Synthesis and characterization of β-trifluoromethyl-substituted pyrrolidines

Article abstract of DOI:10.1002/ejoc.201300121

A practical synthetic approach to the construction of a library of three isomeric/homologous β-trifluoromethyl-substituted pyrrolidines is disclosed. All products were prepared in multigram quantities from a common precursor. The key synthetic step was a [3+2] cycloaddition reaction. The influence of the trifluoromethyl group on the physicochemical characteristics of the pyrrolidine fragment was studied. Three β-(trifluoromethyl)ated pyrrolidines have been synthesized on multigram scales. The influence of the CF₃ group on the physicochemical properties of the pyrrolidine fragment has been studied. Copyright

Full text of DOI:10.1002/ejoc.201300121

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FULL PAPER
DOI: 10.1002/ejoc.201300121
Synthesis and Characterization of β-Trifluoromethyl-Substituted Pyrrolidines
Vladimir S. Yarmolchuk,[a,b] Oleg V. Shishkin,[c] Viktoriia S. Starova,[b]
Olga A. Zaporozhets,[b] Olga Kravchuk,[a] Sergey Zozulya,[a] Igor V. Komarov,[d] and
Pavel K. Mykhailiuk*[a,b]
Keywords: Synthetic methods / Medicinal chemistry / Drug design / Drug discovery / Nitrogen heterocycles / Amines /
Fluorine
A practical synthetic approach to the construction of a library
of three isomeric/homologous β-trifluoromethyl-substituted
pyrrolidines is disclosed. All products were prepared in
multigram quantities from a common precursor. The key syn-
thetic step was a [3+2] cycloaddition reaction. The influence
of the trifluoromethyl group on the physicochemical charac-
teristics of the pyrrolidine fragment was studied.
Introduction
Pyrrolidine is one of the most frequently used aliphatic
amines in organic chemistry.[1] Moreover, this residue can
be found in many bioactive compounds[2] including nine
FDA-approved drugs.[3] It is not surprising therefore that
substituted pyrrolidine analogues are valuable building
blocks that are used in both drug discovery and agrochemi-
stry projects (Figure 1).[4] On the other hand, practical ap-
plication of building blocks in pharmaceutical and agro-
chemical industry strongly depends not only on their con-
ceptual attractiveness, but also on their chemical availabil-
ity.[1,5] Therefore, elaboration of short and high-yielding
synthetic approaches to pyrrolidine analogues is important.
The incorporation of fluorine, trifluoromethyl groups, or
other fluorinated fragments into organic molecules can sig-
nificantly change their physicochemical and biological
properties.[11,12] In particular, the trifluoromethyl substitu-
ent effectively influences the pKa of the neighboring func-
tional groups, lipophilicity, solubility, conformational pref-
erences, and hydrolytic and metabolic stabilities.[13] There-
fore, the trifluoromethyl group is widespread in bioactive
compounds.[14]
Combination of the principles described above leads to
conceptually attractive α-(trifluoromethyl)- (1) and β-(tri-
[a] Enamine Ltd.,
Oleksandra Matrosova Street 23, Kyiv 01103, Ukraine
Fax: +38-44-537-32-53
E-mail: Pavel.Mykhailiuk@gmail.com
Homepage: http://418lab.chem.univ.kiev.ua/showcv.php?id=3
[b] Department of Chemistry, National Taras Shevchenko Univer-
sity of Kyiv,
Volodymyrska Street 64, Kyiv 01033, Ukraine
[c] SSI, Institute for Single Crystals, National Academy of Science
of Ukraine,
60 Lenina ave., Kharkiv 61001, Ukraine
[d] Institute of High Technologies, National Taras Shevchenko
University of Kyiv,
Figure 1. Biologically active compounds featuring pyrrolidine or
substituted pyrrolidine residues: antimigraine agent Almotriptan;[6]
anticholinergic drug Procyclidine;[7] antidiabetic drug Mitiglinide;[8]
κ-opioid agonist drug Asimadoline;[9] potent dipeptidyl peptidase-
4 inhibitor PF-734200.[10]
Volodymyrska Street 64, Kyiv 01033, Ukraine
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300121.
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P. K. Mykhailiuk et al.
FULL PAPER
fluoromethyl)pyrrolidines (2). Indeed, during the last dec- group in pyrrolidine 9 was expected to be cleaved by stan-
ade the use of these amines was covered in more than 100 dard hydrogenolysis (Scheme 1).
patents, unveiling thereby their high potential.[15] Several
synthetic approaches to α-(trifluoromethyl)pyrrolidine have
been described in the literature.[16] Unexpectedly, synthesis
of pyrrolidine 2 has not been reported in the open literature.
Preparation of milligram quantities of this compound was
briefly mentioned in only one patent.[17] In that report,
however, the compounds were characterized only by mass
spectroscopy without providing other spectroscopic data.
Hence, our motivation in this work was to develop and pub-
lish a practical approach to the synthesis of amine 2. We
report here the preparation of multigram quantities of 2
and also its isomeric homologues, 3 and 4. The influence of
the trifluoromethyl substituent on the lipophilicity, meta-
bolic stability, and basicity of the obtained compounds has
been studied.
Chemistry
Alkene 8 is a gas under ambient conditions (b.p.
–18 °C),[23] therefore the cycloaddition reaction was per-
formed at –30 °C in dichloromethane as a solvent. Tri-
fluoroacetic acid was used to generate the corresponding
ylide. The reaction proceeded smoothly to give the expected
product 9 in an excellent isolated yield of 95% (Scheme 2).
Subsequent catalytic hydrogenation of the N-benzyl group
of 9 over Pd/C afforded the target amine 2·HCl. It is impor-
tant to note that the developed synthetic protocol was fully
reproducible upon scaling up and was successfully used to
prepare 50 g of product 2·HCl in one synthesis run.
Results and Discussion
Scheme 2. Synthesis of amine 2·HCl.
Retrosynthetic Analysis
This reliable and reproducible procedure was then used
to prepare the novel isomeric homologues of amine 2 – bi-
s(trifluoromethyl)-substituted pyrrolidines 3 and 4. In fact,
[3+2] cycloaddition of 5 with alkene 10 smoothly gave pyr-
rolidine 11 in 97% yield (Scheme 3). Standard cleavage of
the N-benzyl group in 11 by hydrogenolysis over Pd/C as a
catalyst provided amine 3·HCl. Again, the procedure was
reproducible, leading to the straightforward preparation of
35 g of the product in one batch.
To synthesize pyrrolidine 2, we decided to take advantage
of the well-known strategy for construction of β-substituted
pyrrolidines: the [3+2] cycloaddition between electron-de-
ficient alkenes and azomethine ylides.[18] N-Benzyl-substi-
tuted reagent 5 was chosen out of the many possibilities
to access the azomethine ylide, because the acid-catalyzed
reaction of 5 with methyl acrylate (6) was previously re-
ported to generate the β-proline derivative 7 in 98% yield
in kilogram quantity.[19] Because the electronegativities of
the trifluoromethyl and carboxymethyl substituents are very
similar,[20] we suggested that 5 would also react with tri-
fluoromethylethylene (8).[21,22] The corresponding N-benzyl
Scheme 3. Synthesis of amine 3·HCl.
Synthesis of amine 4 started from bis(trifluoromethyl)-
acetylene 12 (Scheme 4). Thus, [3+2] cycloaddition of 12
with 5 gave alkene 11 in 70% isolated yield after distillation.
However, attempts to perform a one-pot synthesis of amine
4 by extensive hydrogenation of both the N-Bn groups and
the C=C double bond failed, giving instead a complex mix-
ture. Therefore, we decreased the basicity of the nitrogen
atom by using the N-Boc protecting group. Following this
scenario, 13 was treated first with CH3CHClOC(O)Cl/
MeOH to provide amine 14·HCl, and then with Boc2O/
NEt3 to afford 15. In contrast to 13, hydrogenation of al-
kene 15 over Pd/C as a catalyst took place smoothly to give
pyrrolidine 16 as a single stereoisomer. Finally, acidic cleav-
Scheme 1. (a) Synthesis of 7 described in the literature;[19] (b) Ret-
rosynthetic analysis of amine 2.
2
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β-Trifluoromethyl-Substituted Pyrrolidines
Scheme 4. Synthesis of amine 4·HCl.
age of the N-Boc group in 16 gave the target amine 4·HCl.
By using this procedure 30 g of the product was synthesized
in a single run.
To determine the relative stereoconfiguration of 16 and
4·HCl, we performed acylation of 4·HCl by CbzCl to afford
the crystalline derivative 17 (Scheme 5). Single crystals of
the product were obtained by slow evaporation of its di-
luted solution in methanol. X-ray diffraction analysis of
carbamate 17 revealed the cis-configuration of the trifluoro-
methyl groups in the pyrrolidine ring.
Scheme 6. Synthesis of 18.
The experimental pKa(H) value of amine 19 was 9.3,
whereas the pKa(H) of amine 9 was 7.2, indicating that in-
corporation of the electron-withdrawing trifluoromethyl
group at the β-position to a nitrogen atom led to ΔpKa(H)
= –2.1 (Table 1). The measured pKa(H) of compounds 11
and 18 was 4.8 and 4.7, respectively. It is interesting to note
that the introduction of the second β-trifluoromethyl group
had a significantly higher impact on the basicity of the pyr-
rolidine than that of the first: ΔpKa(H) = –2.4 (11) and –2.5
(18). Two explanations seem reasonable to assume. First,
electrostatic interaction between C–Fδ– and N+–H can par-
tially stabilize the protonated amine form after introduction
Scheme 5. Synthesis and molecular structure of 17 according to X-
ray diffraction data. Thermal ellipsoids of atoms are shown at 30%
probability levels.
Table 1. Measured physicochemical and biochemical characteristics
of compounds 9, 11, 18, and 19.
Influence of the Trifluoromethyl Group on pKa
In medicinal chemistry, the basicity of nitrogen atoms
is an important characteristic of bioactive compounds.[24]
Therefore, the influence of the trifluoromethyl group on the
pKa(H) of the amino group in the pyrrolidine fragment was
studied. For this purpose, N-benzyl derivatives 9, 11, and
18 were compared with the reference compound 19. Amine
18 was obtained from pyrrolidine 4·HCl in 65% yield by
reductive amination with benzaldehyde (Scheme 6). The
pKa measurements were performed by potentiometric ti-
tration (see the Supporting Information).
[a] pKa values for the corresponding conjugate acids are shown.
[b] Experimental logarithm of the n-octanol/water distribution co-
efficient at pH 7.2. [c] Intrinsic lipophilicity of the neutral base, ac-
cording to logP = logD + log10[1 + 10(pKa–pH)]. [d] Intrinsic clear-
ance rate CLint (mg/[minμL]) measured in mouse liver microsomes.
[e] No decomposition was observed during 30 min.
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of the first trifluoromethyl group. Incorporation of the sec- 2–4 seem to be useful replacements for the pyrrolidine resi-
ond group does not provide this stabilization and hence the due, because this substitution will increase lipophilicity of
first CF3 group decreases the basicity to a lesser extent than the corresponding derivatives.
the second CF3 group does. Alternatively, the bulky tri-
fluoromethyl group can prevent protonation of the nitrogen
Impact of the Trifluoromethyl Group on Metabolic Stability
atom in 11 and 18, in contrast to amine 9. The second hy-
pothesis is partially confirmed by X-ray crystal structure
analysis of compound 11·HCl (Figure 2) in which one of
the trifluoromethyl groups is in close proximity to the N–
H group and is, therefore, expected to sterically prevent the
protonation of amine 11. Unfortunately, we could not grow
single crystals of either 9·HCl or 18·HCl, and hence the
origin of the different effects of the trifluoromethyl groups
on the nitrogen basicity is still not fully clear.
Aliphatic amines are readily oxidized metabolically. Typi-
cal transformations include N-dealkylation and N-oxi-
dation. Important factors influencing the metabolic sta-
bility of amines are the basicity of the amino group and its
steric accessibility.[26] Therefore, incorporation of electron-
withdrawing, bulky substituents near the basic amine center
has frequently been used to block metabolic degradation.[27]
Taking this into account, we expected that amines 9, 11 and
18 would have metabolic stability superior to that of amine
19. To test this hypothesis experimentally, all compounds
were subjected to standardized preparations of mouse liver
microsomes, and the remaining unchanged material was de-
termined at several time intervals during incubation at
37 °C. This test yielded pseudo-first-order rate constants for
oxidative degradation and intrinsic clearance rates (CLint
)
that provided useful indications for phase I metabolism.
Unexpectedly, however, all the trifluoromethyl-substituted
amines 9, 11, and 18 had higher clearance rate than stable
compound 19 (Table 1). In our opinion, this fact clearly
demonstrates that under the experimental conditions N-de-
benzylation is the predominant metabolic pathway. If N-
oxidation were the main pathway, then incorporation of the
electron-withdrawing bulky trifluoromethyl group would be
expected to increase the metabolic stability. The most prob-
able explanation is that oxidation of the PhCH2 group oc-
curs first, followed by N-dealkylation.
Figure 2. Compound 11·HCl; Schematic representation and molec-
ular structure according to X-ray diffraction data. C–H atoms are
omitted for clarity. Thermal ellipsoids of atoms are shown at 20%
probability levels.
Impact of the Trifluoromethyl Group on Lipophilicity
Lipophilicity is another key characteristic of bioactive
compounds. For example, oral drugs must be lipophilic
enough to effectively cross the biomembrane. Therefore, the
influence of the trifluoromethyl substituent on the lipophil-
icity of the pyrrolidine core was also studied. The experi-
mental lipophilicity (logD) of amines, measured at pH 7.2,
reflects the intrinsic lipophilicity of the neutral compound
(logP) and the effect of partial protonation at the given
pH.[25] Because the trifluoromethyl group impacted both
basicity and intrinsic lipophilicity, it was decided to analyze
these two effects separately.
Incorporation of the trifluoromethyl group at the β-posi-
tion to the nitrogen atom, as in 9, led to a significant in-
crease in the intrinsic lipophilicity, with ΔlogP = 3.0–2.1 =
0.9 (Table 1). Incorporation of the second trifluoromethyl
group increased further the logP of the both 11 and 18. It
Application Area
Having developed reliable and scalable procedures to
generate a library of isomeric/homologous trifluoromethyl-
ated pyrrolidines 2, 3, and 4, and having comprehensively
characterized the products, we want to briefly highlight here
several, in our opinion, most interesting application areas
for these compounds.
1. Pharmaceuticals and Agricultural Products
As mentioned in the introduction, the pyrrolidine motif
is also important to mention that, in contrast to the parent occurs frequently in medicinal chemistry and agrochemis-
amine 19, the determined logP and logD for pyrrolidines try. Moreover, during the last decade, the trifluoromethyl-
11 and 18 were identical. In compound 9, these characteris- ated amine 2 has been widely applied in drug discovery pro-
tics were similar. The observation clearly indicated that the jects. We feel, however, that the full potential of this com-
trifluoromethyl substituent in 9 partially hindered proton- pound is not yet uncovered, probably due to the absence of
ation of the nitrogen atom at pH 7.2. At the same time, this the corresponding published synthetic protocols in the open
protonation was hindered completely in compounds 11 and literature. Moreover, in spite of huge potential, to the best
18.
of our knowledge, no lead structures bearing the residue of
In general, incorporation of the trifluoromethyl moiety 2 are currently known. On the other hand, the well-de-
into the pyrrolidine fragment both increases the intrinsic scribed and easily available 4-(trifluoromethyl)piperidine is
lipophilicity (logP) and prevents protonation of the nitro- commonly used in both agrochemistry and medicinal chem-
gen atom. Therefore, when low absorption of the pyrrol- istry. As a representative example, we mention here the pub-
idine-containing bioactive compounds is observed, amines lication by Merck of the identification of the promising
4
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β-Trifluoromethyl-Substituted Pyrrolidines
Scheme 7. The published drug discovery project of Merck on the identification of the nootropic agent 20 bearing the 4-(trifluoromethyl)
piperidine residue.[28]
nootropic agent 20, which reached preclinical trials
(Scheme 7).[28] The lead compound 21 had moderate ac-
tivity. Installing the methyl group into the piperidine ring
(22) led to a 10-fold improvement in the potency, probably
due to the enhanced lipophilic interactions with the recep-
tor. Finally, the inclusion of the more bulky trifluoromethyl
group additionally increased the activity of the compound
by a factor of ca. 20 (20).
Scheme 8. Model iminium ion catalyzed Diels–Alder reaction.
Compound 1·HPF6 was used as both the catalyst and as the
19F NMR probe.[31]
In the same way, compounds 2–4 seem to be very promis-
ing building blocks, especially for those drug discovery pro-
jects for which SAR-optimization around the pyrrolidine
fragment is needed. Furthermore, both pyrrolidines 3 and
4, with six fluorine atoms, are attractive candidates for ag-
rochemistry – the field in which polyfluorinated heterocy-
clic compounds are currently prevailing.[29]
Similar to 4-(trifluoromethyl)piperidine and compound
1, we feel that amines 2–4 can also be used as 19F NMR
probes.
Conclusions
2. As 19F NMR Probes
We have developed practical synthetic approaches to a
small library of isomeric/homologous β-(trifluoromethyl)-
pyrrolidines 2–4. Thus, 30–50 g of the target compounds
were easily obtained in a single synthesis run, starting from
the common precursor 5. Incorporation of the trifluorome-
thyl substituent into the pyrrolidine fragment had a signifi-
cant effect on the pKa(H), logD, and CLint characteristics.
In particular, the trifluoromethyl group reduced the basicity
of the pyrrolidine fragment and increased its lipophilicity.
With rapid access to multigram quantities, we therefore be-
lieve that pyrrolidines 2–4 will find applications in drug dis-
covery and in agrochemistry as valuable building blocks,
and in mechanistic studies as 19F NMR probes.
Recently, Colby and colleagues used 4-(trifluoromethyl)-
piperidine as a 19F NMR probe (Figure 3).[30] In particular,
the authors prepared compound 23, which had a biological
activity similar to that of active pharmacological agent Par-
thenolide. Using 19F NMR spectroscopic analysis, they
monitored the behavior of 23 both in the presence and ab-
sence of glutathione to obtain valuable data on the mecha-
nism of action of Parthenolide.
Experimental Section
General: Solvents were purified according to standard procedures.
Melting points were measured in open capillary tubes with a Thiele
apparatus. Analytical TLC was performed with Polychrom SI F254
plates. Column chromatography was performed using silica gel
(230–400 mesh) as the stationary phase. 1H and 13C and all 2D
NMR spectra were recorded at 499.9 or 400.4 MHz for 1H, at 124.9
or 100.4 MHz for 13C, and at 470.0 MHz for 19F nuclei with a
Bruker Avance 500 spectrometer. Chemical shifts are reported in
ppm downfield from TMS (1H, 13C) and CFCl3 (19F) as an internal
standard. MS analyses were recorded with an LCMS instrument
with chemical ionization (CI) or GC–MS instrument with electron
impact ionization (EI).
Figure 3. Structure of Parthenolide and its analogue 23 labeled by
4-(trifluoromethyl)piperidine.[30]
The work of Tomkinson et al. is also worth mentioning
in this context. The authors used pyrrolidine 1 simulta-
neously as both the catalyst and as the 19F NMR probe to
monitor the kinetics of the iminium ion catalyzed Diels–
Alder reaction (Scheme 8).[31]
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1-Benzyl-3-(trifluoromethyl)pyrrolidine (9): Compound 5 (80.0 g,
0.34 mol, 1 equiv.) was dissolved in anhydrous dichloromethane
(1500 mL) under an argon atmosphere. The obtained solution was
cooled to –30 °C and alkene 9 (38.8 g, 0.40 mol, 1.2 equiv.) was
added at the same temperature. A solution of trifluoroacetic acid
(3.84 g, 0.034 mol, 0.1 equiv.) in anhydrous dichloromethane
(250 mL) was added dropwise at –20 °C, and the obtained solution
was first stirred at the same temperature for 4 h and then for 5 h
at room temperature. The reaction mixture was neutralized by ad-
dition of a saturated aqueous solution of NaHCO3, then the or-
ganic phase was washed with brine (3ϫ 250 mL), separated, and
dried with anhydrous Na2SO4. The solvent was removed under re-
duced pressure on a rotary evaporator and the resulting oil was
purified by flash chromatography (hexane/ethyl acetate/trifluoroe-
thanol, 68:22:10) to give product 9 (73.3 g, 0.32 mol, 95%) as a
colorless oil. TLC [SiO2, hexane/ethyl acetate/trifluoroethanol =
68:22:10]: Rf = 0.60. C12H14F3N (229.24): calcd. C 62.87, H 6.16,
N 6.11; found C 62.99, H 6.22, N 5.98. 1H NMR (500 MHz,
CDCl3, Me4Si): δ = 1.96 (m, 1 H), 2.07 (m, 1 H), 2.53 (m, 2 H),
2.75 (m, 1 H), 2.89 (m, 2 H), 3.65 (t, J = 13.0 Hz, 2 H, CH2Ph),
7.28–7.36 (m, 5 H, PhH) ppm. 13C NMR (125 MHz, CDCl3,
Me4Si): δ = 24.8 (CH2), 41.5 (q, J = 27 Hz, CHCF3), 53.3
(CH2NBn), 53.5 (CH2NBn), 59.9 (CH2Ph), 127.2 (CH, Ph), 127.9
(q, J = 279 Hz, CF3), 128.4 (CH, Ph), 128.7 (CH, Ph), 138.7 (CH,
Ph) ppm. 19F NMR (477 MHz, CDCl3; Me4Si): δ = –71.5 (d, J =
1 Hz) ppm. MS (CI): m/z (%) = 230.
2 H, CH2CH2N), 2.87 (s, 2 H, CCH2N), 3.66 (s, 2 H, CH2Ph),
7.24–7.31 (5 H, PhH) ppm. 13C NMR (125 MHz, CDCl3, Me4Si):
δ = 28.5, 53.2, 54.9, 56.1 (m, J = 27.0 Hz), 59.1, 125.3, 127.3, 128.3,
128.5, 129.5, 138.1 ppm. 19F NMR (477 MHz, CDCl3, Me4Si): δ =
–72.4 (s) ppm. MS (CI): m/z (%) = 298.
3,3-Bis(trifluoromethyl)pyrrolidine Hydrochloride (3·HCl): Com-
pound 11 (50.0 g, 0.17 mol) was dissolved in anhydrous methanol
(400 mL) and 10% palladium on charcoal (8.0 g) was added. This
mixture was hydrogenated at room temperature at a hydrogen pres-
sure of 20 atm. for 17 h. The catalyst was then filtered through
a pad of Celite (ca. 1 cm), which was subsequently washed with
anhydrous methanol (2ϫ 150 mL). Then 12 n aq. HCl (21 g,
0.21 mol, 1.2 equiv.) was added to the obtained solution and the
solvents were evaporated to dryness under reduced pressure to af-
ford amine 3·HCl (36.5 g, 0.15 mol, 90% yield) as a colorless solid,
m.p. 194 °C. C6H8ClF6N (243.58): calcd. C 29.59, H 3.31, Cl 14.55,
N 5.75; found C 29.67, H 3.37, Cl 14.62, N 5.82. 1H NMR
(500 MHz, D2O, Me4Si): δ = 2.61 (t, J = 7.1 Hz, 2 H), 3.55 (t, J =
7.1 Hz, 2 H), 3.88 (s, 2 H, CH2) ppm. 13C NMR (125 MHz, D2O,
Me4Si): δ = 27.5, 46.1, 46.5, 56.2 [m, J = 28.0 Hz, C(CF3)2], 124
(q, J = 284.2 Hz, CF3) ppm. 19F NMR (477 MHz, D2O, Me4Si): δ
= –71.5 (m, J = 16.0 Hz) ppm. MS (CI): m/z (%) = 208.
1-Benzyl-3,4-bis(trifluoromethyl)-2,5-dihydro-1H-pyrrole (13): Com-
pound 5 (75.0 g, 0.32 mol, 1 equiv.) was dissolved in anhydrous
dichloromethane (2000 mL) under an argon atmosphere. The ob-
tained solution was cooled to –40 °C and alkyne 12 (102.0 g,
0.63 mol, 2 equiv.) was added at the same temperature. A solution
of trifluoroacetic acid (3.6 g, 0.032 mol, 0.1 equiv.) in anhydrous
dichloromethane (300 mL) was added dropwise below –40 °C. The
obtained solution was first stirred at the same temperature for 6 h
and then for 7 h at room temperature. The reaction mixture was
then neutralized by addition of saturated aqueous NaHCO3. The
organic phase was washed with brine (4ϫ 200 mL), separated, and
dried with anhydrous Na2SO4. The solvent was removed under re-
duced pressure (rotary evaporator) and the resulting oil was puri-
fied by column chromatography (hexane/ethyl acetate/trifluoro-
ethanol = 75:15:10) to give 13 (65.3 g, 0.22 mol, 70% yield) as a
colorless oil. TLC [SiO2, hexane/ethyl acetate/trifluoroethanol =
75:15:10]: Rf = 0.4. C13H11F6N (295.22): calcd. C 52.89, H 3.76, N
3-(Trifluoromethyl)pyrrolidine Hydrochloride (2·HCl): Compound 9
(73.3 g, 0.32 mol) was dissolved in anhydrous methanol (750 mL)
and 10% palladium on charcoal (15.0 g) was added. This mixture
was hydrogenated at room temperature under a hydrogen pressure
of 20 atm. for 10 h. The catalyst was then filtered through a pad of
Celite (ca. 1 cm), which was subsequently washed with anhydrous
methanol (2ϫ 150 mL). Concentrated aqueous hydrochloric acid
(39.0 g, 0.38 mol, 1.2 equiv.) was added to the obtained solution,
then the solvents were evaporated under reduced pressure to afford
pyrrolidine 2·HCl (49.1 g, 0.28 mol, 87%) as a colorless solid, m.p.
87–89 C. C5H9ClF3N (175.58): calcd. C 34.20, H 5.17, Cl 20.19, N
7.98; found C 34.11, H 5.22, Cl 20.25, N 8.13. 1H NMR (500 MHz,
D2O, Me4Si): δ = 2.15 (m, 1 H), 2.29 (m, 1 H), 3.32 (m, 2 H), 3.42
(m, 2 H), 3.55 (m, 1 H) ppm. 13C NMR (125 MHz, D2O, Me4Si):
δ = 24.3 (CH2CH), 40.8 (q, J = 30.1 Hz, CHCF3), 44.6 (CH2N),
45.7 (CH2N), 126.5 (q, J = 277.2 Hz, CF3) ppm. 19F NMR
(477 MHz, DMSO, Me4Si): δ = –69.1 (d, J = 8.1 Hz) ppm. MS
(CI): m/z (%) = 140.
1
4.74; found C 52.75, H 3.83, N 4.81. H NMR (500 MHz, CDCl3,
Me4Si): δ = 3.85 (s, 2 H, CH2Ph), 3.90 (s, 4 H, CH2N), 7.34–7.43
(m, 5 H, C6H5) ppm. 13C NMR (125 MHz, CDCl3, Me4Si): δ =
59.3 (CHNCH2), 59.5 (NCH2Ph), 120.1 (q, J = 274 Hz, CF3), 127.6
(CH, Ph), 128.5 (CH, Ph), 128.7 (CH, Ph), 133.6 (m, CHCF3),
137.7 (CH, Ph) ppm. 19F NMR (477 MHz, CDCl3, Me4Si): δ =
–61.9 (s) ppm. MS (CI): m/z (%) = 296.
1-Benzyl-3,3-bis(trifluoromethyl)pyrrolidine (11): Compound
5
(123.0 g, 0.518 mol, 1 equiv.) was diluted in anhydrous dichloro-
methane (1000 mL) under an argon atmosphere. The obtained
solution was cooled to –20 °C and alkene 10 (93.5 g, 0.57 mol,
1.1 equiv.) was added at the same temperature. A solution of tri-
fluoroacetic acid (5.9 g, 0.05 mol, 0.1 equiv.) in anhydrous dichloro-
methane (250 mL) was added dropwise at –20 °C and the obtained
solution was first stirred at the same temperature for 4 h and then
for 3 h at room temperature. The reaction mixture was then neu-
tralized by addition of saturated aqueous NaHCO3. The organic
tert-Butyl 3,4-Bis(trifluoromethyl)-2,5-dihydro-1H-pyrrole-1-carb-
oxylate (15): α-Chloroethyl chloroformate (26.6 g, 0.186 mol,
1.1 equiv.) was added to a solution of 13 (50.0 g, 0.17 mol, 1 equiv.)
in anhydrous dichloroethane (250 mL) with vigorous stirring at
0 °C for 20 min under argon. The reaction mixture was then heated
at reflux for 3 h, then cooled and the solvent was removed under
reduced pressure (rotary evaporator). The obtained oil was diluted
phase was washed with brine (3ϫ 300 mL), separated, and dried in anhydrous methanol (750 mL) then heated at reflux for 3 h. The
with anhydrous sodium sulfate Na2SO4. The solvent was removed
under reduced pressure (rotary evaporator) and the resulting oil
was purified by flash chromatography (hexane/ethyl acetate/tri-
fluoroethanol, 68:22:10) to give product 11 (149.0 g, 0.5 mol, 97%
yield) as a colorless oil. TLC [SiO2, hexane/ethyl acetate/trifluoro-
ethanol = 68:22:10]: Rf = 0.45. C13H13F6N (297.24): calcd. C 52.53,
H 4.41, N 4.71; found C 52.60, H 4.37, N 4.81. 1H NMR
solvent was removed to dryness under vacuum, and the obtained
intermediate 14·HCl was directly used in the next step without fur-
ther purification. Boc2O (45.8 g, 0.21 mol, 1.25 equiv.) was added
dropwise to the suspension of 14·HCl in anhydrous dichlorometh-
ane (400 mL) at room temperature. The reaction mixture was
stirred for 5 h at 40 °C, then cooled and washed with water (2ϫ
100 mL), 10% aqueous solution of citric acid (2ϫ 100 mL), a satu-
(500 MHz, CDCl3, Me4Si): δ = 2.21 (m, 2 H, CH2CH2N), 2.72 (m, rated solution of NaHCO3 (3ϫ 100 mL), and brine (3ϫ 100 mL),
6
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β-Trifluoromethyl-Substituted Pyrrolidines
then the organic phase was separated and dried with anhydrous
Na2SO4. The solvent was removed under reduced pressure to afford
cis-1-Benzyl-3,4-bis(trifluoromethyl)pyrrolidine (18): Triethylamine
(1.45 g, 0.014 mol, 1.2 equiv.), benzaldehyde (1.3 g, 0.013 mol,
the product 15 (39.9 g, 0.13 mol, 77% from 13) as a white solid, 1 equiv.), and NaBH(OAc)3 (3.56 g, 0.017 mol, 1.45 equiv.) were
m.p. 88–91 °C. C11H13F6NO2 (305.22): calcd. C 43.29, H 4.29, N
4.59, O 10.48; found C 43.32, H 4.16, N 4.62, O 10.38. H NMR
(500 MHz, CDCl3, Me4Si): δ = 1.49 [s, 9 H, C(CH3)3], 4.49 (br s,
consecutively added to a cold suspension of amine 4·HCl (3.0 g,
0.012 mol, 1 equiv.) in anhydrous THF (100 mL) at room tempera-
ture. The reaction mixture was stirred for 12 h at room temperature,
1
2 H, CH2N), 4.53 (br s, 2 H, CH2N) ppm. 13C NMR (125 MHz, then diluted with saturated NaHCO3 (100 mL) and extracted with
CDCl3, Me4Si): δ = 28.3 (s, CH3), 53.4 (s, CH2), 81.1 [s, C(CH3)3], dichloromethane (3ϫ 50 mL). The organic phase was washed with
119.4 (q, J = 265.2 Hz, CF3), 131.8 (m, CHCF3), 153.0 (s,
C=O) ppm. 19F NMR (477 MHz, CDCl3, Me4Si): δ = –62.2 ppm.
MS (CI): m/z (%) = 305.
water (50 mL) and brine (3ϫ 50 mL), then separated and dried
with anhydrous Na2SO4. The solvent was removed under reduced
pressure to afford crude 18, which was purified by flash chromatog-
raphy (hexane/ethyl acetate/trifluoroethanol, 68:22:10) to give pure
18 (2.3 g, 0.008 mol, 65%) as a yellow oil. TLC (SiO2, hexane/ethyl
acetate/trifluoroethanol, 68:22:10): Rf = 0.3. C13H13F6N (297.24):
tert-Butyl cis-3,4-Bis(trifluoromethyl)pyrrolidine-1-carboxylate (16):
Compound 15 (39.9 g, 0.13 mol) was dissolved in anhydrous meth-
anol (500 mL) and 10% palladium on charcoal (5.0 g) was added.
This mixture was hydrogenated at room temperature under hydro-
gen pressure of 5 atm. for 3 h, then the catalyst was filtered through
a pad of Celite (ca. 1 cm), which was subsequently washed with
anhydrous methanol (2ϫ 100 mL). The solvent was evaporated un-
der reduced pressure to afford 16 (40.0 g, 0.13 mol, 100%) as a
colorless solid, m.p. 44–47 °C. C11H15F6NO2 (307.23): calcd. C
43.00, H 4.92, N 4.56, O 10.41; found C 43.09, H 5.01, N 4.49, O
10.38. 1H NMR (500 MHz, CDCl3, Me4Si): δ = 1.47 [s, 9 H,
1
calcd. C 52.53, H 4.41, N 4.71; found C 52.48, H 4.49, N 4.65. H
NMR (500 MHz, CDCl3, Me4Si): δ = 2.71 (m, 2 H, CHCF3), 3.11
(m, 2 H, CH2NBn), 3.21 (m, 2 H, CH2NBn), 3.72 (s, 2 H, CH2Ph),
7.31–7.39 (m, 5 H, PhH) ppm. 13C NMR (125 MHz, CDCl3,
Me4Si): δ = 42.8 (m, CHCF3), 53.2 (s, CH2NBn), 59.6 (s,
NCH2Ph), 125.8 (q, J = 280.1 Hz, CF3), 127.5, 128.49, 128.5,
137.9 ppm. 19F NMR (477 MHz, CDCl3, Me4Si): δ = –65.9
(m) ppm. MS (CI): m/z (%) = 298.
Supporting Information (see footnote on the first page of this arti-
cle): Crystallographic data and structure description for com-
pounds 11·HCl and 17. Spectroscopic data for all new compounds.
pKa, logD and CLint measurements for compounds 9, 11, 18, and
19.
C(CH3)3], 3.10 (br s,
2 H, CHCF3), 3.64–3.78 (m, 4 H,
CH2N) ppm. 13C NMR (125 MHz, CDCl3, Me4Si): δ = 28.3 (s,
CH3), 42.7 (m, CHCF3), 45.1 (s, CH2N), 80.8 [s, C(CH3)3], 124.8
(q, J = 276.0 Hz, CF3), 153.7 (s, C=O) ppm. 19F NMR (477 MHz,
CDCl3, Me4Si): δ = –67.4 (d, J = 4.1 Hz) ppm. MS (CI): m/z (%)
= 307.
Acknowledgments
cis-3,4-Bis(trifluoromethyl)pyrrolidine Hydrochloride (4·HCl): HCl
(12 n aq., 30 g, 0.29 mol, 2.2 equiv.) was slowly added to an ice-cold
solution of 16 (40.0 g, 0.13 mol, 1 equiv.) in anhydrous methanol
(200 mL). The reaction mixture was stirred for 5 h at 50 °C, then
cooled and the solvent was removed under reduced pressure (rotary
evaporator) to afford amine 4·HCl (30.9 g, 0.13 mol, 98%) as a
colorless solid. M. p. = 136–139 °C. C6H8ClF6N (243.58): calcd. C
29.59, H 3.31, Cl 14.55, N 5.75; found C 29.52, H 3.29, Cl 15.01,
N 5.69. 1H NMR (500 MHz, D2O, Me4Si): δ = 3.67 (m, 4 H,
CH2N), 3.73 (m, 2 H, CHCF3) ppm. 13C NMR (125 MHz, D2O,
Me4Si): δ = 42.1 (m, CHCF3), 44.7 (s, CH2N), 123.4 (q, J =
281.1 Hz, CF3) ppm. 19F NMR (477 MHz, D2O, Me4Si): δ = –65.8
(m) ppm. MS (CI): m/z (%) = 207.
All authors are grateful to Prof. Andrei Tolmachev for helpful dis-
cussion and Enamine Ltd. for financial support of the work.
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Benzyl cis-3,4-Bis(trifluoromethyl)pyrrolidine-1-carboxylate (17):
Triethylamine (4.8 g, 0.048 mol, 2.4 equiv.) and a solution of benzyl
chloroformate (3.56 g, 0.021 mol, 1.1 equiv.) in THF (50 mL) was
consecutively added dropwise to an ice-cold suspension of 4·HCl
(5.0 g, 0.020 mol, 1 equiv.) in anhydrous THF (100 mL). The ob-
tained mixture was stirred for 5 h at room temperature, then the
reaction mixture was diluted with saturated NaHCO3 (100 mL) and
extracted with dichloromethane (3ϫ 50 mL). The organic phase
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0.017 mol, 87% yield) as
a yellow solid, m.p. 84–86 °C.
C14H13F6NO2 (341.25): calcd. C 49.28, H 3.84, N 4.10, O 9.38;
found C 49.33, H 3.92, N 4.14, O 9.46. 1H NMR (500 MHz,
CDCl3, Me4Si): δ = 3.13 (br s, 2 H, CHCF3), 3.76–3.87 (m, 4 H,
CH2NCbz), 5.18 (q, J = 13.1 Hz, 2 H, CH2O), 7.35–7.40 (m, 5
H, PhH) ppm. 13C NMR (125 MHz, CDCl3, Me4Si): δ = 42.7 (m,
CHCF3), 45.0 (s, CH2NCbz), 45.6 (s, CH2NCbz), 67.5 (s, CH2O),
124.9 (m, J = 257.1 Hz, CF3), 128.0, 128.3, 128.6, 136.2, 154.2 (s,
C=O) ppm. 19F NMR (477 MHz, CDCl3, Me4Si): δ = –67.3 ppm.
MS (CI): m/z (%) = 341.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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P. K. Mykhailiuk et al.
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Received: January 23, 2013
Published Online: ᭿
8
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/KAP1
Date: 27-03-13 18:57:36
Pages: 9
β-Trifluoromethyl-Substituted Pyrrolidines
Fluorinated Pyrrolidines
Three β-(trifluoromethyl)ated pyrrolidines
have been synthesized on multigram scales.
The influence of the CF3 group on the
physicochemical properties of the pyrrol-
idine fragment has been studied.
V. S. Yarmolchuk, O. V. Shishkin,
V. S. Starova, O. A. Zaporozhets,
O. Kravchuk, S. Zozulya, I. V. Komarov,
P. K. Mykhailiuk* ............................. 1–9
Synthesis and Characterization of β-Tri-
fluoromethyl-Substituted Pyrrolidines
Keywords: Synthetic methods / Medicinal
chemistry / Drug design / Drug discovery /
Nitrogen heterocycles / Amines / Fluorine
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