Synthesis of 2- and 3-trifluoromethylmorpholines: Useful building blocks for drug discovery

Article abstract of DOI:10.1016/j.tet.2013.03.067

2- and 3-Trifluoromethylmorpholines were prepared in racemic and optically active forms. The synthesis commenced from the commercially available 2-trifluoromethyloxirane. The elaborated procedures were scalable, and the products were obtained in multigram quantities. The obtained compounds were comprehensively characterized by crystallographic analysis, fluorescence measurements, solubility, pK_a, logD parameters, and clearance rate. The potential of the synthesized amines as the building blocks for drug discovery is thus demonstrated.

Full text of DOI:10.1016/j.tet.2013.03.067

Accepted Manuscript
Synthesis of 2- and 3-Trifluoromethylmorpholines: useful building blocks for drug
discovery
Andriy V. Shcherbatiuk, Oleg S. Shyshlyk, Dmytro V. Yarmoliu, Oleg V. Shishki,
Svitlana V. Shishkina, Viktoriia S. Starova, Olga A. Zaporozhets, Sergey Zozulya,
Roman Moriev, Olga Kravchuk, Olga Manoilenko, Andrey A. Tolmachev, Pavel K.
Mykhailiuk
PII:
S0040-4020(13)00456-0
10.1016/j.tet.2013.03.067
TET 24158
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 1 December 2012
Revised Date: 27 February 2013
Accepted Date: 18 March 2013
Please cite this article as: Shcherbatiuk AV, Shyshlyk OS, Yarmoliu, DV, Shishki, OV, Shishkina
SV, Starova VS, Zaporozhets OA, Zozulya S, Moriev R, Kravchuk O, Manoilenko O, Tolmachev AA,
Mykhailiuk PK, Synthesis of 2- and 3-Trifluoromethylmorpholines: useful building blocks for drug
discovery, Tetrahedron (2013), doi: 10.1016/j.tet.2013.03.067.
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
our customers we are providing this early version of the manuscript. The manuscript will undergo
copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please
note that during the production process errors may be discovered which could affect the content, and all
legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT
Synthesis of 2- and 3-Trifluoromethylmorpholines: useful building blocks
for drug discovery.
Andriy V. Shcherbatiuk,a,b Oleg S. Shyshlyk,a,b Dmytro V. Yarmoliuk,a,b Oleg V. Shishkin,c Svitlana
V. Shishkina,c Viktoriia S. Starova,b Olga A. Zaporozhets,b Sergey Zozulya,a Roman Moriev,a Olga
Kravchuk,a Olga Manoilenko,a Andrey A. Tolmachev,a,b and Pavel K. Mykhailiuka,b
aEnamine Ltd., Oleksandra Matrosova Street, 23, Kyiv 01103, Ukraine
bDepartment of Chemistry, Taras Shevchenko National University of Kyiv, Volodymyrska str., 64, 01601 Kyiv, Ukraine
cSTC, ´Institute for Single Crystalls,´ National Academy of Science of Ukraine, 60 Lenina ave., Kharkiv 61001, Ukraine
Pavel.Mykhailiuk@gmail.com
Cl
O
F
O
NH
CF3
N
O
N
N
N
N
Gefitinib
Synthesis
Fluorescence
Clearance
Solubility
X-Ray
O
N
NH
Open space for
drug discovery
O
N
O
Cl
Moclobenide
pKa
logD
CF3
O
O
O
NHAc
N
N
F
O
Linezolid
Abstract
2- and 3-Trifluoromethylmorpholines were prepared in racemic and optically active forms. The
synthesis commenced from the commercially available 2-trifluoromethyloxirane. The elaborated
procedures were scalable, and the products were obtained in multigram quantities. The obtained
compounds were comprehensively characterized by crystallographic analysis, fluorescence
measurements, solubility, pKa, logD parameters and clearance rate. The potential of the synthesized
amines as the building blocks for drug discovery is thus demonstrated.
Key words
Morpholine, fluorine, trifluoromethyl group, drug discovery, trifluoropropylene oxide.
1

ACCEPTED MANUSCRIPT
Introduction
The morpholine fragment is commonplace in organic chemistry and drug discovery. Many bioactive
compounds,1,2 including nineteen FDA-approved drugs,3 contain this subunit (Figure 1). High
popularity of the morpholine moiety is caused by several factors. First, the oxygen atom in the
morpholine core can participate in the donor-acceptor type interactions with the corresponding
receptor, increasing binding affinity.4 Second, the electronegative effect of the oxygen atom reduces
the basicity of the nitrogen atom, compared to that of e.g. piperidine, which often has a beneficial
influence on pharmacological properties of a lead structure.5 Finally, attachment of the morpholine
fragment to lipophilic scaffolds frequently leads to improved aqueous solubility6 - an important
prerequisite of the launched oral pharmaceuticals.7 It is not surprising therefore that in modern drug
design, substituted morpholine derivatives are of great demand and use.8 Hence, elaboration of
synthetic approaches aimed at practical, rapid access to novel low-molecularweight morpholine
analogues is of genuine practical importance.
Cl
O
F
O
NHAc
N
O
NH
N
O
N
N
F
O
N
Gefitinib
Linezolid
2000, Pfizer
2003, AstraZeneca
OH
O
O
O
N
N
NH
O
N
NHtBu
N
N
N
S
NHCO2Et
S
O
Cl
O
Timolol
1978, Merck
Moricizine
1990, BMS
Moclobenide
1999, Roche
Figure 1. Some marketed drugs possessing the morpholine fragment.
Incorporation of the trifluoromethyl group into organic compounds can significantly change their
physicochemical and pharmacological characteristics. In fact, the trifluoromethyl substituent
effectively influences pKa of the neighboring functional groups, lipophilicity of the compound, its
solubility, conformational preferences, hydrolytic and metabolic stabilities.9 Indeed, medicinal
chemists gladly use the beneficial properties of the CF3-substituent in order to fine-tune the activity,
selectivity and ADMET parameters of “hit” structures (Figure 2).10,11,12 Incorporation of the CF3-group
into bioactive compounds usually requires the corresponding trifluoromethylated building blocks.13
Medicinal chemists are encouraged to test a full library of isomeric building blocks in order to perform
full structure-activity relationship studies. This strategy enables stepwise modulation of the compound
geometry, while keeping its molecular weight constant, according the “minimal modification
principle.”14
2

ACCEPTED MANUSCRIPT
hydrolitic
stability
increased
F
pKa of amino group
CF3
CF3
O
O
N
Cl
H
HN
N
O
CN
H
MeO2S
Odanacatib
Efavirenz
2008, Merck
1998, BMS
CF3
enhanced
lipophilicity
O
metabolic
stability
N
N
N
F3C
CF3
CF3
N
H2N
O
O
N
HO
CF3
F
interractions
with receptor
F
N
F
F
O
HO
OH
HN
NH
Falicalcitral
2001, Sumitomo
Sitagliptin
Aprepitant
2003, Merck
2006, Merck
Figure 2. Some pharmacologically important compounds with the trifluoromethyl group.
Given the importance of morpholines and its analogues in medicinal area, isomeric 2- (1) and 3-
trifluoromethylmorpholines (2) seem to be conceptually attractive (Figure 3). The presence of the
trifluoromethyl substituent at a definite position of the morpholine core would multidimensionally
change its metabolic stability, bacisity and lipophilicity. Although, during the last decade several
patents mentioning application of amines 1, 2 in drug discovery projects appeared,15 their preparation
is still not comprehensively described in the literature.16,17
O
O
CF3
O
N
H
N
H
N
H
CF3
Morpholine
1
2
Figure 3. Morpholine and its trifluoromethylated analogues 1, 2.
In this work, we report on the practical multigram preparation of amines 1, 2 in the both racemic and
optically active forms. The obtained compounds are comprehensively characterized by
crystallographic analysis, fluorescence measurements, solubility, pKa, logD parameters and clearance
rate. The usefulness of amines 1, 2 as the building blocks has been studied.
Results and Discussion
Design. The logic of our retrosynthetic approach to both compounds 1 and 2 is depicted in Scheme 1.
The key synthesis step - construction of the morpholinone core (3, 4) - was planned to be performed
by cyclization of the corresponding N-protected 1- (5) and 2-trifluoromethyl-substituted 2-
aminoalcohols (6)18 with 2-chloroacetylchloride. Reduction of the amide bond in 3, 4 followed by
cleavage of the N-protecting group was expected to provide the target amines.
3

ACCEPTED MANUSCRIPT
PG: protecting group
O
HO
O
CF3
CF3
CF3
O
N
HN
N
H
PG
3, 4
PG
5, 6
1, 2
Scheme 1. Retrosynthetic analysis of amines 1 and 2.
In a search for an appropriate N-protecting group, we investigated a benzyl group, because a) it is an
electron-donating group, which might facilitate the acylation reaction of the deactivated amino moiety
in compound 6;19 b) it can be cleaved from the nitrogen atom by hydrogenolysis in quantitative yield.20
Chemistry. The synthesis of amine
1
commenced from the commercially available
trifluoromethyloxirane 7 (Scheme 2). Ring-opening reaction with benzylamine afforded compound 5
according to the literature protocol.21 Acylation of amine 5 with 2-chloroacetylchloride followed by
cyclization of the obtained intermediate 8 by K2CO3 gave pure morpholinone 3 in 62% isolated yield.
Reduction of amide 3 with NaBH4/Et2O*BF3 resulted in formation of amine 9. Finally, cleavage of N-
benzyl group by hydrogenolysis using 10% Pd/C as a catalyst accomplished the preparation of amine
1*HCl in 87% yield. The structure of the obtained compound was confirmed by X-Ray
crystallographic analysis (Figure 4).
O
N
CF3
K2CO3
MeOH/H2O
Cl HO
CF3
HO
HN
CF3 ClCH2COCl
Et3N, CH2Cl2
CF3
BnNH2
O
70%
Ref. 20
62%
(2 steps)
O
O
N
Ph
Ph
Ph
7
5
8
3
Et2O*BF3
NaBH4, THF
O
N
CF3
Pd/C, H2
MeOH
O
CF3
*HCl
81%
87%
N
H
single run:
Ph
43 g
1
9
Scheme 2. Synthesis of amine 1.
For the preparation of amine 2, aminoalcohol 5 was converted first into aziridine 1022 by treating with
PPh3/CCl4 (Scheme 3).23 Ring-opening reaction of compound 10 with aq. sulfuric acid gave the
isomeric aminoalcohol 6 in 76% yield.24 Uneyama et. al. reported previously,21 that mono-acylation of
alcohol 6 proceeded at the hydroxyl group, because of the reduced reactivity of the amino function.17
Therefore, we used excess of 2-chloroacetylchloride to form the bis-acylated product 11. Cyclization
of intermediate 11 with K2CO3 gave morpholinone 4 in 63% yield. Reduction of amide 4 with
NaBH4/Et2O*BF3 gave tertiary amine 12. Subsequent cleavage of N-benzyl group in compound 12 by
hydrogenolysis over Pd/C as a catalyst finished the synthesis of amine 2*HCl. The structure of
morpholine 2*HCl was confirmed by X-Ray crystallographic analysis (Figure 4).
4

ACCEPTED MANUSCRIPT
O
Cl
Cl
PPh3, CCl4
Et3N, MeCN
CF3
HO
HN
CF3
H2SO4
H2O
ClCH2COCl
Et3N, CH2Cl2
HO
HN
6
O
N
N
30%
76%
Ref. 23
CF3
Ph
O
CF3
Ph
Ph
10
11
5
Ph
O
N
O
Et2O*BF3
NaBH4, THF
K2CO3
MeOH/H2O
Pd/C, H2
MeOH
O
*HCl
CF3
CF3
Ph
63%
(2 steps)
73%
89%
O
N
CF3
N
H
single run:
Ph
2
4
12
11 g
Scheme 3. Synthesis of amine 2.
The practical application of various building blocks in medicinal projects strongly depends on the
usefulness of the corresponding synthetic protocols to them.25 Even the most conceptually attractive
compounds, which are scarcely accessible, have a low potential to find the true implementation in
medicinal research. Therefore, it is important to emphasize that the optimized synthetic procedures to
amines 1, 2 were fully reproducible upon scaling up and were appropriately used to prepare multigram
quantities of the target products. In particular, 43 g of amine 2 and 11 g of amine 126 were easily
obtained in one synthesis run from epoxide 7.27
Both the molecules 1 and 2 are chiral. Therefore, we next demonstrated the utility of the developed
protocols for the preparation of the optically active compounds. Oxide (S)-7 was obtained by kinetic
resolution of rac-7 according to the literature procedure (Scheme 4).28 Enantiomerically pure amines
(S)-1 and (R)-2 were synthesized from (S)-7, following the above described strategy.29 Optical purity
of the obtained products was >97% ee, as revealed by Mosher`s reagent30 and chiral HPLC
(Supporting information).
(R,R)-cobalt
salen catalyst
O
CF3
O
CF3
CF3
*HCl
CF3
H2O
*HCl
O
O
42%
ee > 99%
Ref. 27
N
H
N
H
rac-7
(S)-7
(S)-1
(R)-2
Scheme 4. Synthesis of amines (S)-1 and (R)-2.
Crystallographic analysis. To reveal the impact of the trifluoromethyl substituent on the geometry of
the morpholine, crystallographic analysis of the both amines 1 and 2 was performed (Figure 4).
Crystals of the compounds, suitable for an X-Ray diffraction study, were obtained by a slow
evaporation of diluted solutions of 1*HCl and 2*HCl in ethanol.
a)
5

ACCEPTED MANUSCRIPT
b)
Figure 4. Molecular structure according to X-ray diffraction data of a) compound 1*HCl; b)
compound 2*HCl. Thermal ellipsoids for compound 1*HCl are shown at the 30 % probability level;
for compound 2*HCl - at the 50 % probability level.
Analysis of the molecular structure of two molecules (A and B) observed in the asymmetric part of the
unit cell of compound 1*HCl and compound 2*HCl demonstrated that the heterocycle adopted a chair
conformation with the packing parameters31 S = 1.16, Θ = 3.3°, Ψ = 2.6° for 1A; S = 1.18, Θ = 3.1°, Ψ
= 10.7° for 1B and S = 1.20, Θ = 2.3°, Ψ = 14.2° for 2. In both compounds, the trifluoromethyl group
had an equatorial orientation (the N(1)-C(3)-C(4)-C(5) torsion angle is -177.7(8)° in 1A and 178.7(9)°
in 1B and the O(1)-C(3)-C(4)-C(5) torsion angle is -178.2(2)° in molecule 2). One could expect that
the trifluoromethyl group might influence the bond lengths within the heterocycle. Comparison of the
bond lengths in the molecules of morpholine hydrochloride32 and 1*HCl, 2*HCl, however, did not
show a clear correlation (Figure 5).
6

ACCEPTED MANUSCRIPT
O
O
CF3
1.430
O
CF3
1.418
O
1.414
1.414
1.434
1.416
1.418
1.413
1.506
1.506
1.512
1.499
1.476
1.501
1.498
1.514
1.485
1.492
1.480
1.474
1.498
1.464
1.483
1.479
N
H
N
H
N
H
N
H
CF3
1*HCl
molecule B
1*HCl
molecule A
2*HCl
Morpholine*HCl
Figure 5. Selected bond lengths (Å) in morpholine hydrochloride32 and 1*HCl, 2*HCl according to X-
Ray data.
Quantum-chemical calculations by m06-2x/aug-cc-pvtz method33,34 using GAUSSIAN09 program35
for nonprotonated molecules of morpholine and 1, 2 confirmed that the trifluoromethyl group did not
have significant influence on the bond lengths within the heterocycle (see Supporting Information).
Influence of the trifluoromethyl group on pKa. In medicinal chemistry, the pKa of functional groups
is an important characteristic of bioactive compounds.36 Therefore, an influence of the trifluoromethyl
substituent on the pKa of the amino group in compounds 9 and 12 was studied next. Amine 13 was
used as a reference point. pKa measurements were performed by potentiometric titration (see
Supporting Information).
Table 2. Measured physicochemical and biochemical properties of compounds 9, 12, 13.
O
O
CF3
O
Characteristic
N
N
N
CF3
12
13
9
Ph
Ph
Ph
a
pKa
7.6
1.4
1.8
423
84
5.2
1.7
b
logD7.4
logPc
Sol. (pH 7.4)e
Sol. (pH 10)f
2.9
2.9
72
>2.5d
>2.5
97
70
80
g
CLint
14
42
52
a pKa values for the corresponding conjugated acids are shown. b Experimental logarithm of the n-octanol/water distribution
d
coefficient at pH 7.4. c Intrinsic lipophilicity of the neutral base, according to logP = logD + log10(1 + 10(pKa-pH)). Not
precisely determined because of insufficient UV absorption. e Kinetic aqueous solubility in 50 mM phosphate buffer (pH
7.4). f Kinetic aqueous solubility in 50 mM glycine buffer (pH 10). g Intrinsic clearance rate CLint (mg/(min×µL)) measured
in mouse liver microsomes.
The experimental pKa of amine 13 was 7.6, whereas the pKa of amine 9 was 5.2, indicating that
incorporation of the trifluoromethyl group at the β-position to a nitrogen atom led to ∆pKa = -1.4
(Table 2).37 The measured pKa of compound 12 was 1.7. The α-trifluoromethyl group made amine 12
six orders of magnitude (!) less basic than the parent compound 13 (∆pKa = -5.9). Two factors seemed
to be responsible for such a strong effect. Indeed, the electron-withdrawing nature of the
trifluoromethyl group effectively reduced the basicity of the adjacent nitrogen atom.19 Additionally,
however, the bulky α-trifluoromethyl substituent might have sterically prevented protonation of the
nitrogen atom which additionally decreased the basicity.
7

ACCEPTED MANUSCRIPT
O
N
O
N
CF3
O
N
CF3
Ph
Ph
Ph
13
9
12
basicity
Figure 6. Schematic representation of basicity of compounds 9, 12 and 13.
Toxicity of bioactive compounds is frequently associated with basic nitrogen atoms.36,38 Given the
fact, that incorporation of the trifluoromethyl group into the morpholine fragment does not have any
valuable effect on the compound conformation, but does effectively reduce basicity of the nitrogen
atom (Figure 6), amines 1 and 2 seem to be promising replacements for the morpholine residue, if high
toxicity of the corresponding bioactive derivatives is observed.
Impact of the trifluoromethyl group on fluorescence. With the aim to estimate an influence of the
trifluoromethyl group on the morpholine fragment comprehensively, fluorescence measurements of
both compounds 9 and 12 were performed. N-benzyl morpholine 13 was used as the reference point.
Excitation spectra of all compounds in aqueous solution (λem = 447 nm) had two maxima - at 277 and
364 nm (Supporting information). Under excitation at the both 277 and 364 nm, the fluorescence
spectra still had one identical maximum at 447 nm. Importantly, however, that both the fluorescence
and emission spectra of trifluoromethyl-substituted compounds 9 and 12 had significantly higher
intensity than those of amine 13 under identical concentrations. This difference indicated for the
change of polarity and lipophilicity of the morpholine fragment upon incorporation of the
trifluoromethyl substituent. Subsequent logD/logP measurements confirmed this suggestion.
Impact of the trifluoromethyl group on lipophicility. Lipophilicity is another key characteristic of
bioactive compounds. For example, oral drugs must be lipophilic enough to effectively cross the
biomembrane. Therefore, we next studied an influence of the trifluoromethyl substituent on the
lipophilicity of the morpholine core. The experimental lipophilicity (logD) of amines, measured at pH
7.4, reflects the intrinsic lipophilicity of the neutral compound (logP) and the effect of partial
protonation at the given pH.39 Since the trifluoromethyl group impacted both basicity and intrinsic
lipophilicity, we decided to separate the two effects.
Incorporation of the trifluoromethyl group at the β-position to a nitrogen atom (9) led to significant
increase of the intrinsic lipophilicity with ∆logP = 2.9-1.8 = 1.1 (Table 2). An increase of logP was
also seen for compound 12. It is worth mentioning, that in contrast to the parent amine 13, in
compound 9 the determined logP and logD characteristics were identical. This observation clearly
indicated that the trifluoromethyl fragment in amine 9 completely preserved protonation of a nitrogen
atom at pH 7.4. The same effect seemed to be true for compound 12.
In general, incorporation of the trifluoromethyl moiety into the morpholine fragment increases the
intrinsic lipophilicity (logP) and prevents protonation of the nitrogen atom. The latter effect results in
more pronounced increase of the logD7.4 (2.9-1.4 = 1.5 for 9) value compared to that of logP (1.5 vs
1.1 for 9). Therefore, if low absorption of morpholine-containing bioactive compounds is observed,
amines 1 and 2 seem to be useful replacements for the morpholine residue, because this substitution
will increase lipophilicity of the corresponding derivatives.
Impact of the trifluoromethyl group on aqueous solubility. The changes in lipophilicity are also
supposed to influence the solubility. Therefore, we measured the aqueous solubility of compounds 9,
12 and 13 (Table 2).
At pH 10 the aqueous solubility of the reference compound 13 was ca. 5 times higher than that at pH
7.4. Obviously, this difference was due to partial protonation of the nitrogen atom at pH = 7.4 (pKa of
13 = 7.6), which increased the water solubility. Incorporation of the trifluoromethyl substituent (9, 12)
8

ACCEPTED MANUSCRIPT
prevented protonation of the nitrogen atom. Therefore, aqueous solubility of the both compounds 9, 12
at pH 7.4 (nitrogen atom is not protonated) was very similar to that of compounds 9, 12, 13 at pH 10
(nitrogen atom is not protonated either) and was in the range 72-97 mM. From these data, two
important conclusions can be made. Replacement of the morpholine fragment for amines 1 and 2 in
organic compounds significantly reduces their water solubility, under the beneficial conditions for
protonation of a nitrogen atom - for example in N-alkyl morpholines at pH 7.4. On the other hand,
such replacement seems to not significantly change the aqueous solubility of organic compounds when
nitrogen atom is not protonated - for example in amides of morpholine.
Impact of the trifluoromethyl group on metabolic stability. In medicinal chemistry incorporation of
fluorine-containing substitutions into organic compounds is frequently used to block their metabolic
degradation.10,40 Therefore, amines 9 and 12 were expected to have higher metabolic stability
compared to that of amine 13. To text this hypothesis experimentally, all compounds were subjected
to standardized preparations of mouse liver microsomes, and the remaining unchanged material was
determined at several time intervals of incubation at 37 °C. This test yielded pseudo-first-order rate
constants for oxidative degradation, intrinsic clearance rates (CLint), that provided useful indications
for phase I metabolism. Unexpectedly, however, both trifluoromethyl-substituted amines 9, 12 had
higher clearance rate over that of compound 13 (Table 2, Figure 7).
O
N
O
N
CF3
O
N
CF3
Ph
Ph
Ph
13
9
12
metabolic stability
Figure 7. Relative metabolic stability of compounds 9, 12, 13 measured in mouse liver microsomes.
Recently, Wuitschik et al observed a similar anomaly.39 In particular, incorporation of the
electronegative oxetane unit near the basic nitrogen atom led to an increase of the clearance rate. The
authors explained this observation by “strong basicity-lowering effect on the amine by the close
oxetane unit, rendering the compound much more lipophilic (logD) than its parent amine and thus
increasing its exposure to membrane-bound cytochrome P450 enzymes.” Taking into account the low
basicity of both compounds 9 and 12, the same explanation seems to be valid for our case.
Impact of the trifluoromethyl group on reactivity. Keeping in mind that incorporation of the
trifluoromethyl substituent into the morpholine fragment drastically decreased basicity of the amino
group, it was very important to find out whether the amines 1 and 2 could be functionalized at the
nitrogen atom. Acylation of the amino group is the most frequently used reaction in medicinal
chemistry,41 and therefore exactly this transformation was investigated.
Bioactive morpholine derivative 14 was randomly selected from recent literature (Figure 8).42 This
compound was reported to be a potent inhibitor of FKBP12 protein, which catalyzed the cis-trans
isomerization of peptidyl-prolyl bonds.
9

ACCEPTED MANUSCRIPT
O
N
O
Kd (µM) = 0.2
S
14
Figure 8. Structure of the potent inhibitor 14 of FBKP12 protein and its binding affinity.43
In this context, we performed the one-step acylation of both amines 1 and 2 with acid 15 to afford the
trifluoromethylated analogues 16 and 17 of bioactive compound 14 (Scheme 5).
O
N
O
N
CF3
O
O
CF3
HO2C
CF3
N
H
CF3
N
H
S
1
2
O
O
S
S
TBTU
TBTU
DMF, NEt3
r.t.
DMF, NEt3
r.t.
55%
75%
17
15
16
Scheme 5. Synthesis of compounds 16, 17.
Both reactions smoothly proceeded in dimethylformamide at room temperature using TBTU as a
coupling agent. Pure product 16 was isolated form the reaction mixture in 55% yield, whereas product
17 - in 75% yield. Compounds 16, 17 were chemically stable and did not decompose upon storage.
The all above described experiments clearly demonstrate that in spite of reduced nucleophilicity of the
amino group, both amines 1 and 2 do have a high potential to be used as the valuable building blocks
for drug discovery projects.
Conclusion
We have developed practical synthetic approaches to isomeric 2- and 3-trifluromethyl-substituted
morpholines 1, 2. The compounds were obtained in both racemic and enantiomerically pure forms. 43
g of amine 1 and 11 g of amine 2 were easily obtained in one synthesis run from oxirane 3.
Incorporation of the trifluoromethyl substituent into the morpholine fragment did not change its
geometry, but did have a significant effect on the fluorescent properties, pKa, logD and CLint
characteristics. In particular, the trifluoromethyl group reduced the basicity of the morpholine
fragment and increased its lipophilicity. In spite of reduced lipophilicity of the amino group, acylation
of the both amines 1 and 2 was easily performed under standard reaction conditions. With rapid
multigram access, we therefore believe that building blocks 1, 2 will find true practical applications in
drug discovery projects. Especially these amines seem to be useful, when biologically active
derivatives of morpholine are a) toxic due to the basic nitrogen atom; b) have low absorption because
of a low lipophilicity; c) have additional lipophilic substituents on the morpholine core, which are
involved in the hydrophobic interactions with a receptor.43
Experimental section
10

ACCEPTED MANUSCRIPT
Solvents were purified according to standard procedures. Column chromatography was performed
1
using Kieselgel Merck 60 (230-400 mesh) as the stationary phase. H-, 19F-, 13C-NMR spectra were
recorded on at 499.9 MHz, 470.3 MHz and 124.9 MHz. Chemical shifts are reported in ppm downfield
from TMS (1H, 13C) or CFCl3 (19F) as internal standards. MS analyses were done on an LCMS
instrument with chemical ionization (CI) or GCMS instrument with electron impact ionization (EI).
N-Benzyl-1-trifluoromethylaminoethanol (5)
Trifluoromethyloxirane 7 (175.0 g, 1.56 mol) was added dropwise under stirring to benzylamine
(170.0 g, 1.56 mol) in order to produce a slight reflux. After cooling to ca. 40 C, the solution was
diluted with n-hexane (200 mL) and the stirring was continued for additional 2 h. The formed
precipitate was filtered off, washed with n-hexane (100 mL), n-hexane/ether (1:1, 100 mL) and dried
in air to yield 5 (242.1 g, 1.10 mol, 70% yield) as a white solid.
NMR spectroscopic data are identical to those reported previously.21
N-Benzyl-2-trifluoromethylmorpholin-5-one (3)
Chloroacetylchloride (60.0 g, 0.53 mol) was added dropwise to a mixture of aminoalcohol 5 (112.0 g,
0.51 mol) and NEt3 (112.0 g, 1.11 mol) in CH2Cl2 (1000 mL) under cooling with ice-bath. The mixture
was stirred overnight. Next, the reaction mixture was diluted with water, organic was washed with
saturated NaHCO3 solution, brine, dried and evaporated under reduced pressure. The dark oily residue
was taken up in methanol (500 mL). K2CO3 (100.0 g) and water (50 mL) were added and the mixture
was heated at reflux for 15 h. After cooling to room temperature, the mixture was evaporated to
dryness and semi-solid residue was dissolved in CH2Cl2 (500 mL), organic was washed with water
(2*250 mL), 2N HCl solution (250 mL), brine, dried over Na2SO4 and evaporated under reduced
pressure to obtain product 3 (82.0 g, 317.0 mmol, 62% yield) as a slightly yellow oil which was used
without any further purifications.
ν
max (KBr) 3033, 2927, 1665, 1494, 1452, 1413, 1348, 1280, 1178, 1150, 1083, 1043 cm-1
.
1H NMR (500 MHz; CDCl3; Me4Si), δ: 7.25-7.45 (5H, m); 4.75 (1H, d, J = 14.0 Hz); 4.56 (1H, d, J =
14.0 Hz); 4.48 (1H, d, J = 16.5 Hz); 4.27 (1H, d, J = 16.5 Hz); 4.25-4.15 (1H, m); 3.51 (1H, t, J = 11.5
Hz); 3.31 (1H, dd, J = 11.5, 3.0 Hz).
13C NMR (125 MHz; CDCl3; Me4Si), δ: 165.2 (s); 135.3 (s); 128.9 (s); 128.3 (s); 128.1 (s); 122.8 (q,
1J(C,F) = 278 Hz); 71.4 (q, 2J(C,F) = 34 Hz); 67.4 (s); 49.8 (s); 43.8 (s).
19F NMR (375 MHz; CDCl3; CFCl3), δ: -77.6 (d, 3J(F,H) = 7.5 Hz).
MS (m/z): 259 (M)+.
N-Benzyl-2-trifluoromethylmorpholine (9)
To a cooled solution of morpholinone 3 (82.0 g, 317 mmol) in dry THF (1000 mL) powdered sodium
borohydride was added (23.5 g, 620 mmol) in one portion. A mixture was stirred at 0 °C for 30 min
and Et2O*BF3 (82.6 mL, 620 mmol, freshly distilled over CaH2) was added dropwise over 45 min
while maintaining internal temperature -5 °C. The reaction mixture was heated at reflux for 2 h and
was allowed to stir overnight at room temperature. Next, methanol (250 mL) was carefully added
dropwise to the mixture under cooling with ice-bath. The reaction mixture was evaporated to dryness.
2N solution of HCl was added to the residue (750 mL). The above obtained solution heated at reflux
for 2 h. After cooling to room temperature it was extracted with CH2Cl2 (3*500 mL). The combined
organic phase was dried over Na2SO4 and evaporated under reduced pressure to obtain pure 9 (62.7 g,
256.0 mmol, 81% yield) as a colorless oil.
νmax (KBr) 2861, 1450, 1300, 1258, 1229, 1148, 1124, 1015 cm-1
.
1H NMR (500 MHz; CDCl3; Me4Si), δ: 7.4-7.26 (5H, m); 3.99 (2H, pseudo d, broad); 3.73 (1H, td, J =
11.0; 2.5 Hz); 3.58 (2H, s); 2.93 (1H, d, J = 11.0 Hz); 2.70 (1H, d, J = 11.0 Hz); 2.27 (1H, td, J = 11.0,
2.5 Hz), 2.21 (1H, t, J = 11.0 Hz).
13C NMR (125 MHz; CDCl3; Me4Si), δ: 137 (s); 129 (s); 128.5 (s); 127.5 (s); 123.5 (q, 1J(C,F) = 277.0
Hz); 73.7 (q, 2J(C,F) = 31.0 Hz); 67 (s); 63 (s); 52.2 (s); 51.2 (s).
19F NMR (375 MHz; CDCl3; CFCl3), δ: -78 (d, 3J(F,H) = 7.5 Hz).
11

ACCEPTED MANUSCRIPT
MS (m/z): 245 (M)+.
Anal. calcd for C12H14F3NO: C, 58.77; H, 5.75; N, 5.71. Found: C, 58.94; H, 5.59; N, 5.97.
2-Trifluoromethylmorpholine hydrochloride (1*HCl)
To a solution of amine 9 (62.7 g, 256.0 mmol) in methanol (400 mL) concentrated HCl (50 mL) and
Pd/C (10%, 20.0 g) were added. The mixture was vented off several times with Ar and stirred for 3 h
under atmosphere of H2. The mixture was filtered off and evaporated to dryness. The residue was
treated with a mixture of ether/acetone (1:1, 200 mL) and filtered off to yield pure 1 (43.1 g, 225.0
mmol, 87% yield) as a white solid, m.p. 187-188 ºC.
νmax (KBr) 3129, 2942, 2770, 2483, 2387, 1541, 1462, 1417, 1393, 1370, 1278, 1188, 1171, 1117,
1081, 1066, 1045 cm-1
.
1H NMR (500 MHz; DMSO-d6; Me4Si), δ: 10.18 (2H, bs); 4.68-4.59 (1H, m); 4.12 (1H, dd, J = 14.0
Hz, 3.0 Hz); 3.99 (1H, t, J = 12.0 Hz); 3.43 (1H, d, J = 12.0 Hz); 3.25 (1H, d, J = 12.0 Hz); 3.10 (1H,
td, J = 14.0, 3.0 Hz); 3.02 (1H, t, J = 12.0 Hz).
1
2
13C NMR (125 MHz; DMSO-d6; Me4Si), δ: 123.1 (q, J(C,F) = 278 Hz); 70.3 (q, J(C,F) = 32.5 Hz);
63.8 (s); 42.1 (s); 40.8 (s).
19F NMR (375 MHz; DMSO-d6; CFCl3), δ: -76.63 (d, 3J(F,H) = 7.5 Hz).
MS (m/z): 156 (M+1-Cl)+.
Anal. calcd for C5H9ClF3NO: C, 31.35; H, 4.74; N, 7.31. Found: C, 31.71; H, 4.70; N, 7.58.
N-Benzyl-trifluoromethylaziridine (10)
CCl4 (600 mL) was added to a solution of triphenylphosphine (625.0 g, 2.38 mol) in dry acetonitrile
(1650 mL) and the mixture was stirred for 1 h. A solution of compound 5 (130 g, 594.0 mmol) in
acetonitrile (2500 mL) and Et3N (415 mL) were added and the mixture was stirred for a 24 h. The
mixture was filtered off. The precipitate was extensively washed with hexane (1000 mL). The
combined organic phases were evaporated to dryness. Distillation of crude product under reduced
pressure afforded pure aziridine 10 (40 g, 199 mmol, 31% yield) as a slightly yellow liquid. B.p.= 120
°C (20 mbar). NMR spectroscopic data are identical to those reported previously.22
N-Benzyl-2-trifluoromethylaminoethanol (6)
To a suspension of trifluoromethylaziridine 10 in water (600 mL) was added conc. H2SO4 (11.7 mL,
210.0 mmol) and the mixture was stirred for a 24 h. Next, a mixture was extracted with CH2Cl2 (2*500
mL) and organic phase was discarded. Water phase was poured into saturated NaHCO3 solution. The
product was extracted with CH2Cl2 (2*500 mL) and the combined organic phases was dried and
removed under reduced pressure to obtain pure 6 (33.0 g, 150.0 mmol, 76.3% yield). NMR
spectroscopic data are identical to those reported previously.24
N-Benzyl-3-trifluoromethylmorpholin-5-one (4)
Chloroacetylchloride (51.0 g, 45.0 mmol) was added dropwise to a mixture of compound 6 (33.0 g,
150.0 mol) and NEt3 (60.0 g, 594.0 mmol) in CH2Cl2 (1000 mL) under cooling with ice-bath. The
mixture was allowed to stir for 48 h. Next, the mixture was diluted with water, organic phase was
washed with saturated NaHCO3 solution, brine, dried and evaporated under reduced pressure. The dark
oily residue was taken up in methanol (500 mL). To the above obtained solution solid K2CO3 (100.0 g)
and water (50 mL) were added and the mixture was refluxed for 15 h. After cooling to room
temperature, it was evaporated to dryness and semi-solid residue was dissolved in CH2Cl2 (500 mL).
The organic was washed with water (2*250 mL), 2N HCl solution (250 mL), brine, dried over Na2SO4
and evaporated under reduced pressure to obtain 4 (24.5 g, 95.0 mmol, 63% yield) as a yellow oil
which was used without any further purifications.
νmax (KBr) 3032, 2877, 1769, 1668, 1496, 1453, 1424, 1361, 1301, 1264, 1229, 1166, 1136, 1098,
1014 cm-1
.
12

ACCEPTED MANUSCRIPT
1H NMR (500 MHz; CDCl3; Me4Si), δ: 7.41-7.26 (5H, m); 5.83 (1H, d, J = 15.0 Hz); 4.44 (1H, d, J =
17.0 Hz); 4.29 (1H, d, J = 17.0 Hz); 4.23 (1H, d, J = 12.5 Hz); 3.89 (1H, d, J = 15.0 Hz); 3.67 (1H; dt,
J = 12.5 Hz, 2.5 Hz); 3.63-3.57 (1H, m).
13C NMR (125 MHz; CDCl3; Me4Si), δ: 167 (s); 135 (s); 129 (s); 128.6 (s); 128.3 (s); 124.7 (q, 1J(C,F)
= 284.0 Hz); 67.6 (s); 63.2 (s); 54.2 (q, 2J(C,F) = 29.0 Hz), 47.7 (s).
19F NMR (375 MHz; CDCl3; CFCl3), δ: -70.3 (d, 3J(F,H) = 7.5 Hz).
MS (m/z): 259 (M)+.
N-benzyl-3-trifluoromethylmorpholine (12)
Similar to 9, by reduction of N-benzyl-3-trifluoromethylmorpholin-5-one 4 (24.5 g, 95.0 mmol) N-
benzyl-3-trifluoromethylmorpholine 12 (16.5 g, 67.0 mmol, 73% yield) was obtained as a slightly
yellow oil.
νmax (KBr) 2971, 2860, 1495, 1454, 1371, 1258, 1148, 1124, 1057, 1015 cm-1
.
1H NMR (500 MHz; CDCl3; Me4Si), δ: 7.42-7.28 (5H, m); 4.08 (1H, dd, J = 11.0 Hz, 3.0 Hz); 3.99
(1H, d, J = 13.5 Hz); 3.92-3.84 (2H, m); 3.81 (1H, dt, J = 11.0 Hz, 3.0 Hz); 3.69 (1H, td, J = 11.0 Hz,
3.0 Hz); 3.22-3.12 (1H, m); 3.06 (1H, t, J = 11.0 Hz); 2.46 (1H, d, J = 11.0 Hz).
13C NMR (125 MHz; CDCl3; Me4Si), δ: 137.4 (s); 128.7 (s); 128 (s); 127.5 (s); 126 (q, 1J(C,F) = 289.0
Hz); 66.8 (s); 65.2 (s); 59.3 (s); 58.5 (q, 2J(C,F) = 29.0 Hz); 46.7 (s).
19F NMR (375 MHz; CDCl3; CFCl3), δ: -64.5 (d, 3J(F,H) = 7.5 Hz).
MS (m/z): 245 (M)+.
Anal. calcd for C12H14F3NO: C, 58.77; H, 5.75; N, 5.71. Found: C, 59.05; H, 5.44; N, 5.93.
3-Trifluoromethylmorpholine hydrochloride (2*HCl)
Similar to amine 1, from N-benzyl-3-trifluoromethylmorpholine 12 (16.5 g, 67.0 mmol) 3-
trifluoromethyl-morpholine hydrochloride 2*HCl (11.4 g, 60.0 mmol, 89% yield) was obtained as a
white solid, m.p. 182-184 ºC.
νmax (KBr) 2922, 2648, 2473, 1604, 1587, 1449, 1397, 1315, 1272, 1220, 1184, 1145, 1114, 1095,
1055, 1030 cm-1
.
1H NMR (500 MHz; DMSO-d6; Me4Si), δ: 12.0-10.0 (2H, broad s); 4.60-4.46 (1H, m); 4.12 (1H, dd, J
= 16.0 Hz, 4.0 Hz); 3.94 (1H, d, J = 16.0 Hz); 3.86 (1H, d, J = 12.5 Hz); 3.82-3.75 (1H, m); 3.23 (1H,
d, J = 16.0 Hz); 3.61 (1H, dd, J = 12.5 Hz, 4.0 Hz);
1
13C NMR (500 MHz; DMSO-d6; Me4Si), δ: 123.2 (q, J(C,F) = 280 Hz); 63.4 (s); 62.2 (s); 53.1 (q,
2J(C,F) = 31 Hz); 43.1 (s).
19F NMR (375 MHz; DMSO-d6; CFCl3), δ: -76.35 (d, 3J(F,H) = 7.5 Hz).
MS (m/z): 156 (M+1-Cl)+.
Anal. calcd for C5H9ClF3NO: C, 31.35; H, 4.74; N, 7.31. Found: C, 31.64; H, 4.93; N, 7.63.
All optically active compounds were obtained following exactly the same procedures used for the
synthesis of racemic mixtures. Analytical and NMR characteristics of the obtained compounds are
identical those of racemates.
(S)-Trifluoromethyloxirane ((S)-7)
(S)-trifluoromethyloxirane (S-7) was obtained according to the literature procedure.28
(S)-N-Benzyl-2-trifluoromethylmorpholin-5-one ((S)-3)
[ά]D25 = -37.22 (c = 0.395, MeOH).
(S)-N-Benzyl-2-trifluoromethylmorpholine, ((S)-8)
[ά]D25 = +3.25 (c = 2.00, MeOH).
(S)-2-Trifluoromethylmorpholine hydrochloride, ((S)-1*HCl)
[ά]D25 = -5.96 (c = 0.46, MeOH).
13

ACCEPTED MANUSCRIPT
(R)-N-Benzyl-2-trifluoromethylaminoethanol ((R)-6)
(R)-N-benzyl-2-trifluoromethylaminoethanol was obtained according to the literature procedure.24
(R)-N-Benzyl-3-trifluoromethylmorpholin-5-one, ((R)-4)
[ά]D25 = -113.76 (c = 0.35, MeOH).
(R)-N-Benzyl-3-trifluoromethylmorpholine, ((R)-12)
[ά]D25 = +3.44 (c = 1.50, MeOH).
(R)-3-Trifluoromethylmorpholine hydrochloride, ((R)-2*HCl)
[ά]D25 = -2.64 (c = 0.84, MeOH).
4-{[(4-isopropylphenyl)thio]acetyl}-2-(trifluoromethyl)morpholine (16)
A mixture of amine 1*HCl (200 mg, 1.04 mmol), (4-isopropylphenyl)thioacetic acid (220 mg, 1.04
mmol), TBTU (335 mg, 1.04 mmol) and NEt3 (0.290 mL, 2.08 mmol) in DMF (10 mL) was stirred for
15 h. at room temperature. The solution was evaporated to dryness and the residue was purified by
column chromatography using hexane/MeOtBu = 3/1 mixture as an eluent to give pure 16 (199 mg,
0.57 mmol, R f = 0.4, 55% yield) as an oil.
ν
max (KBr) 2963, 2870, 1650, 1444, 1407, 1306, 1261, 1176, 1145, 1127, 1093, 1054 cm-1
.
1H NMR (500 MHz; CDCl3; Me4Si, 2 rotamers), δ: 7.40 (2H, d, J = 8.0 Hz); 7.20 (2H, d, J = 8.0 Hz);
4.49 (0.5H, d, J = 13.0 Hz); 4.40 (0.5H, d, J = 13.0 Hz); 3.99 (1H, t, J = 12.0 Hz); 3.85-3.70 (4H, m);
3
3.57-3.52 (1H, m); 3.32 (0.5H, t, J(H,H) = 12.0 Hz); 3.23 (0.5H, t, J = 12.0 Hz); 2.91-2.79 (2H, m);
1.24 (6H, d, J = 7.0 Hz).
13C NMR (125 MHz; CDCl3; Me4Si, 2 rotamers), δ: 167.7 (s); 149.1-148.7 (2s); 131.9 (s); 131.4 (s);
1
2
130.7 (s); 130.4 (s); 127.4 (s) 122.8 (q, J(C,F) = 277.5 Hz); 73.5-72.6 (2q, J(C,F) = 31.0 Hz); 66.5
(s); 66.3 (s); 46.7 (s); 45.9 (s); 44.9 (s); 41.4 (s); 40.2 (s); 36.8-36.7 (2s); 33.8 (s); 23.8 (s).
19F NMR (375 MHz; CDCl3; CFCl3, 2 rotamers), δ: -77.9 (d, 3J(F,H) = 7.5 Hz); -78.1 (d, 3J(F,H) = 7.5
Hz).
MS (m/z): 348 (M+1)+.
Anal. calcd for C16H20F3NO2S: C, 55.32; H, 5.80; N, 4.03. Found: C, 55.65; H, 5.47; N, 4.14.
4-{[(4-isopropylphenyl)thio]acetyl}-3-(trifluoromethyl)morpholine (17)
Compound 17 was obtained from amine 2*HCl (170 mg, 0.89 mmol) following exactly the same
procedure used for ht synthesis of compound 16. Crude product was purified by column
chromatography eluting using CHCl3/MeOtBu = 95/5 as an eluent to yield pure product 17 as an oil
(230 mg, Rf = 0.4, 75% yield).
νmax (KBr) 2963, 2872, 1779, 1639, 1460, 1381, 1264, 1236, 1138, 1097, 1052 cm-1
.
1H NMR (500 MHz; CDCl3; Me4Si, 2 rotamers), δ: 7.41 (2H, d, J = 8.5 Hz); 7.21 (2H, d, J = 8.5 Hz);
4.96-4.19 (2H, m); 3.94 (1H, m); 3.75 (2H, s); 3.75-3.15 (4H, m); 2.90 (1H, m); 1.25 (6H, d, J = 7.0
Hz).
13C NMR (125 MHz; CDCl3; Me4Si, 2 rotamers), δ: 168.6 (s); 149.0 (s); 131.9-131.8 (2s); 130.0 (s);
1
2
127.4-127.1 (2s); 124.9 (q, J(C,F) = 285.0 Hz); 66.4-66.2 (2 s); 63.8-63.5 (2 s); 48.5 (q, J(C,F) =
30.0 Hz); 43.5 (s); 38.6 (s); 37.0 (s); 36.6 (s); 33.8 (s); 23.8 (s).
19F NMR (375 MHz; CDCl3; CFCl3, 2 rotamers), δ: -69.9 (d, 3J(F,H) = 7.5 Hz); -70.2 (d, 3J(F,H) = 7.5
Hz).
MS (m/z): 348 (M+1)+.
Anal. calcd for C16H20F3NO2S: C, 55.32; H, 5.80; N, 4.03. Found: C, 55.55; H, 5.53; N, 3.79.
Acknowledgement
Authors are very grateful to O. Kucher for Mosher`s reagent; and to O. Artamonov, R. Iminov for the
helpful discussions on the manuscript.
14

ACCEPTED MANUSCRIPT
Supporting Information Available.
Full spectroscopic data for all new compounds. Determination of pKa, logD, solubility, clearance rate
and fluorescence measurements for compounds 9, 12, 13. Crystallographic data for amines 1*HCl,
2*HCl. This material is available free of charge via the Internet at http://pubs.acs.org.
15

ACCEPTED MANUSCRIPT
References
(1) Wijtmans, R.; Vink, M. K. S.; Schoemaker, H. E.; van Delft, F. L.; Blaauw, R. H.; Rutjes, F.
P. J. T. Synthesis 2004, 641.
(2) September 2012 substructure search in ChEMBL database revealed 33942 bioactive
compounds bearing the fragment of morpholine.
(3) Nineteen small molecule FDA-approved drugs contain morphloline unit: Wishart, D. S.;
Knox, C.; Guo, A. C.; Cheng, D.; Shrivastaya, S.; Tzur, D.; Gautam, B.; Hassanali, M. Nucleic
Acids Res. 2008, 36 Database issue, D.901.
(4) Bissantz, C.; Kuhn, B.; Stahl, M. J. Med. Chem. 2010, 53, 5061.
(5) Morgenthaler, M.; Schweizer, E.; Hoffmann-Roeder, A.; Benini, F.; Martin, R. E.; Jaeschke,
G.; Wagner, B.; Fischer, H.; Bendels, S.; Zimmerli, D.; Schneider, J.; Diederich, F.; Kansy, M.;
Mueller K. ChemMedChem 2007, 2, 1100.
(6) (a) Ndungu, M.; Krumm, S. A.; Yan, D.; Arrendale, R. F.; Reddy, G. P.; Evers, T.; Howard,
R.; Natchus, M. G.; Saindane, M. T.; Liotta, D. C.; Plemper, R. K.; Snyder, J. P.; Sun, A. J. Med.
Chem. 2012, 55, 4220. (b) Sohma, Y.; Hayashi, Y.; Ito, T.; Matsumoto, H.; Kimura, T.; Kiso, Y.
J. Med. Chem. 2003, 46, 4124. (c) Lundquist, J. T.; Harnish, D. C.; Kim, C. Y.; Mehlmann, J. F.;
Unwalla, R. J.; Phipps, K. M.; Crawley, M. L.; Commons, T.; Green, D. M.; Xu, W.; Hum, W.-
T.; Eta, J. E.; Feingold, I.; Patel, V.; Evans, M. J.; Lai, K.; Borges-Marcucci, L.; Mahaney, P. E.;
Wrobel, J. E. J. Med. Chem. 2010, 53, 1774.
(7) Lipinski, C. A. J. Pharmacol. Toxicol. Methods 2000, 44, 235.
(8) (a) Malagu, K.; Duggan, H.; Menear, K.; Hummersone, M.; Gomez, S.; Bailey, C.; Edwards,
P.; Drzewiecki, J.; Leroux, F.; Quesada, M. J.; ermann, G.; Maine, S.; Molyneaux, C.-A.; Le
Gall, A.; Pullen, J.; Hickson, I.; Smith, L.; Maguire, S.; Martin, N.; Smith, G.; Pass, M. Bioorg.
Med. Chem. Lett. 2009, 19, 5950. (b) Zask, A.; Kaplan, J.; Verheijen, J. C.; Richard, D. J.;
Curran, K.; Brooijmans, N.; Bennett, E. M.; Toral-Barza, L.; Hollander, I.; Ayral-Kaloustian, S.;
Yu, K. J. Med. Chem. 2009, 52, 7942. (c) A. M. Venkatesan, Z. Chen, O. D. Santos, C.
Dehnhardt, E. D. Santos, S. Ayral-Kaloustian, R. Mallon, I. Hollander, L. Feldberg, J. Lucas, K.
Yu, I. Chaudhary, T. S. Mansour Bioorg. Med. Chem. Lett. 2010, 20, 5869. (d) Verheijen, J. C.;
Yu, K.; Toral-Barza, L.; Hollander, I.; Zask, A. Bioorg. Med. Chem. Lett. 2010, 20, 375.
(9) (a) Yale, H. L. J. Med. Pharm. Chem. 1959, 1, 121. (b) Walborsky, H. M.; Lanc, J. H. J. Am.
Chem. Soc. 1956, 78, 4314. (c) Muller, N. J. Pharm. Sci. 1986, 75, 87. (d) Park, B. K.;
Kitteringham, N. R.; O’Neill, P. M. Annu. Rev. Pharmacol. Toxicol. 2001, 41, 443. (e) Della, E.
W. J. Am. Chem. Soc. 1967, 89, 5221. (f) Chaume, G.; Barbeau, O.; Lesot, P.; Brigaud T. J. Org.
Chem. 2010, 75, 4135.
(10) Selected reviews: (a) Kirk, K. L. Org. Proc. 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) Böhm,
H.-J.; Banner, D.; Bendels, S.; Kansy, M.; Kuhn, B.; Müller, K.; Obst-Sander, U.; Stahl, M.
ChemBioChem 2004, 5, 637.
(11) Selected Books: (a) Modern Fluoroorganic Chemistry, Kirsch, P., Ed.; Wiley-VCH,
Weinheim, 2004. (b) Fluorine in Medicinal Chemistry and Chemical Biology, Ojima, I., Ed.;
Blackwell Publishing, 2009. (c) Bioorganic and Medicinal Chemistry of Fluorine, Begue, J.-P.;
Bonnet-Delpon, D.; John Wiley & Sons, New Jersey, 2008.
(12) At the moment, at least 45 FDA-approved drugs bear the trifluoromethyl group (Ref. 3).
(13) Soloshonok, V.A., editor. Fluorine-Containing Synthons. American Chemical Society;
Washington, DC: 2005.
16

ACCEPTED MANUSCRIPT
(14) Wermuth, C. G. Application strategies for the primary structure-activity relationship
exploration. In The Practice of Medicinal Chemistry, 3rd ed.; Wermuth, C. G., Ed.; Academic
Press/Elsevier: Amsterdam, 2008; p. 422.
(15) (a) Kuehnert, S.;Bahrenberg, G.; Kless, A.; Schroeder, W.; Lucas, S. US2012101079, 2012.
(b) Macdonald, G. J.; De Boeck, B. C. A. G.; Leenaerts, J. E. WO2011064288, 2011. (c) van
Brandt, S. F. A.; de Cleyn M. A. J.; Gijsen, H. J. M.; Berthelot, D. J.-C.; Surkyn, M.
WO2011086099, 2011. (d) Arrington, K.; Dudkin, V.; Layton, M.; Pero J.; Reif, A.
WO2011156245, 2011. (e) Fukunaga, K.; Kohara, T.; Watanabe, K.; Usui, Y.; Uehara, F.;
Yokoshima, S.; Sakai, D.; Kusaka, S.-I.; Nakayama, K. WO2007119463, 2007. (f) Brown, D. S.
EP1163237, 2004. (g) Kawashima, S.; Matsuno, T.; Yaguchi, S.; Watanabe, T.; Inaba, M.
US6251900, 2001.
(16) Some trifluoromethylated morpholines with additional substituents are described in:
Nonnenmacher, J.; Grellepois, F.; Portella, C. Eur. J. Org. Chem. 2009, 22, 3726.
(17) 30 August 2012 - during our work - the patent mentioning the first synthesis of amine 1
appeared: De Boeck, B. C. A. G.; Rombouts, G.; Leenaerts, J. E.; Macdonald, G. J. 2012,
WO2012/113850 A2.
(18) For some reviews and papers on trifluoromethylated aminoalcohols, see: (a) Mloston, G.;
Obijalska, E.; Heimgartner, H. J. Fluorine Chem. 2010, 131, 829. (b) Begue, J.-P.; Bonnet-
Delpon, D. Trifluoromethylated Amino Alcohols: In Biomedical Frontiers of Fluorine
Chemistry; Ojima, I., Mccarthy, J. R.; Welch, J. T., Eds.; Washington, American Chemical
Society, 1996. (c) Fustero, S.; Albert, L.; Aceña, J. L.; Sanz-Cervera, J. F.; Asensio, A. Org. Lett.
2008, 10, 605.
(19) α-Trifluoromethyl group significantly reduces nucleophilicity of the amine function: (a)
Burger, K.; Muetze, K.; Hollweck, W.; Koksch, B. Tetrahedron 1998, 54, 5915. (b) Sani, M.;
Volonterio, A.; Zanda, M. ChemMedChem 2007, 2, 1693.
(20) T. W. Green, P. G. M. Wuts, Protective Groups in Organic Synthesis, Wiley-Interscience,
New York, 1999, 748.
(21) Dunn, C.; Gibson, C. L.; Suckling, C. J. Tetrahedron 1996, 52, 13017.
(22) Katagiri, T.; Ihara, H.; Takahashi, M.; Kashino, S.; Furuhashi, K.; Uneyama, K.
Tetrahedron: Assym. 1997, 8, 2933.
(23) Grellepois, F.; Nonnenmacher, J.; Lachaud, F.; Portella, C. Org. Biomol. Chem.
2011, 9, 1160.
(24) Katagiri, T.; Takahashi, M.; Fujiwara, Y.; Ihara, H.; Uneyama, K. J. Org. Chem. 1999, 64,
7323.
(25) a) Ward, R. A.; Kettle, J. G. J. Med. Chem. 2011, 54, 4670. (b) Roughley, S. D.; Jordan, A.
M. J. Med. Chem. 2011, 54, 3451.
(26) Several runs were performed to convert aminoalcohol 5 into aziridine 10 on a multigram
scale, otherwise the reaction yield significantly decreased (Supporting information). Subsequent
preparation of amine 2 (11 g) was performed in one synthesis run.
(27) Indeed, a lot of experimentation was needed to find the proper reaction conditions for each
transformation. In this letter, however, only optimized protocols are described.
(28) Schaus, S. E.; Brandes, B. D.; Larrow, J. F.; Tokunaga, M.; Hansen, K. B.; Gould, A. E.;
Furrow, M. E.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 1307.
17

ACCEPTED MANUSCRIPT
(29) The only modification was made for the transformation of (R)-10 into (R)-4: the reaction
was performed in trifluoroacetyc acid at room temperature in order to avoid the possible
racemization (Supporting information).
(30) Dale, J. A.; Dull, D. L.; Mosher, H. S. J. Org. Chem. 1969, 34, 2543.
(31) Zefirov, N. S.; Palyulin,V. A.; Dashevskaya, E. E. J. Phys. Org. Chem. 1990, 3, 147.
(32) Loehlin, J. H.; Okasako, E. L. N. Acta Crystallogr., Sect.B: Struct. Sci 2007, 63, 132.
(33) Zhao, Y.; Truhlar, D.G. Theor. Chem. Acc. 2008, 120, 215.
(34) Kendall, R. A.; Dunning, T. H., Jr.; Harrison, R. J. J. Chem. Phys. 1992, 96, 6796.
(35) Gaussian 09, Revision B.01. M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M.
A. Robb, J. R. Cheeseman, G. Scalmani, V. Barone, B. Mennucci, G. A. Petersson, H. Nakatsuji,
M. Caricato, X. Li, H. P. Hratchian, A. F. Izmaylov, J. Bloino, G. Zheng, J. L. Sonnenberg, M.
Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O.
Kitao, H. Nakai, T. Vreven, J. A. Montgomery, Jr., J. E. Peralta, F. Ogliaro, M. Bearpark, J. J.
Heyd, E. Brothers, K. N. Kudin, V. N. Staroverov, T. Keith, R. Kobayashi, J. Normand, K.
Raghavachari, A. Rendell, J. C. Burant, S. S. Iyengar, J. Tomasi, M. Cossi, N. Rega, J. M.
Millam, M. Klene, J. E. Knox, J. B. Cross, V. Bakken, C. Adamo, J. Jaramillo, R. Gomperts, R.
E. Stratmann, O. Yazyev, A. J. Austin, R. Cammi, C. Pomelli, J. W. Ochterski, R. L. Martin, K.
Morokuma, V. G. Zakrzewski, G. A. Voth, P. Salvador, J. J. Dannenberg, S. Dapprich, A. D.
Daniels, O. Farkas, J. B. Foresman, J. V. Ortiz, J. Cioslowski, D. J. Fox, Gaussian, Inc.,
Wallingford CT, 2010.
(36) Morgenthaler, M.; Schweizer, E.; Hoffmann-Roeder, A.; Benini, F.; Martin, R. E.; Jaeschke,
G.; Wagner, B.; Fischer, H.; Bendels, S.; Zimmerli, D.; Schneider, J.; Diederich, F.; Kansy, M.;
Muller, K. ChemMedChem 2007, 2, 1100.
(37) Elguero, J.; Yranzo, G. I.; Laynez, J.; Jimenez, P.; Menendez. M.; Catalhn, J.; Paz, J. L. G.;
Anvia, F.; Traft, R. W. J. Org. Chem. 1991, 56, 3942.
(38) Jamieson, C.; Moir, E. M.; Rankovich, Z.; Wishart, G. J. Med. Chem. 2006, 49, 5029.
(39) Excellent review on the topic: Wuitschik, G.; Carreira, E. M.; Wagner, B.; Fischer, H.;
Parrilla, I.; Schuler, F.; Rogers-Evans, M.; Muller, K. J. Med. Chem. 2010, 53, 3227.
(40) Jean, D. J. S; Fotsch, C. J. Med. Chem. 2012, 55, 6002.
(41) Jordan, A. M.; Roughley, S. D. J. Med. Chem. 2011, 54, 3451.
(42) Stebbins, J. L.; Zhang, Z.; Chen, J.; Wu, B.; Emdadi, A.; Williams, M. E.; Cashman, J.;
Pellecchia, M. J. Med. Chem. 2007, 50, 6607.
(43) Amines 1, 2 seem also to be useful in agrochemistry: (a) Morpholine Fungicides for the
Treatment of Powdery Mildew. In Bioactive Heterocyclic compound classes. Part 2.
Agrochemicals, Lamberth, C.; Dinges, J., Eds.; Wiley-VCH, Weinheim, 2012; p. 119. (b)
Morpholines. In Metabolic Pathways of Agrochemicals. Part 2. Insecticides and Pesticides,
Roberts, T.; Hutson, D., Eds.; Royal Society of Chemistry: Cambridge, 1999; p. 1225. (c) Hong,
W. Agricultural products based on fluorinated heterocyclic compounds. In Fluorinated
Heterocyclic Compounds: Synthesis, Chemistry and Applications, Petrov, V. A., Ed.; John Wiley
& Sons, Inc., Publishers: New Jersey, 2009; p. 399. (d) Theodoridis, G. Fluorine Containing
Agrochemicals: An Overview of Recent Developments. In Fluorine and the Environment,
Tressaud, A., Ed.; Elsevier, 2006; p. 121.
18