Anal. Calcd for C18H25FN2O3: C, 64.27; H, 7.49; N, 8.33. Found: C,
64.30; H, 7.56; N, 8.39.
19F NMR (477 MHz; D2O; C6F6; 2 diastereoisomers s are present)
d
: ꢁ143.5 (m).
MS (CI, m/z): 281 (Mþ1-tBu), 237 (Mþ1-Boc).
20
Anal. Calcd for C13H16FNO2: C, 65.81; H, 6.80; N, 5.90. Found: C,
[
a
]
D
þ83.45ꢀ (c 0.725 g/100 mL, MeOH).
65.94; H, 6.71; N, 5.82.
Crystals of 18a suitable for X-ray diffraction study were obtained
by a slow evaporation of a diluted solution of 18a in diethyl ether.
LCeMS: 238 (Mþ).
[a
]
20 þ11.29ꢀ (c 0.366 g/100 mL, MeOH).
D
4.11. tert-Butyl-3-fluoro-3-([((1R)-1-phenylethyl)amino]car-
bonyl)pyrrolidine-1-carboxylate (18a). Crystallization from
diethyl ether
4.8. 3-Fluoro-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxamide
(16)
The mixture of diastereomers 18 (10 g, 0.03 mol) was dissolved
in dry diethyl ether (500 mL). Obtained solution was left in a good
ventilating hood for 2 days at room temperature. After this time,
the obtained crystals (4.4 g, 0.013 mol, 44% yield) (95:5 mixture of
the diastereomers) were collected by filtration and recrystallization
was repeated with this material for obtain better diastereomeric
purity. Upon second recrystallization 3.7 g (0.012 mol, 37% yield) of
18a (de>98/2) was obtained.
To a solution of acid 15 (17.0 g, 0.0729 mol) in THF (250 mL) was
added CDI (14.0 g, 0.086 mol) at 0ꢀ C. The solution was heated at
reflux for 4 h. After cooling to a room temperature, (NH4)2CO3
(14.0 g, 146 mol) was added. The solution was heated at reflux for
5 h. The solvent was evaporated under vacuum followed by addi-
tion of water (150 mL). The solution was cooled to 5 ꢀC. The formed
precipitate was filtered off, and dried in air to afford the pure amide
16 (16.3 g, 96%) as a white solid. Mp¼130e131 ꢀC.
1H NMR (500 MHz; CDCl3, Me4Si; 2 diastereoisomers are pres-
4.12. tert-Butyl-(3R)-3-fluoro-3-([((1R)-1-phenylethyl)amino]
carbonyl)pyrrolidine-1-carboxylate (18b)
ent) d: 1.37 (3H, m, CH3), 2.17 (1H, m), 2.46e2.57 (2H, m), 2.80e3.07
(2H, m), 3.07e3.30 (2H, m), 5.93e6.37 (2H, 2s, NH2), 7.19e7.31 (5H,
m, C6H5).
13C NMR (125 MHz; DMSO; Me4Si; 2 diastereoisomers are
Rf¼0.46. 1.7 g (0.0051 mmol, 40% yield). The compound was
obtained as oil that solidified upon long standing. Mp¼90e91 ꢀC.
present),
d
: 22.7 (d, J¼23 Hz), 36.2 (m), 51.4 (d, J¼34 Hz), 62.1 (m),
1H NMR (500 MHz; CDCl3, Me4Si; 2 conformers are present)
d:
64.0 (s), 101.3 (dd, 1JCF¼194 Hz, 2JCF¼14 Hz, CF), 127.1 (s, C6H5), 128.2
(s, C6H5), 128.9 (s, C6H5), 144.2 (s, C6H5), 172.4 (m, CONH2).
19F NMR (477 MHz; DMSO; C6F6; 2 diastereoisomers s are
1.45 (s, 9H, C(CH3)3), 1.55 (d, 3H, J¼6.8 Hz, CHCH3), 2.22 (m, 1H),
2.56 (m, 1H), 3.51 (m, 1H), 3.60e3.83 (m, 3H), 5.14 (m, 1H, CHCH3),
6.77 (1H, br s, NH), 7.26e7.41 (m, 5H, C6H5).
present),
d
: ꢁ141.3 (ꢁ142.1) (2 m, F).
13C NMR (125 MHz; CDCl3; Me4Si; 2 conformers are present),
d:
Anal. Calcd for C13H17FN2O: C, 66.08; H, 7.25; N, 11.86. Found: C,
66.19; H, 7.11; N, 11.99.
21.9 (s, CH3), 28.4 (s, C(CH3)3), 35.1 (m), 44.4 (m), 49.0 (2s), 55.1 (m),
79.9 (s, C(CH3)3), 102.7 (m, 1JCF¼193 Hz, CF), 126.1 (s, C6H5), 127.7 (s,
C6H5), 128.8 (s, C6H5), 142.4 (s, C6H5), 154.0 (s, HNC]O), 167.5 (m,
CONCH2).
LCeMS: 237 (Mþ).
[a
]
20 ꢁ13.02ꢀ (c 1.04 g/100 mL, MeOH).
D
19F NMR (477 MHz; CDCl3; C6F6; 2 conformers are present)
d:
4.9. tert-Butyl-3-fluoro-3-([((1R)-1-phenylethyl)amino]car-
bonyl)pyrrolidine-1-carboxylate (18)
ꢁ158.1 (ꢁ158.6) (2m).
Anal. Calcd for C18H25FN2O3: C, 64.27; H, 7.49; N, 8.33. Found: C,
64.23; H, 7.54; N, 8.41.
MS (CI, m/z): 281 (Mþ1-tBu), 237 (Mþ1-Boc).
To a stirred solution of acid 8 (3.0 g, 0.0129 mol) in THF (75 mL)
was added CDI (2.5 g, 0.0154 mol) at 0 ꢀC in argon atmosphere. The
reaction mixture was heated at reflux for 2 h. The solution was
cooled to 0 ꢀC followed by addition of (R)-1-phenylethylamine
(1.6 g, 0.0132 mol). The reaction mixture was heated at reflux for
3 h. The solvent was evaporated under vacuum. CH2Cl2 (100 mL)
was added to the residue. The organic phase was washed with
water (2ꢂ50 mL),10% aq citric acid (2ꢂ50 mL), saturated solution of
NaHCO3 (2ꢂ50 mL) and again with water (50 mL). The organic
phase was dried over Na2SO4 and evaporated under vacuum to give
a mixture of diastereomers 18 as a colorless oil. Column chroma-
tography (hexane/EtOAc¼3/2) was used to separate these isomers.
MS (CI, m/z): 281 (Mþ1-tBu), 237 (Mþ1-Boc).
20
[
a
]
þ73.48ꢀ (c 0.650 g/100 mL, MeOH).
D
4.13. tert-Butyl-(3R)-3-fluoro-3-([((1R)-1-phenylethyl)amino]
methyl)pyrrolidine-1-carboxylate (19a)
To a stirred solution of amide 18a (3.0 g, 0.0089 mol) in THF
(50 mL) under argon atmosphere a solution of BH3$SMe2 in THF
(2.2 mL, 0.0220 mol, 10 N) was added at 0 ꢀC. The reaction mixture
was heated at reflux for 8 h. The reaction mixture was cooled to 0ꢀ C
followedbyadditionofMeOH(25 mL). A solutionwasheated atreflux
for 30 min. The solvent was evaporated under vacuum to afford the
pure amine 19a (2.78 g, 0.0086 mmol, 97% yield) as a colorless oil.
1H NMR (500 MHz; CDCl3, Me4Si; 2 conformers are present)
d:
4.10. tert-Butyl-(3S)-3-fluoro-3-([((1R)-1-phenylethyl)amino]
carbonyl)pyrrolidine-1-carboxylate (18a)
1.32 (3H, s, CHCH3), 1.44 (9H, s, C(CH3)3), 1.64 (1H, s), 1.75e1.92 (1H,
m), 2.07 (1H, m), 2.51 (1H, m), 2.86 (1H, t, J¼14.0 Hz), 3.29 (1H, m),
3.41e3.51 (2H, m), 3.64e3.74 (2H, m), 7.21e7.30 (5H, m, C6H5).
Rf¼0.38. 1.7 g (0.0051 mol, 40% yield). Mp¼111e112 ꢀC.
13C NMR (125 MHz; CDCl3; Me4Si; 2 conformers are present),
d:
1H NMR (500 MHz; CDCl3, Me4Si; 2 conformers are present)
d:
24.8 (s, CHCH3), 28.5 (s, C(CH3)3), 34.4 (d, J¼23 Hz), 44.3 (2s), 52.2
(m), 54.8 (m), 58.5 (m), 79.5 (s, C(CH3)3), 103.0 (q, J¼85 Hz, CF),
126.6 (s, C6H5), 127 (s, C6H5), 128.5 (s, C6H5), 145.3 (s, C6H5), 154.4 (s,
NC]O).
1.48 (s, 9H, C(CH3)3),1.55 (d, 3H, J¼6.8 Hz, CHCH3), 2.15 (m,1H), 2.49
(m, 1H), 3.50 (m, 1H), 3.64e3.92 (3H, m), 5.15 (m, 1H), 6.75 (br s, 1H,
NH), 7.25e7.41 (m, 5H, C6H5).
Please cite this article in press as: Yarmolchuk, V. S.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.03.002

V.S. Yarmolchuk et al. / Tetrahedron xxx (2014) 1e7
7
19F NMR (477 MHz; CDCl3; C6F6; 2 conformers are present)
d:
Gorichko and Prof. Igor Komarov for the support of the project, to
Prof. Oleg Shishkin for crystallographic analysis, and to Olga Man-
oilenko for HPLC separations.
ꢁ156.0 (m).
Anal. Calcd for C18H27FN2O2: C, 67.05; H, 8.44; N, 8.69. Found: C,
67.13; H, 8.51; N, 8.64.
MS (ES, m/z): 323 (Mþ).
Supplementary data
4.14. tert-Butyl-(3S)-3-fluoro-3-([((1R)-1-phenylethyl)amino]
methyl)pyrrolidine-1-carboxylate (19b)
Copies of NMR spectra for all new compounds. Supplementary
data related to this article can be found at http://dx.doi.org/10.1016/
j.tet.2014.03.002.
Compound 19b (1.40 g, 0.0043 mmol, 96% yield, colorless oil)
was synthesized from 14b (1.52 g, 0.0045 mol) following the pro-
cedure used to synthesize amine 19a.
References and notes
1H NMR (500 MHz; CDCl3, Me4Si; 2 conformers are present)
d:
1. For example: (a) Asahina, Y.; Takei, M.; Kimura, T.; Fukuda, Y. J. Med. Chem.
2008, 51, 3238; (b) Inagaki, H.; Miyauchi, S.; Miyauchi, R. N.; Kawato, H. C.;
Ohki, H.; Matsuhashi, N.; Kawakami, K.; Takahashi, H.; Takemura, M. J. Med.
Chem. 2003, 46, 1005; (c) Kim, B. C.; Kim, K.-Y.; Lee, H. B.; Shin, H. Org. Process
Res. Dev. 2008, 12, 626; (d) Thomas, A.; Gopalan, B.; Lingam, P.; Rao, V. S.; Shah,
D. M. WO2006040625, 2006. (e) Feng, J.; Zhang, Z.; Wallace, M. B.; Stafford, J.
A.; Kaldor, S. W.; Kassel, D. B.; Navre, M.; Shi, L.; Skene, R. J.; Asakawa, T.;
Takeuchi, K.; Xu, R.; Webb, D. R.; Gwaltney, S. L. J. Med. Chem. 2007, 50, 2297.
2. (a) Kirk, K. L. Org. Process Res. Dev. 2008, 12, 305; (b) Filler, R.; Saha, R. Future
Med. Chem. 2009, 1, 777; (c) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V.
Chem. Soc. Rev. 2008, 37, 320; (d) Hagmann, W. K. J. Med. Chem. 2008, 51, 4359;
(e) Bohm, H.-J.; Banner, D.; Bendels, S.; Kansy, M.; Kuhn, B.; Muller, K.; Obst-
Sander, U.; Stahl, M. ChemBioChem 2004, 5, 637; (f) Mykhailiuk, P. K.; Starova,
V.; Iurchenko, V.; Shishkina, S. V.; Shishkin, O. V.; Khilchevskyi, O.; Zaporozhets,
O. A. Tetrahedron 2013, 69, 4066.
3. Selected Books: (a) Modern Fluoroorganic Chemistry; Kirsch, P., Ed.; Wiley-VCH:
Weinheim, Germany, 2004; (b) Fluorine in Medicinal Chemistry and Chemical
Biology; Ojima, I., Ed.; Blackwell: 2009; (c) Bioorganic and Medicinal Chemistry
of Fluorine; Begue, J.-P., Bonnet-Delpon, D., Eds.; John Wiley & Sons: New Jersey,
NJ, 2008.
4. (a) Miller, W. H.; Pendrak, I.; Seefeld, M. A. WO2006/2047 A2, 2006; (b)
Verniest, G.; Piron, K.; Van Hende, E.; Thuring, J. W.; Macdonald, G.; Derooseb,
F.; De Kimpe, N. Org. Biomol. Chem. 2010, 8, 2509; (c) Barsanti, P. A.; Xia Y.;
Wang, W.; Mendenhall, K. G.; Lagniton, L. M.; Ramurthy, S.; Phillips, M. C.;
Subramanian, S.; Boyce, R.; Brammeier, N. M.; Constantine, R.; Duhl, D.; Walter,
A. O.; Abrams, T. J.; Renhowe, P. A. US2007/37853 A1, 2007. (d) Wang, W.;
Barsanti, P. A.; Xia, Y.; Boyce, R.; Pecchi, S.; Brammeier, N.; Phillips, M. C.;
Mendenhall, K.; Wayman, K.; Lagniton, L. M.; Constantine, R.; Yang, H.; Mieuli,
E.; Ramurthy, S.; Jazan, E.; Sharma, A.; Jain, R.; Subramanian, S.; Renhowe, P. A.;
Bair, K. W.; Duhl, D.; Walter, A.; Abrams, T.; Huh, K.; Martin, E.; Knapp, M.; Le, V.
P. US2006/9472 A1, 2006.
5. Harwood, L. M.; Vickers, R. J. Azomethineylides In Synthetic Applications of 1,3-
Dipolar Cycloaddition Chemistry Toward Heterocycles and Natural Products;
Padwa, A., Pearson, W. H., Eds.; Wiley: New York, NY, 2003; p 169.
6. Yarmolchuk, V. S.; Mykhailiuk, P. K.; Komarov, I. V. Tetrahedron Lett. 2011, 52,
1300.
7. Reaction of compound 2 with other fluorine-substituted alkenes: (a) Qiu, Y.-L.;
Ying, L.; Or, Y. S.; Wang, C.; Long, J. US2009/0004140 A1, 2009; Chem. Abstr.
2009, 150, 98139. (b) Mason, J. M.; Murkin, A. S.; Li, L.; Schramm, V. L.; Gain-
sford, G. J.; Skelton, B. W. J. Med. Chem. 2008, 51, 5880; (c) Rogel, O.; Rondeau, J.
-M.; Rueeger, H.; Simic, O.; Sirockin, F.; Tintelnot-Blombey, M. WO2007/140980
A1, 2007; Chem. Abstr. 2007, 147, 323011. (d) Bonini, B. F.; Boschi, F.; Franchini,
M. C.; Fochi, M.; Fini, F.; Mazzanti, A.; Ricci, A. Synlett 2006, 543.
8. Reaction of compound 2 and its analogues with trifluoromethyl-substituted
alkenes: (a) Begue, J.-P.; Bonnet-Delpon, D.; Lequeux, T. Tetrahedron Lett.
1993, 34, 3279; (b) Bonnet-Delpon, D.; Begue, J.-P.; Lequeux, T.; Ourevitch, M.
Tetrahedron 1996, 52, 59; (c) Fukui, H.; Shibata, T.; Naito, T.; Nakano, J.; Mae-
jima, T.; Senda, H.; Iwatani, W.; Tatsumi, Y.; Suda, M.; Arika, T. Bioorg. Med.
Chem. Lett. 1998, 8, 2833; (d) Li, Q.; Wang, W.; Berst, K. B.; Claiborne, A.; Has-
vold, L.; Raye, K.; Tufano, M.; Nilius, A.; Shen, L. L.; Flamm, R.; Alder, J.; Marsh,
K.; Crowell, D.; Chu, D. T. W.; Plattner, J. J. Bioorg. Med. Chem. Lett. 1998, 8, 1953;
(e) Yarmolchuk, V. S.; Shishkin, O. V.; Starova, V. S.; Zaporozhets, O. A.; Krav-
chuk, O.; Zozulya, S.; Komarov, I. V.; Mykhailiuk, P. K. Eur. J. Org. Chem. 2013,
3086.
1.36 (s, 3H, CHCH3), 1.46 (s, 9H, C(CH3)3), 1.60 (s, 1H), 1.86 (m, 1H),
2.24 (br s, 1H), 2.43 (m, 1H), 2.63 (m, 1H), 2.84 (m, 1H), 3.34 (m, 1H),
3.48e3.60 (m, 2H), 3.77 (m, 1H), 7.23e7.34 (m, 5H, s, C6H5).
13C NMR (125 MHz; CDCl3; Me4Si; 2 conformers are present),
d:
24.6 (s, CHCH3), 28.5 (s, C(CH3)3), 34.3 (m), 44.3 (m), 51.9 (m), 54.7
(m), 58.5 (2s), 79.4 (s, C(CH3)3),103.1 (q, J¼84 Hz, CF), 126.5 (s, C6H5),
127.0 (s, C6H5), 128.5 (s, C6H5), 145.4 (s, C6H5), 154.3 (s, NC]O).
19F NMR (477 MHz; CDCl3; C6F6; 2 conformers are present)
d:
ꢁ155.9 (m).
€
€
Anal. Calcd for C18H27FN2O2: C, 67.05; H, 8.44; N, 8.69. Found: C,
67.18; H, 8.45; N, 8.52.
MS (ES, m/z): 323 (Mþ).
[
a]
20 ꢁ18.21ꢀ (c 1.36 g/100 mL, MeOH).
D
4.15. tert-Butyl-(3R)-3-aminomethyl-3-fluoropyrrolidine-1-
carboxylate (Boc-(R)-1)
Compound 19a (1.25 g, 0.0039 mol) was dissolved in anhydrous
methanol (100 mL) and 10% palladium on charcoal (500 mg) was
added. This mixture was hydrogenated at 60 ꢀC under a hydrogen
pressure of 30 atm for 24 h. The catalyst was then filtered through
a pad of Celite (approx. 1 cm), which was subsequently washed
with anhydrous methanol (2ꢂ50 mL). The organic phase was
evaporated under vacuum to afford the pyrrolidine Boc-(R)-1 as
a colorless oil (0.76 g, 0.0035 mol, 90% yield).
1H NMR (500 MHz; CDCl3, Me4Si; 2 conformers are present)
d:
1.44 (s, 9H, C(CH3)3), 1.65 (br s, 2H, NH2), 1.89 (m, 1H), 2.14 (m, 1H),
2.91e3.09 (m, 2H), 3.37 (m, 1H), 3.48 (m, 1H), 3.63 (m, 2H).
13C NMR (125 MHz; CDCl3; Me4Si; 2 conformers are present),
d:
28.1 (s), 33.3e33.9 (d, J¼23.1 Hz), 43.8 (m), 46.3 (m), 53.6 (m), 79.2
(s), 103.3 (m, CF), 153.3 (s, NC]O).
19F NMR (477 MHz; CDCl3; C6F6; 2 conformers are present)
d:
ꢁ158.5 (m).
Anal. Calcd for C10H19FN2O2: C, 55.03; H, 8.77; N, 12.83. Found:
C, 55.18; H, 8.64; N, 12.75.
t
t
GCeMS (EI, m/z): 198 (MꢁHF)þ, 145 (Mꢁ Bu)þ,142 (MꢁFꢁ Bu)þ.
[
a]
20 ꢁ17.21ꢀ (c 1.095 g/100 mL, MeOH).
D
4.16. tert-Butyl-(3S)-3-aminomethyl-3-fluoropyrrolidine-1-
carboxylate (Boc-(S)-1)
Compound Boc-(S)-1 (0.19 g, 0.0009 mol, 90% yield) was syn-
thesized from 19b (0.31 g, 0.0010 mol) following the procedure
used to synthesize Boc-(R)-1.
9. (a) Hosomi, A.; Sakata, Y.; Sakurai, H. Chem. Lett. 1984, 1117; (b) Padwa, A.; Dent,
W. J. Org. Chem. 1987, 52, 235.
10. Fukui, H.; Kobayashi, K.; Nakata, T.; Shibata, T.; Naito, T.; Nakano, J. Anal. Sci.
1997, 13, 689.
Spectral and analytical characteristics of Boc-(S)-1 are identical
to those of Boc-(R)-1.
11. Nagata, K.; Kuga, Y.; Higashi, A.; Kinoshita, A.; Kanemitsu, T.; Miyazaki, M.; Itoh,
T. J. Org. Chem. 2013, 78, 7131.
12. (a) Gerlach, K.; Hoffmann, H. M. R.; Wartchow, R. J. Chem. Soc., Perkin Trans. 1
1998, 3867; (b) Fray, A. H.; Meyers, A. I. J. Org. Chem. 1996, 61, 3362.
13. Atomic coordinates and crystallographic parameters for compound 18a
were deposited at the Cambridge Crystallographic Data Centre under
959241.
[
a]
20 þ19.02ꢀ (c 1.205 g/100 mL, MeOH).
D
Acknowledgements
14. Dale, J. A.; Dull, D. L.; Mosher, H. S. J. Org. Chem. 1969, 34, 2543.
15. (a) Hunter, L. Beilstein J. Org. Chem. 2010, 6, 38; (b) Sparr, Z. C.; Gilmour, R.
Angew. Chem., Int. Ed. 2011, 50, 11860.
All authors are grateful to Prof. Andrei Tolmachev and Dr.
Nataliia Tolmacheva for financial support of the work, to Dr. Marian
Please cite this article in press as: Yarmolchuk, V. S.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.03.002