One-Pot Synthesis of Functionalized β-Fluoroalkylated Mannich-Type Products from N-Aryl N,O-Acetals

Article abstract of DOI:10.1055/s-0035-1561324

A variety of functionalized β-amino-β-fluoroalkyl carbonyl compounds are accessible via a novel one-pot Mannich-type reaction of CF₂- and CF₃-containing N-aryl N,O-acetals with lithium enolates of ketones, esters, and nitriles. The resulting β-fluoroalkylated β-aminocarbonyl compounds are promising peptide surrogates to be used in drug development and for biological applications.

Full text of DOI:10.1055/s-0035-1561324

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–J
paper
A
S. Wunder et al.
Paper
Synthesis
One-Pot Synthesis of Functionalized β-Fluoroalkylated Mannich-
Type Products from N-Aryl N,O-Acetals
Swetlana Wundera
Amrei Deutscha
Carl Deutsch*b
Anja Hoffmann-Röder*a
O
O
R
H
, LHMDS
N
OEt
CF3
N,O-acetal
LHMDS
CH2Cl2, –78 °C
aldimine formed in situ
R
H
N
CF3
Ar
N
Ar
Ar
CH2Cl2, –78 °C to r.t.
CF3
a Center for Integrated Protein Science Munich (CIPSM) at the
Department of Chemistry, Ludwig-Maximilians-Universität,
Butenandtstr. 5–13, 81377 Munich, Germany
b Medicinal Chemistry, Merck, Frankfurter Str. 250, 64293
Darmstadt, Germany
β-trifluoromethylated
Mannich-type products
24 examples, up to 92% yield
anja.hoffmann-roeder@cup.lmu.de
Dedicated to Professor Dr. Rolf Huisgen on the occasion of his
95th birthday
Received: 05.11.2015
Accepted after revision: 15.12.2015
Published online: 26.01.2016
isopolarities between C–CF3 and C=O entities, as well as
their increased metabolic stability, α-trifluoromethylated
amines have remained an underrepresented, yet interesting
class of amide bioisosteres.5 Thus, only a few examples of
pharmaceuticals featuring NH–CH(CF3) or N=C(CF3) motifs
DOI: 10.1055/s-0035-1561324; Art ID: ss-2015-t0645-op
Abstract A variety of functionalized β-amino-β-fluoroalkyl carbonyl
compounds are accessible via a novel one-pot Mannich-type reaction of
CF2- and CF3-containing N-aryl N,O-acetals with lithium enolates of ke-
tones, esters, and nitriles. The resulting β-fluoroalkylated β-aminocar-
bonyl compounds are promising peptide surrogates to be used in drug
development and for biological applications.
are currently available.6 The cathepsin
K
inhibitor
Odanacatib7 is a prominent example for compounds featur-
ing a NH–CH(CF3) group, whereas the corresponding imine
derivatives are represented by the small-molecule systemic
inhibitor of enteroviruses and rhinoviruses Pleconaril.8
Mannich bases (β-amino ketones) are particularly use-
ful building blocks9 for the preparation of nitrogen contain-
ing biologically active compounds.10 Their chemistry has
been intensively studied and they can be easily converted
into other multifunctional compounds (e.g., β-amino esters,
γ-amino alcohols, or 1,3-diamines).11 Likewise, the corre-
sponding β-trifluoromethylated β-amino ketones are
promising units for bioorganic and medicinal chemistry ap-
plications and various approaches towards their syntheses
have been reported. The Mannich-type nucleophilic addi-
tion reaction represents an established methodology for
synthesis of β-amino-β-trifluoromethyl carbonyl com-
pounds, whereby efficient asymmetric syntheses can be
achieved through applications of chiral auxiliaries.12 In
most of these methods, preformed N-tert-butanesulfinyl-
(3,3,3)-trifluoroacetaldimines13 or other trifluoromethyl al-
dimines14 are used, whereas only a few reactions based on
trifluoroacetaldehyde ethyl hemiacetal15 or N,O-acetals16
derived from trifluoroacetaldehyde are known. Since this
latter approach does not require expensive chiral N-sulfi-
nylamides and controlled reaction conditions, it would be
particularly useful for initial biological testing and lead op-
timization studies, for which enantiomerically pure com-
pounds are not necessarily required. Thus, the development
of a simple and economical one-pot protocol for the syn-
Key words fluoroalkylated compounds, N,O-acetals, trifluoroethyl-
amine, difluoroethylamine, Mannich-type reaction
Drug-development based on a multidimensional opti-
mization (MDO) approach is a great challenge and includes
the fine-tuning of physicochemical properties and ADME
(absorption, distribution, metabolism, and excretion).1 In
particular, nitrogen-containing compounds mostly require
modulation of their basicity, as this affects properties such
as lipophilicity, membrane permeability, binding potency
including side effects like hERG inhibition2 and metabolic
stability, all of which will be addressed in the course of the
MDO process. In recent years, the strategic placement of
fluorine atoms in close proximity to nitrogen has become a
common tool to fine-tune the molecular properties of bio-
logically active amines by affecting their absorption and
distribution behavior.3 In general, the incorporation of fluo-
rinated groups leads to a lower basicity of neighboring
amines, due to the high electrophilicity of fluorine atoms.
Lead optimization studies have shown that introduction of
a trifluoromethyl group adjacent to an amine enhances the
metabolic stability of the compound significantly. More-
over, this transformation leads to a decrease in the pKa val-
ue of approximately 5.7 units, thus matching the pKa values
of amides.1,4 However, despite structural similarities and
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

B
S. Wunder et al.
Paper
Synthesis
thesis of β-amino-β-trifluoromethyl carbonyl compounds
via Mannich-type nucleophilic addition reaction to various
N-aryl N,O-acetals is highly desirable and presented herein.
In contrast to the corresponding aldimines, trifluoro-
methylated N,O-acetals derived from 1-ethoxy-2,2,2-tri-
fluoroethanol are readily available and shelf-stable com-
pounds.17,18 Upon base treatment a transient aldimine in-
termediate is formed, which subsequently can be attacked
by C-nucleophiles to furnish the desired β-amino-β-trifluo-
romethyl carbonyl compounds. In our studies, we focused
on ketones, but also other C–H acidic compounds (esters,
nitriles) can be employed as nucleophiles. Hence, by using
3-chloro-N-(1-ethoxy-2,2,2-trifluoroethyl)aniline (1a) as a
model compound and LHMDS for deprotonation, the corre-
sponding imine species was generated and reacted with an
in situ forming lithium enolate of acetophenone. Low to
moderate yields of the desired product 2a were obtained in
various solvents at 55 °C (Table 1, entries 1–4). However,
the yield of 2a was significantly improved when the reac-
tion was performed at a temperature of –78 °C to room
temperature using dichloromethane as solvent (entry 7).
Even higher yields were achieved by using N-(1-ethoxy-
2,2,2-trifluoroethyl)pyrazin-2-amine (1b) as substrate un-
der the same conditions (entry 8). The application of tetra-
hydrofuran, which is usually the solvent of choice in
Mannich-type reactions, and diethyl ether at –78 °C to
room temperature resulted in slightly lower yields of the
desired product 2b (entries 9 and 10). The employment of
alternative non-nucleophilic bases such as DBU, NaHMDS,
KHMDS, or LDA was found detrimental (data not shown).
Having identified suitable conditions for the Mannich-
type reaction, we briefly looked at its scope by varying the
substitution pattern of the aromatic ring within the hemi-
aminal ether (Table 2). Thus it was found that electron-poor
Table 2 Reaction of Acetophenone with Aromatic N,O-Acetals
O
Ph
H
LHMDS (2.3 equiv)
O
N
OEt
H
+
Ar
N
CH2Cl2, –78 °C to r.t. Ar
Ph
Rf
Rf
1
2
Entry Ar
Rf
Time (h) Yield (%)a Product
1b
CF3
1
1
1
71
92
72
2a
2b
2c
Cl
N
2
3
CF3
CF3
Table 1 Optimization Studies
N
N
O
Ph
H
N
H
N
OEt
O
LHMDS (2 equiv)
Ph
1 h
N
N
+
CF3
CF3
Cl
Cl
1a
2a
4
CF3
0.3
92
2d
Entry
Solvent
Temp (°C)
Yield (%)a
1
2
3
4
5
6
7
toluene
THF
55
38
26
46
8
5
6
CF3
CF3
1
2
52
64
2e
2f
F3C
55
CH2Cl2
MeCN
CH2Cl2
CH2Cl2
CH2Cl2
55
55
MeO
N
r.t.
61
38
71
0
7
8
9
CF3
1
2
1
78
2g
2h
2i
–78 to r.t.
O
Ph
H
N
N
H
N
N
N
OEt
O
LHMDS (2 equiv)
1 h
Ph
N
N
CF2H
CF2CF3
quant.
quant.
+
CF3
CF3
N
N
1b
2b
8
9
CH2Cl2
THF
–78 to r.t.
–78 to r.t.
–78 to r.t.
92
89
91
a Yield of isolated product after flash chromatography.
b Use of 2 equiv LHMDS.
10
Et2O
a Yield of isolated product after flash chromatography.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

C
S. Wunder et al.
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Synthesis
Table 3 (continued)
Entry R1 R2
N,O-acetals comprising pyrazine and quinoline groups are
particularly well suited for this reaction and provide the
target β-trifluoromethylated β-amino ketones 2b and 2d in
high yields (Table 2, entries 2 and 4). Interestingly, the cor-
responding N,O-acetal featuring a (4-trifluoromethyl)phe-
nyl substituent only afforded the desired reaction product
2e with a moderate yield of 52% (entry 5), most presumably
due to difficulties during the purification step. In contrast,
difluoromethylated and pentafluoroethylated β-amino ke-
tones are accessible in almost quantitative yields by sub-
jecting the corresponding N,O-acetals 1h and 1i to the reac-
tion conditions described above (entries 8 and 9).
With regard to the scope of C-nucleophiles applicable to
this Mannich-type reaction, we examined at first acetophe-
none-derived ketones with both electron-withdrawing and
electron-donating substituents on the aromatic ring. To our
delight, halogen, methoxy, and nitro groups, as well as ni-
trile and ester functionalities are tolerated by the reaction
conditions to furnish the desired β-trifluoromethylated β-
amino ketones 3a–f in reasonable yields (Table 3, entries 2–
7). Moreover, ketones carrying furan or indole residues, as
well as (E)-4-phenylbut-3-en-2-one reacted smoothly to
give the corresponding Mannich-type products 3h–j (en-
tries 9–11), whereas 2′,3′,4′,5′,6′-pentafluoroacetophenone
only afforded low yields of β-amino ketone 3g (entry 8),
due to the formation of significant amounts of side prod-
ucts. A more sluggishly proceeding reaction was also ob-
served for sterically hindered substrates such as 2-methyl-
1-phenylpropan-1-one, as expected (entry 13). Last but not
least, successful applications of diethyl malonate, ethyl ace-
tate as well as 2,6-dichlorophenylacetonitrile as substrates
demonstrated once more the synthetic versatility of this
approach to readily access functionalized β-trifluorometh-
ylated β-amino carbonyl compounds 3m–o (entries 14–16).
R3
Yield (%)a Product
MeO
O
O
O
O
4
H
H
88
3c
5
6
7
H
H
H
H
H
H
82
75
91
3d
3e
3f
CO2Me
NO2
CN
F
F
F
F
O
8
H
H
35
3g
F
O
O
O
9
H
H
H
H
58
67
3h
3i
N
10
O
11
H
H
64
3j
O
O
12
13
H
Me
Me
68
22
3k
3l
Table 3 Reaction of Pyrazyl N,O-Acetals with Various Nucleophiles
R3
Me
LHMDS
(2.3 equiv)
H
N
H
R2
R1
R1
R3
N
N
OEt
N
N
N
+
R2
CH2Cl2
–78 °C to r.t.,
1–2 h
CF3
CF3
Cl
1b
3
14
H
CN
60
3m
Entry R1
R2
R3
Yield (%)a Product
Cl
15
16
H
H
CO2Et
H
CO2Et
CO2Et
59
25
3n
3o
O
O
O
1
2
3
H
H
92
62
90
2b
3a
3b
a Yield of isolated product after flash chromatography.
H
H
H
Br
In summary, we have devised an efficient one-pot pro-
cedure for the synthesis of a broad range of functionalized
β-amino-β-trifluoromethyl carbonyl derivatives using read-
ily accessible, shelf-stable N-aryl N,O-acetals and lithium
enolates derived from ketones, esters, as well as nitriles.
The reaction is easy to perform and allows rapid formation
H
OMe
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

D
S. Wunder et al.
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Synthesis
of novel trifluoromethylated Mannich-type products, which
are useful potential building blocks for pharmaceutical and
biological applications. Moreover, the reaction protocol can
be successfully applied to the synthesis of functionalized β-
difluoromethylated and β-pentafluoroethylated Mannich-
type products.
0.89 mmol). After stirring at r.t. (2 h), aqueous workup, flash chroma-
tography (chex → chex/EtOAc, 9:1), and recrystallization (chex), the β-
amino ketone 2a (138 mg, 0.42 mmol, 71%) was obtained as a color-
less crystalline solid; mp 98 °C; Rf = 0.61 (chex/EtOAc, 2:1).
1H NMR (400 MHz, DMSO-d6): δ = 8.07–7.93 [m, 2 H, H2ph, H6ph],
7.73–7.62 [m,
1 H, H4ph], 7.55 [m, 2 H, H3ph, H5ph], 7.11 [t,
J(H5,H4/H6) = 8.1 Hz, 1 H, H5], 6.77 [br s, 1 H, H2], 6.65 [m, 2 H, H4,
H6], 6.30 [d, J(NH,CH) = 8.4 Hz, 1 H, NH], 4.87–4.76 [m, 1 H, CH], 3.62
[dd, J(CH2,CH2) = 17.8 Hz, J(CH2,CH) = 10.0 Hz, 1 H, CH2], 3.44 [dd,
J(CH2,CH2) = 17.8 Hz, J(CH2,CH) = 2.5 Hz, 1 H, CH2].
All reactions were carried out under an argon atmosphere using dried
glassware. Commercially available reagents and solvents were used
without further purification. Dry CH2Cl2 (SeccoSolv®) was purchased
from Merck KGaA. N,O-Acetal substrates were synthesized according
to standard procedures from 1-ethoxy-2,2,2-trifluoroethanol and the
corresponding amines using PTSA in EtOH.17 Purification was per-
formed by flash chromatography and N,O-acetal substrates were
dried under reduced pressure prior to use. Reactions were monitored
by TLC with precoated silica gel 60 F254 aluminum plates (Merck
KGaA) using UV light as the visualizing agent. The crude β-amino-β-
trifluoromethyl carbonyl compounds were purified by MPLC with a
CombiFlash Rf Teledyne ISCO or by standard flash chromatography
using silica gel (35–70 μm) from Acros Organics. Analytical RP-HPLC
was measured on a JASCO system with a Phenomenex Luna C18 col-
umn (5 μm, 250 × 4.6 mm). HR-EI mass spectra were recorded on a
Finnigan MAT95Q or on a Finnigan MAT90. HR-ESI mass spectra were
recorded on a Thermo Finnigan LTQ FT or on a Bruker maXis equipped
with a Waters Acquity UPLC using a Kinetex C18 column (2.6 μ, 100 A)
at 40 °C and HPLC-MS was performed on Agilent 1100 and Agilent
1200 systems using Chromolith Speed ROD RP-18e columns. In all
cases, mixtures of H2O (eluent A) and MeCN (eluent B) were used as
solvents; if required, 0.05% formic acid or 0.1% TFA was added. 1H, 13C,
and 19F spectra were recorded on a Varian 400 MHz, 600 MHz and
800 MHz spectrometer or on a Bruker Avance II 300 MHz, 400 MHz,
and 500 MHz spectrometer in DMSO-d6 or CDCl3. The chemical shifts
are reported in ppm relative to the signal of the deuterated solvent.
Standard abbreviations were used to denote the signal multiplicities.
Melting points were measured on a Melting Point B-540 Büchi appa-
ratus.
13C NMR (101 MHz, DMSO-d6): δ = 194.97 [C=O], 148.96 [C1], 136.13
[C1ph], 133.55 [C3], 133.52 [C4ph] 130.34 [C5], 128.73 [C3ph, C5ph],
128.09 [C2ph, C6ph], 126.58 [q, 1J(C,F) = 283.8 Hz, CF3], 116.47 [C4],
111.93 [C2], 111.35 [C6], 50.16 [q, 2J(C,F) = 29.7 Hz, CH], 37.54 [CH2].
19F NMR (376 MHz, DMSO-d6): δ = –74.25 [d, J(CF3,CH) = 7.4 Hz, CF3].
HR-EI-MS: m/z calcd for
C
16H13ClF3NO+ [M]+: 327.0638; found:
327.0641.
HPLC-MS (0.05% formic acid; 0 min, 0% B → 2.0 min, 100% B, flow: 3.3
mL/min): tR = 1.98 min, λ = 220 nm.
4,4,4-Trifluoro-1-phenyl-3-(pyrazin-2-ylamino)butan-1-one (2b)
According to the general procedure, N-(1-ethoxy-2,2,2-trifluoroeth-
yl)pyrazin-2-amine (1b; 100 mg, 0.45 mmol) was dissolved in dry
CH2Cl2 (7 mL), treated with LHMDS (1.0 M solution in toluene,
1.04 mL, 1.04 mmol), and reacted with acetophenone (0.08 mL,
0.68 mmol). After stirring at r.t. (1 h), aqueous workup, flash chroma-
tography (chex → chex/EtOAc, 4:1), and recrystallization (chex), the β-
amino ketone 2b (123 mg, 0.42 mmol, 92%) was obtained as a color-
less crystalline solid; mp 128 °C; Rf = 0.20 (chex/EtOAc, 2:1).
1H NMR (400 MHz, DMSO-d6): δ = 8.04 [dd, J(H6,H5) = 2.8 Hz,
J(H6,H3) = 1.5 Hz, 1 H, H6], 8.01–7.94 [m, 3 H, H3, H2ph, H6ph], 7.82 [d,
J(H5,H6) = 2.8 Hz, 1 H, H5], 7.70–7.63 [m, 1 H, H4ph], 7.58–7.51 [m, 2
H, H3ph, H5ph], 7.48 [d, J(NH,CH) = 8.2 Hz, 1 H, NH], 5.50–5.38 [m, 1 H,
CH], 3.65 [dd, J(CH2,CH2) = 17.8 Hz, J(CH2,CH) = 9.8 Hz, 1 H, CH2], 3.52
[dd, J(CH2,CH2) = 17.8 Hz, J(CH2,CH) = 3.3 Hz, 1 H, CH2].
13C NMR (101 MHz, DMSO-d6): δ = 195.03 [C=O], 153.90 [C2], 141.26
[C6], 136.08 [C1ph], 133.55 [C5], 133.02 [C4ph], 132.91 [C3], 128.74
[C3ph, C5ph], 128.07 [C2ph, C6ph], 126.22 [q, 1J(C,F) = 282.8 Hz, CF3]
47.17 [q, 2J(C,F) = 30.5 Hz, CH], 37.12 [CH2].
Addition of Ketones to N-Aryl N,O-Acetals 1a–i; General Procedure
N-Aryl hemiaminal ether 1 (1 equiv) was placed in a dry Schlenk flask
equipped with a magnetic stirrer and a septum, and dissolved in dry
CH2Cl2 (ca. 0.06 M). The solution was flushed with argon and cooled
to –78 °C before LHMDS (1.0 M solution in toluene, 2.0–3.3 equiv)
was added dropwise. Stirring was continued at –78 °C for 10 min, the
ketone (1.5–2.5 equiv) was added, the reaction mixture was allowed
to warm up to r.t. and stirred for 1–2 h (TLC and LC-MS control). After
complete consumption of the starting material, the solution was
quenched with H2O (10 mL) and extracted with CH2Cl2 (3 × 20 mL).
The combined organic phases were dried over Na2SO4 and the solvent
was removed under reduced pressure. Purification by flash or column
chromatography and optional subsequent crystallization from
chex/EtOAc furnished the desired β-amino β-fluoroalkylated carbonyl
compounds 2a–i and 3a–o.
19F NMR (376 MHz, DMSO-d6): δ = –74.37 [d, J(CF3,CH) = 7.9 Hz, CF3].
HR-EI-MS: m/z calcd for
C
14H12F3N3O+ [M]+: 295.0932; found:
295.0931.
HPLC-MS (0.05% formic acid; 0 min, 0% B → 2.0 min, 100% B, flow: 3.3
mL/min): tR = 1.59 min, λ = 220 nm.
4,4,4-Trifluoro-3-(4-methylpyrimidin-2-ylamino)-1-phenylbutan-
1-one (2c)
Following the general procedure, N-(1-ethoxy-2,2,2-trifluoroethyl)-4-
methylpyrimidin-2-amine (1c; 100 mg, 0.43 mmol) was dissolved in
dry CH2Cl2 (7 mL), treated with LHMDS (1.0 M solution in toluene,
0.98 mL, 0.98 mmol), and reacted with acetophenone (0.08 mL,
0.64 mmol). After stirring at r.t. (2 h), aqueous workup, flash chroma-
tography (chex → chex/EtOAc, 4:1), and recrystallization (chex), the β-
amino ketone 2c (97 mg, 0.31 mmol, 72%) was obtained as a colorless
crystalline solid; mp 109 °C; Rf = 0.35 (chex/EtOAc, 2:1).
3-[(3-Chlorophenyl)amino]-4,4,4-trifluoro-1-phenylbutan-1-one
(2a)
According to the general procedure, 3-chloro-N-(1-ethoxy-2,2,2-tri-
fluoroethyl)aniline (1a; 150 mg, 0.59 mmol) was dissolved in dry
CH2Cl2 (7 mL), treated with LHMDS (1.0 M solution in toluene,
1.18 mL, 1.18 mmol), and reacted with acetophenone (0.10 mL,
1H NMR (400 MHz, DMSO-d6): δ = 8.19 [br s, 1 H, H6], 8.00–7.91 [m, 2
H,
H2ph
,
H6ph],
7.65
[tt,
J(H4ph,H3ph/H5ph) = 7.4 Hz,
J(H4ph,H2ph/H6ph) = 1.1 Hz, 1 H, H4ph], 7.53 [m, 3 H, NH, H3ph, H5ph],
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6.60 [d, J(H5,H6) = 5.0 Hz, 1 H, H5], 5.54–5.39 [m, 1 H], 3.74 [dd,
J(CH2,CH2) = 17.7 Hz, J(CH2,CH) = 10.3 Hz, H, CH2], 3.39 [dd,
J(CH2,CH2) = 17.6 Hz, J(CH2,CH) = 2.9 Hz, 1 H, CH2], 2.25 [s, 3 H, CH3].
13C NMR (101 MHz, DMSO-d6): δ = 195.89 [C=O], 167.89 [C4], 162.05
[C2], 157.85 [C6], 136.70 [C1ph], 134.02 [C4ph], 129.24 [C2ph, C6ph],
128.19 [C3ph, C5ph], 126.78 [q, 1J(C,F) = 283.1 Hz, CF3], 111.53 [C5],
48.51 [q, 2J(C,F) = 30.2 Hz, CH], 37.21 [CH2], 24.00 [CH3].
13C NMR (101 MHz, CDCl3): δ = 194.90 [C=O], 148.67 [C1], 136.16
[C1ph], 134.14 [C4ph], 129.05 [C3ph, C5ph], 128.31 [C2ph, C6ph], 126.92
[q, 3J(C,F) = 3.8 Hz, C3, C5], 125.97 [q, 1J(C,F) = 283.2 Hz, CF3], 124.77
[d, 1J(C,F) = 270.6 Hz, CF3], 121.15 [q, 2J(C,F) = 32.8 Hz, C4], 113.19 [C2,
C6], 51.80 [q, 2J(C,F) = 30.7 Hz, CCF3], 38.34 [CH2].
1
19F NMR
J(CF3,CH) = 7.1 Hz, CF3].
(376 MHz,
CDCl3): δ = –61.40
[CF3],
–75.66
[d,
19F NMR (376 MHz, DMSO-d6): δ = –74.48 [br s, CF3].
HRMS (ESI–): m/z calcd for C17H12F6NO− [M − H]−: 360.0828; found:
360.0835.
HRMS (ESI+): m/z calcd for C15H15F3N3O+ [M + H]+: 310.1162; found:
310.1162.
HPLC (0.1% TFA; 0 min, 4% B → 15 min, 100% B, flow: 1 mL/min): tR =
19.85 min, λ = 214 nm.
HPLC (0.1% TFA; 0 min, 4% B → 15 min, 100% B, flow: 1 mL/min): tR =
13.93 min, λ = 214 nm.
4,4,4-Trifluoro-3-[(4-methoxyphenyl)amino]-1-phenylbutan-1-
one (2f)
4,4,4-Trifluoro-1-phenyl-3-(quinolin-8-ylamino)butan-1-one (2d)
Following the general procedure, N-(1-ethoxy-2,2,2-trifluoroethyl)-4-
methoxyaniline (1f; 170 mg, 0.68 mmol) was dissolved in dry CH2Cl2
(10 mL), treated with LHMDS (1.0 M solution in toluene, 1.56 mL,
1.56 mmol), and reacted with acetophenone (0.12 mL, 1.02 mmol).
After stirring at r.t. (2 h), aqueous workup, flash chromatography
(chex → chex/EtOAc, 4:1), and recrystallization (chex) the β-amino ke-
tone 2f (140 mg, 0.43 mmol, 64%) was obtained as a colorless crystal-
line solid; mp 90 °C; Rf = 0.53 (chex/EtOAc, 4:1).
According to the general procedure, N-(1-ethoxy-2,2,2-trifluoroeth-
yl)quinolin-8-amine (1d; 100 mg, 0.37 mmol) was dissolved in dry
CH2Cl2 (5 mL), treated with LHMDS (1.0 M solution in toluene,
0.85 mL, 0.85 mmol), and reacted with acetophenone (0.65 mL,
0.56 mmol). After stirring at r.t. (20 min), aqueous workup, and flash
chromatography (chex → chex/EtOAc, 9:1), the β-amino ketone 2d
(117 mg, 0.34 mmol, 92%) was obtained as a light yellow oil; Rf = 0.50
(chex/EtOAc, 3:1).
1H NMR (600 MHz, CDCl3): δ = 7.95 [m, 1 H, H2ph/H6ph], 7.94 [m, 1 H,
H2ph/H6ph], 7.60 [m, 1 H, H4ph], 7.51–7.46 [m, 2 H, H3ph, H5ph], 6.80–
6.76 [m, 2 H, H2, H6], 6.76–6.72 [m, 2 H, H3, H5], 4.69 [m, 1 H, CH],
3.74 [s, 3 H, OCH3], 3.40–3.29 [m, 2 H, CH2].
1H NMR
J(H2,H4) = 1.7 Hz,
J(H4,H2) = 1.7 Hz, 1 H, H4], 7.99–7.93 [m, 2 H, H2ph, H6ph], 7.62–7.54
[m, 1 H, H4ph], 7.51–7.40 [m, 3 H, H6, H3ph, H5ph], 7.36 [dd,
J(H3,H4) = 8.2 Hz, J(H3,H2) = 4.2 Hz,
J(H5,H6) = 8.2 Hz, J(H5,H7) = 1.1 Hz,
J(H7,H6) = 7.6 Hz, 1 H, H7], 6.44 [d, J(NH,CH) = 9.9 Hz, 1 H, NH], 5.10
[dtd, J(CH,NH) = 9.9 Hz, J(CH,CF3) = 7.2 Hz, J(CH,CH2) = 4.7 Hz, 1 H,
CH], 3.63–3.49 [m, 2 H, CH2].
(400 MHz,
CDCl3): δ = 8.68
H, H2], 8.06 [dd, J(H4,H3) = 8.2 Hz,
[dd,
J(H2,H3) = 4.2 Hz,
1
1
1
H, H3], 7.16 [dd,
H, H5], 7.07 [d,
13C NMR (151 MHz, CDCl3): δ = 195.53 [C=O], 153.58 [C4], 139.93
[C1], 136.48 [C1ph], 133.85 [C4ph], 129.94 [C2ph, C6ph], 128.29 [C3ph,
C5ph], 126.34 [q, 1J(C,F) = 283.5 Hz, CF3], 116.13 [C3ph, C5ph], 114.98
[C2ph, C1ph], 55.79 [OCH3], 53.97 [q, 2J(C,F) = 29.5 Hz, CCF3], 38.47
[CH2].
13C NMR (101 MHz, CDCl3): δ = 195.05 [C=O], 147.32 [C2], 142.75
[C4a], 138.16 [C8a], 136.42 [C1ph], 136.20 [C4], 133.82 [C4ph], 128.91
[C3ph, C5ph], 128.73 [C8], 128.34 [C2ph, C6ph], 127.71 [C6], 126.40 [q,
1J(C,F) = 283.3 Hz, CF3], 121.61 [C3], 116.12 [C5], 106.54 [C7], 51.40 [q,
2J(C,F) = 30.5 Hz, CCF3], 39.06 [CH2].
19F NMR (376 MHz, CDCl3): δ = –75.48 [CF3].
HRMS (ESI+): m/z calcd for C17H17F3NO2 [M + H]+: 324.1206; found:
+
324.1210.
HPLC (0.1% TFA; 0 min, 4% B → 15 min, 100% B, flow: 1 mL/min): tR =
18.43 min, λ = 214 nm.
19F NMR (376 MHz, CDCl3): δ = –75.63 [d, J(CF3,CH) = 7.1 Hz, CF3].
HRMS (ESI+): m/z calcd for C19H16F3N2O+ [M + H]+: 345.1209; found:
345.1210.
4,4,4-Trifluoro-1-phenyl-3-(pyridin-2-ylamino)butan-1-one (2g)
According to the general procedure, N-(1-ethoxy-2,2,2-trifluoroeth-
yl)pyridin-2-amine (1g; 100 mg, 0.45 mmol) was dissolved in dry
CH2Cl2 (7 mL), treated with LHMDS (1.0 M solution in toluene,
1.04 mL, 1.04 mmol), and reacted with acetophenone (0.08 mL,
0.68 mmol). After stirring at r.t. (1 h), aqueous workup, flash chroma-
tography (chex → chex/EtOAc, 4:1), and recrystallization (chex), the β-
amino ketone 2g (104 mg, 0.35 mmol, 78%) was obtained as a color-
less crystalline solid; mp 124 °C; Rf = 0.46 (chex/EtOAc, 2:1).
HPLC (0.1% TFA; 0 min, 4% B → 15 min, 100% B, flow: 1 mL/min): tR =
18.93 min, λ = 214 nm.
4,4,4-Trifluoro-1-phenyl-3-{[4-(trifluoromethyl)phenyl]ami-
no}butan-1-one (2e)
Following the general procedure, N-(1-ethoxy-2,2,2-trifluoroethyl)-4-
(trifluoromethyl)aniline (1e; 50 mg, 0.17 mmol) was dissolved in dry
CH2Cl2 (5 mL), treated with LHMDS (1.0 M solution in toluene,
0.40 mL, 0.40 mmol), and reacted with acetophenone (0.03 mL,
0.26 mmol). After stirring at r.t. (1 h), aqueous workup and flash chro-
matography (chex → chex/EtOAc, 5:1), the β-amino ketone 2e (33 mg,
0.09 mmol, 52%) was obtained as a light brown solid; mp 127 °C;
Rf = 0.46 (chex/EtOAc, 3:1).
1H NMR (400 MHz, DMSO-d6): δ = 8.02 [dd, J(H6,H5) = 5.0 Hz,
J(H6,H4) = 1.2 Hz, 1 H, H6], 8.00–7.95 [m, 2 H, H2ph, H6ph], 7.69–7.63
[m,
J(H4,H3) = 8.8 Hz, J(H4,H5) = 7.1 Hz, J(H4,H6) = 1.9 Hz, 1 H, H4], 6.94
[d, J(NH,CH) = 8.4 Hz, H, NH], 6.59 [ddd, J(H5,H4) = 7.0 Hz,
J(H5,H6) = 5.1 Hz, J(H5,H3) = 0.8 Hz, 1 H, H5], 6.51 [d,
J(H3,H4) = 8.4 Hz, 1 H, H3], 5.60–5.44 [m, 1 H, CH], 3.60 [dd,
J(CH2,CH2) = 17.5 Hz, J(CH2,CH) = 9.6 Hz, H, CH2], 3.43 [dd,
1 H, H4ph], 7.56–7.51 [m, 2 H, H3ph, H5ph], 7.41 [ddd,
1
1H NMR (400 MHz, CDCl3): δ = 7.98–7.92 [m, 2 H, H2ph, H6ph], 7.65–
7.59 [m, 1 H, H4ph], 7.50 [dd, J = 8.3 Hz, J = 7.1 Hz, 2 H, H3ph, H5ph],
1
J(CH2,CH2) = 17.5 Hz, J(CH2,CH) = 3.5 Hz, 1 H, CH2].
7.44 [d, J(H3,H2) = J(H5,H6) = 8.5 Hz,
J(H2,H3) = J(H6,H5) = 8.4 Hz, H,
2
H, H3, H5], 6.79 [d,
2
H2, H6], 4.87 [dtd,
13C NMR (101 MHz, DMSO-d6): δ = 195.50 [C=O], 157.47 [C1], 147.33
[C6], 137.18 [C4], 136.34 [C1ph], 133.67 [C4ph], 128.92 [C3ph, C5ph],
128.21 [C2ph, C6ph], 126.59 [q, 1J(C,F) = 283.8 Hz, CF3], 113.32 [C5],
108.74 [C3], 47.56 [q, 2J(C,F) = 30.0 Hz, CH], 37.55 [CH2].
J(CH,NH) = 9.6 Hz, J(CH,CF3) = 7.2 Hz, J(CH,CH2) = 4.3 Hz, 1 H, CH],
4.14 [d, J(NH,CH) = 9.9 Hz, 1 H, NH], 3.45–3.37 [m, 2 H, CH2].
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

F
S. Wunder et al.
Paper
Synthesis
19F NMR (376 MHz, DMSO-d6): δ = –74.34 [d, J(CF3,CH) = 8.0 Hz, CF3].
HRMS (ESI+): m/z calcd for C15H13F5N3O+ [M + H]+: 346.0973; found:
346.0973.
HR-EI-MS: m/z calcd for
C
15H13F3N2O+ [M]+: 294.0980; found:
294.0977.
HPLC (0.1% TFA; 0 min, 4% B → 15 min, 100% B, flow: 1 mL/min): tR =
16.28 min, λ = 214 nm.
HPLC-MS (0.05% formic acid; 0 min, 0% B → 2.0 min, 100% B, flow: 3.3
mL/min): tR = 1.25 min, δ = 220 nm.
1-(4-Bromophenyl)-4,4,4-trifluoro-3-(pyrazin-2-ylamino)butan-
1-one (3a)
4,4-Difluoro-1-phenyl-3-(pyridin-2-ylamino)butan-1-one (2h)
According to the general procedure, N-(1-ethoxy-2,2,2-trifluoroeth-
yl)pyrazin-2-amine (1b; 150 mg, 0.68 mmol) was dissolved in dry
CH2Cl2 (7 mL), treated with LHMDS (1.0 M solution in toluene,
1.56 mL, 1.56 mmol), and reacted with 4-bromoacetophenone
(203 mg, 1.02 mmol). After stirring at 40 °C (2 h), aqueous workup,
flash chromatography (chex/EtOAc, 3:1 → 2:1), and recrystallization
(chex/EtOAc, 9:1), the β-amino ketone 3a (157 mg, 0.42 mmol, 62%)
was obtained as a colorless crystalline solid; mp 112 °C; Rf = 0.24
(chex/EtOAc, 2:1).
1H NMR (500 MHz, DMSO-d6): δ = 8.04 [dd, J(H6,H5) = 2.7 Hz,
J(H6,H3) = 1.4 Hz, 1 H, H6], 7.96 [d, J(H3,H6) = 1.4 Hz, 1 H, H3], 7.94–
7.89 [m, 2 H, H2ph, H6ph], 7.82 [d, J(H5,H6) = 2.7 Hz, 1 H, H5], 7.78–
7.73 [m, 2 H, H3ph, H5ph], 7.46 [d, J(NH,CH) = 8.2 Hz, 1 H, NH], 5.48–
5.35 [m, 1 H, CH], 3.62 [dd, J(CH2,CH2) = 17.8 Hz, J(CH2,CH) = 9.8 Hz, 1
H, CH2], 3.52 [dd, J(CH2,CH2) = 17.8 Hz, J(CH2,CH) = 3.3 Hz, 1 H, CH2].
13C NMR (101 MHz, DMSO-d6): δ = 194.57 [C=O], 154.01 [C2], 141.46
[C6], 135.19 [C1], 133.13 [C3], 133.09 [C5], 131.98 [C3ph, C5ph], 130.26
[C2ph, C6ph], 127.87 [CBr], 126.29 [q, 1J(C,F) = 282.8 Hz, CF3], 47.26 [q,
2J(C,F) = 30.3 Hz, CH], 37.28 [CH2].
19F NMR (471 MHz, DMSO-d6): δ = –74.37 [d, J(CF3,CH) = 7.6 Hz, CF3].
HRMS (ESI+): m/z calcd for C14H12BrF3N3O+ [M + H]+: 374.0110; found:
According to the general procedure, N-(1-ethoxy-2,2-difluoroeth-
yl)pyridin-2-amine (1h; 100 mg, 0.49 mmol) was dissolved in dry
CH2Cl2 (5 mL), treated with LHMDS (1.0 M solution in toluene,
1.13 mL, 1.13 mmol), and reacted with acetophenone (0.09 mL,
0.74 mmol). After stirring at r.t. (2 h), aqueous workup, and flash
chromatography (chex → chex/EtOAc, 4:1), the β-amino ketone 2h
(136 mg, 0.49 mmol, quant.) was obtained as a light brown solid; mp
115 °C; Rf = 0.24 (chex/EtOAc, 3:1).
1H NMR (400 MHz, CDCl3): δ = 8.07 [ddd, J(H6,H5) = 5.1 Hz,
J(H6,H4) = 1.9 Hz, J(H6,H3) = 0.9 Hz, 1 H, H6], 8.00–7.92 [m, 2 H, H2ph
,
H6ph], 7.65–7.54 [m, 1 H, H4ph], 7.53–7.44 [m, 2 H, H3ph, H5ph], 7.40
[ddd, J(H4,H3) = 8.4 Hz, J(H4,H5) = 7.1 Hz, J(H4,H6) = 1.9 Hz, 1 H, H4],
6.62 [ddd, J(H5,H4) = 7.1 Hz, J(H5,H6) = 5.1 Hz, J(H5,H3) = 0.9 Hz, 1 H,
H5], 6.48 [dt, J(H3,H4) = 8.3 Hz, J(H3,H5) = 0.9 Hz, 1 H, H3], 6.20 [td,
J(CHF2,CHF2) = 56.7 Hz, J(CHF2,CH) = 3.1 Hz, 1 H, CHF2], 5.08–4.91 [m,
1 H, CH], 4.89 [d, J(NH,CH) = 9.0 Hz, 1 H, NH], 3.46–3.38 [m, 2 H, CH2].
13C NMR (101 MHz, CDCl3): δ = 197.85 [C=O], 157.16 [C2], 147.97
[C6], 137.61 [C4], 136.58 [C1ph], 133.76 [C4ph], 128.89 [C3ph, C5ph],
128.34 [C2ph, C6ph], 115.45 [t, 1J(CHF2,CHF2) = 244.9 Hz, CHF2], 113.02
[C5], 108.87 [C3], 49.94 [dd, 2J(CH,CHF2) = 24.5 Hz, 2J(CH,CHF2) =
22.8 Hz, CH], 36.73 [CH2].
19F NMR (376 MHz, CDCl3): δ = –125.78 [ddd, J(CHF2,CHF2) = 281.1 Hz,
J(CHF2,CHF2) = 56.4 Hz, J(CHF2,CH) = 10.4 Hz, CHF2], –128.96 [ddd,
J(CHF2,CHF2) = 281.1 Hz, J(CHF2,CHF2) = 56.9 Hz, J(CHF2,CH) = 16.0 Hz,
CHF2].
374.0112.
HPLC-MS (0.05% formic acid; 0 min, 0% B → 2.0 min, 100% B, flow: 3.3
mL/min): tR = 1.74 min, λ = 220 nm.
HRMS (ESI+): m/z calcd for C15H15F2N2O+ [M + H]+: 277.1147; found:
277.1146.
4,4,4-Trifluoro-1-(4-methoxyphenyl)-3-(pyrazin-2-ylamino)bu-
tan-1-one (3b)
HPLC (0.1% TFA; 0 min, 4% B → 15 min, 100% B, flow: 1 mL/min): tR =
10.23 min, λ = 214 nm.
According to the general procedure, 1b (150 mg, 0.68 mmol) was dis-
solved in dry CH2Cl2 (7 mL), treated with LHMDS (1.0 M solution in
toluene, 1.56 mL, 1.56 mmol), and reacted with 4-methoxyacetophe-
none (153 mg, 1.02 mmol). After stirring at r.t. (2 h), aqueous workup,
flash chromatography (chex/EtOAc, 3:1 → 2:1), and recrystallization
(chex/EtOAc, 9:1), the β-amino ketone 3b (199 mg, 0.61 mmol, 90%)
was obtained as a colorless crystalline solid; mp 135 °C; Rf = 0.11
(chex/EtOAc, 2:1).
1H NMR (500 MHz, DMSO-d6): δ = 8.03 [dd, J(H6,H5) = 2.6 Hz,
J(H6,H3) = 1.4 Hz, 1 H, H6], 7.99–7.93 [m, 3 H, H3, H2ph, H6ph], 7.81 [d,
J(H5,H6) = 2.8 Hz, 1 H, H5], 7.47 [d, J(NH,CH) = 8.3 Hz, 1 H, NH], 7.05
[m, 2 H, H3ph, H5ph], 5.52–5.34 [m, 1 H, CH], 3.85 [s, 3 H, OCH3], 3.57
[dd, J(CH2,CH2) = 17.5 Hz, J(CH2,CH) = 9.9 Hz, 1 H, CH2], 3.42 [dd,
J(CH2,CH2) = 17.5 Hz, J(CH2,CH) = 3.2 Hz, 1 H, CH2].
4,4,5,5,5-Pentafluoro-1-phenyl-3-(pyrazin-2-ylamino)pentan-1-
one (2i)
Following the general procedure, N-(1-ethoxy-2,2,3,3,3-pentafluoro-
propyl)pyrazin-2-amine (1i; 100 mg, 0.37 mmol) was dissolved in
dry CH2Cl2 (5 mL), treated with LHMDS (1.0 M solution in toluene,
0.85 mL, 0.85 mmol), and reacted with acetophenone (0.07 mL,
0.55 mmol). After stirring at r.t. (1 h), aqueous workup, and flash
chromatography (chex → chex/EtOAc, 2:1), the β-amino ketone 2i
(130 mg, 0.37 mmol, quant.) was obtained as a light yellow solid; mp
105 °C; Rf = 0.23 (chex/EtOAc, 2:1).
1H NMR (400 MHz, CDCl3): δ = 8.01 [dd, J(H6,H5) = 2.8 Hz,
J(H6,H3) = 1.5 Hz, 1 H, H6], 7.99 [d, J(H3,H6) = 1.5 Hz, 1 H, H3], 7.95–
7.91 [m, 2 H, H2ph, H6ph], 7.90 [m, 1 H, H5], 7.60 [m, 1 H, H4ph], 7.48
[m, 2 H, H3ph, H5ph], 5.73 [m, 1 H, CH], 5.06 [d, J(NH,CH) = 10.0 Hz,
1 H, NH], 3.51–3.46 [m, 2 H, CH2].
13C NMR (101 MHz, DMSO-d6): δ = 193.51 [C=O], 163.59 [COCH3],
154.04 [C2], 141.47 [C6], 133.10 [C3], 133.01 [C5], 130.64 [C2ph, C6ph],
129.17 [C1ph], 126.40 [q, 1J(C,F) = 283.0 Hz, CF3], 114.11 [C3ph, C5ph],
55.73 [OCH3], 47.36 [q, 2J(C,F) = 30.3 Hz, CH], 36.84 [CH2].
13C NMR (101 MHz, CDCl3): δ = 195.68 [C=O], 152.61 [C2], 141.68
[C6], 136.31 [C1ph], 134.84 [C5], 134.01 [C4ph], 132.96 [C3], 129.01
[C3ph, C5ph], 128.27 [C2ph, C6ph], 46.94 [dd, 2J(CH,CF2) = 27.1 Hz,
2J(CH,CF2) = 21.4 Hz, CH], 37.07 [CH2].
19F NMR (376 MHz, CDCl3): δ = –81.84 [CF3], –118.54 [dd, J(CF2,CF2) =
273.6 Hz, J(CF2,CF3) = 7.3 Hz, CF2], –124.82 [dd, J(CF2,CF2) = 273.6 Hz,
J(CF2,CF3) = 19.8 Hz, CF2].
19F NMR (376 MHz, DMSO-d6): δ = –74.34 [d, J(CF3,CH) = 7.8 Hz, CF3].
+
HR-EI-MS: m/z calcd for
C
15H14F3N3O2 [M]+: 325.1038; found:
325.1043.
HPLC-MS (0.05% formic acid; 0 min, 0% B → 2.0 min, 100% B, flow: 3.3
mL/min): tR = 1.60 min, λ = 220 nm.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

G
S. Wunder et al.
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Synthesis
4,4,4-Trifluoro-1-(2-methoxyphenyl)-3-(pyrazin-2-ylamino)bu-
tan-1-one (3c)
4,4,4-Trifluoro-1-(4-nitrophenyl)-3-(pyrazin-2-ylamino)butan-1-
one (3e)
According to the general procedure, 1b (150 mg, 0.68 mmol) was dis-
solved in dry CH2Cl2 (7 mL), treated with LHMDS (1.0 M solution in
toluene, 1.56 mL, 1.56 mmol), and reacted with 2-methoxyacetophe-
none (0.14 mL, 1.02 mmol). After stirring at r.t. (2 h), aqueous work-
up, flash chromatography (chex/EtOAc, 3:1 → 2:1), and recrystalliza-
tion (chex/EtOAc, 9:1), the β-amino ketone 3c (194 mg, 0.59 mmol,
88%) was obtained as a colorless crystalline solid; mp 134 °C; Rf = 0.14
(chex/EtOAc, 2:1).
1H NMR (500 MHz, DMSO-d6): δ = 7.97 [dd, J(H6,H5) = 2.7 Hz,
J(H6,H3) = 1.5 Hz, 1 H, H6], 7.95 [d, J(H3,H6) = 1.5 Hz, 1 H, H3], 7.79
[d, J(H5,H6) = 2.8 Hz, 1 H, H5], 7.60–7.49 [m, 3 H, H2ph, H4ph, H5ph],
7.20 [d, J(NH,CH) = 8.2 Hz, 1 H, NH], 7.03–6.97 [m, 1 H, H3ph], 5.47–
5.37 [m, 1 H, CH], 3.91 [s, 3 H, OCH3], 3.46 [dd, J(CH2,CH2) = 17.4 Hz,
J(CH2,CH) = 4.2 Hz, 1 H, CH2], 3.40 [dd, J(CH2,CH2) = 17.4 Hz, J(CH2,CH) =
9.2 Hz, 1 H, CH2].
According to the general procedure, 1b (100 mg, 0.45 mmol) was dis-
solved in dry CH2Cl2 (7 mL), treated with LHMDS (1.0 M solution in
toluene, 1.04 mL, 1.04 mmol), and reacted with 4′-nitroacetophenone
(111 mg, 0.68 mmol). After stirring at r.t. (1 h) followed by stirring at
40 °C (2 h), TLC and LC-MS control showed that large amounts of
starting material remained. The reaction mixture was cooled to –78 °C
before LHMDS (1.0 M solution in toluene, 0.45 mL, 0.45 mmol) was
added. Stirring was continued at –78 °C for 10 min, 4′-nitroacetophe-
none (75 mg, 0.45 mmol) was added, and the reaction mixture was
stirred at 40 °C (20 h). Subsequent aqueous workup, flash chromatog-
raphy (chex → chex/EtOAc, 4:1), and recrystallization (chex/EtOAc,
9:1) furnished the β-amino ketone 3e (115 mg, 0.34 mmol, 75%) as a
yellow crystalline solid; mp 163 °C; Rf = 0.14 (chex/EtOAc, 2:1).
1H NMR (400 MHz, DMSO-d6): δ = 8.41–8.30 [m, 2 H, H3ph, H5ph],
8.26–8.18 [m,
2 H, H2ph, H6ph], 8.04 [dd, J(H6,H5) = 2.8 Hz,
J(H6,H3) = 1.5 Hz, 1 H, H6], 7.96 [d, J(H3,H6) = 1.5 Hz, 1 H, H3], 7.83
[d, J(H5,H6) = 2.8 Hz, 1 H, H5], 7.47 [d, J(NH,CH) = 8.1 Hz, 1 H, NH],
5.52 – 5.33 [m, 1 H, CH], 3.77–3.60 [m, 2 H, 2 × CH2].
13C NMR (101 MHz, DMSO-d6): δ = 194.63 [C=O], 154.01 [C2], 150.24
[CNO2], 141.46 [C6], 140.72 [C3], 133.17 [C5], 129.70 [C2ph, C6ph],
126.23 [q, 1J(C,F) = 282.8 Hz, CF3] 123.98 [C3ph, C5ph], 47.25 [q,
2J(C,F) = 30.5 Hz, CH], 37.90 [CH2].
13C NMR (101 MHz, DMSO-d6): δ = 196.16 [C=O], 158.68 [COCH3],
153.95 [C2], 141.39 [C6], 134.64 [C4ph], 133.16 [C3], 132.95 [C5],
129.99 [C2ph], 126.51 [C1ph], 126.30 [q, 1J(C,F) = 282.9 Hz, CF3] 120.71
[C3ph], 112.68 [C5ph], 55.97 [OCH3], 47.31 [q, 2J(C,F) = 30.1 Hz, CH],
42.49 [CH2].
19F NMR (471 MHz, DMSO-d6): δ = –74.52 [d, J(CF3,CH) = 7.7 Hz, CF3].
+
HR-EI-MS: m/z calcd for
C
15H14F3N3O2 [M]+: 325.1038; found:
19F NMR (376 MHz, DMSO-d6): δ = –74.47 [d, J(CF3,CH) = 7.8 Hz, CF3].
HRMS (ESI+): m/z calcd for C14H12F3N4O3+ [M + H]+: 341.0856; found:
325.1044.
HPLC-MS (0.05% formic acid; 0 min, 0% B → 2.0 min, 100% B, flow: 3.3
mL/min): tR = 1.62 min, λ = 220 nm.
341.0859.
HPLC-MS (0.05% formic acid; 0 min, 0% B → 2.0 min, 100% B, flow: 3.3
mL/min): tR = 1.62 min, λ = 220 nm.
Methyl 4-[4,4,4-Trifluoro-3-(pyrazin-2-ylamino)butanoyl]benzo-
ate (3d)
4-[4,4,4-Trifluoro-3-(pyrazin-2-ylamino)butanoyl]benzonitrile
(3f)
According to the general procedure, 1b (100 mg, 0.45 mmol) was dis-
solved in dry CH2Cl2 (7 mL), treated with LHMDS (1.0 M solution in
toluene, 1.04 mL, 1.04 mmol), and reacted with methyl 4-acetylben-
zoate (120 mg, 0.68 mmol). After stirring at r.t. (2.5 h), aqueous work-
up, flash chromatography (chex → chex/EtOAc, 4:1), and recrystalliza-
tion (chex), the desired β-amino ketone 3d (130 mg, 0.37 mmol, 82%)
was obtained as a colorless crystalline solid; mp 121 °C; Rf = 0.17
(chex/EtOAc, 2:1).
1H NMR (400 MHz, DMSO-d6): δ = 8.10 [d, J(H2ph,H3ph) = J(H5ph,H6ph) =
2.1 Hz, 4 H, H2ph, H3ph, H5ph, H6ph], 8.04 [dd, J(H6,H5) = 2.8 Hz,
J(H6,H3) = 1.5 Hz, 1 H, H6], 7.96 [d, J(H3,H6) = 1.5 Hz, 1 H, H3], 7.82
[d, J(H5,H6) = 2.8 Hz, 1 H, H5], 7.46 [d, J(NH,CH) = 8.2 Hz, 1 H, NH],
5.49–5.36 [m, 1 H, CH], 3.69 [dd, J(CH2,CH2) = 17.9 Hz, J(CH2,CH)
= 9.7 Hz, 1 H, CH2], 3.59 [dd, J(CH2,CH2) = 17.5 Hz, J(CH2,CH) = 3.1 Hz,
1 H, CH2].
According to the general procedure, 1b (100 mg, 0.45 mmol) was dis-
solved in dry CH2Cl2 (7 mL), treated with LHMDS (1.0 M solution in
toluene, 1.04 mL, 1.04 mmol), and reacted with 4′-cyanoacetophe-
none (99 mg, 0.68 mmol). After stirring at r.t. (1 h) followed by stir-
ring at 40 °C (1 h) TLC and LC-MS control showed that large amounts
of starting material remained. The reaction mixture was cooled to –78 °C
before LHMDS (1.0 M solution in toluene, 0.45 mL, 0.45 mmol) was
added. Stirring was continued at –78 °C (10 min), 4′-cyanoacetophe-
none (65 mg, 0.45 mmol) was added and the reaction mixture was
stirred at 40 °C (1 h). Subsequent aqueous workup, flash chromatog-
raphy (chex → chex/EtOAc, 4:1), and recrystallization (chex) furnished
the β-amino ketone 3f (131 mg, 0.41 mmol, 91%) as a colorless crys-
talline solid; mp 185 °C; Rf = 0.37 (chex/EtOAc, 1:1).
1H NMR (400 MHz, DMSO-d6): δ = 8.18–8.09 [m, 2 H, H3ph, H5ph],
13C NMR (101 MHz, DMSO-d6): δ = 194.84 [C=O], 165.46 [CO2Me],
153.85 [C2], 141.22 [C6], 139.39 [C1ph], 133.47 [C5], 133.00 [C4ph],
132.96 [C3], 129.42 [C3ph, C5ph], 128.38 [C2ph, C6ph], 52.47 [CH3],
8.05–8.02 [m,
2 H, H2ph, H6ph], 8.01 [m, 1 H, H6], 7.96 [d,
J(H3,H6) = 1.4 Hz, 1 H, H3], 7.82 [d, J(H5,H6) = 2.8 Hz, 1 H, H5], 7.46
[d, J(NH,CH) = 8.1 Hz, 1 H, NH], 5.53–5.28 [m, 1 H, CH], 3.68 [dd,
2
47.12 [q, J(C,F) = 30.5 Hz, CH], 37.50 [CH2]. Due to low intensity, the
J(CH2,CH2) = 18.1 Hz, J(CH2,CH) = 9.3 Hz,
1 H, CH2], 3.61 [dd,
signal for CF3 could not be observed.
19F NMR (376 MHz, DMSO-d6): δ = –74.38 [d, J(CF3,CH) = 8.0 Hz, CF3].
HRMS (ESI+): m/z calcd for C16H15F3N3O3+ [M + H]+: 354.1060; found:
354.1061.
J(CH2,CH2) = 18.0 Hz, J(CH2,CH) = 3.9 Hz, 1 H, CH2].
13C NMR (101 MHz, DMSO-d6): δ = 194.84 [C=O], 154.01 [C2], 141.45
[C6], 139.30 [C1ph], 133.16 [C3], 133.15 [C5], 132.94 [C2ph, C6ph],
128.88 [C3ph, C5ph], 126.24 [q, 1J(C,F) = 282.7 Hz, CF3], 118.22 [C≡N],
115.61 [CCN], 47.24 [q, 2J(C,F) = 30.5 Hz, CH], 37.69 [CH2].
HPLC-MS (0.05% formic acid; 0 min, 0% B → 2.0 min, 100% B, flow: 3.3
mL/min): tR = 1.62 min, λ = 220 nm.
19F NMR (376 MHz, DMSO-d6): δ = –74.37 [d, J(CF3,CH) = 7.9 Hz, CF3].
HRMS (ESI+): m/z calcd for C15H12F3N4O+ [M + H]+: 321.0958; found:
321.0959.
HPLC-MS (0.05% formic acid; 0 min, 0% B → 2.0 min, 100% B, flow: 3.3
mL/min): tR = 1.56 min, λ = 220 nm.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

H
S. Wunder et al.
Paper
Synthesis
4,4,4-Trifluoro-1-(perfluorophenyl)-3-(pyrazin-2-ylamino)butan-
1-one (3g)
HRMS (ESI+): m/z calcd for C12H11F3N3O2+ [M + H]+: 286.0798; found:
286.0797.
According to the general procedure, 1b (100 mg, 0.45 mmol) was dis-
solved in dry CH2Cl2 (7 mL), treated with LHMDS (1.0 M solution in
toluene, 1.04 mL, 1.04 mmol), and reacted with 2′,3′,4′,5′,6′-pentaflu-
oroacetophenone (0.10 mL, 0.68 mmol). After stirring at r.t. (1 h) fol-
lowed by stirring at 40 °C (2 h), TLC and LC-MS control showed that
large amounts of starting material remained. The reaction mixture
was cooled to –78 °C before LHMDS (1.0 M solution in toluene,
0.45 mL, 0.45 mmol) was added. Stirring was continued at –78 °C (10
min), 2′,3′,4′,5′,6′-pentafluoroacetophenone (0.07 mL, 0.45 mmol)
was added and the reaction mixture was stirred at 40 °C (20 h). Sub-
sequent aqueous workup, flash chromatography (chex → chex/EtOAc,
4:1), and recrystallization (chex/EtOAc, 9:1) furnished the β-amino
ketone 3g (61 mg, 0.16 mmol, 35%) as a light yellow solid; mp 115 °C;
Rf = 0.30 (chex/EtOAc, 2:1).
1H NMR (400 MHz, DMSO-d6): δ = 8.03–7.97 [m, 2 H, H6, H3], 7.84 [d,
J(H5,H6) = 2.3 Hz, 1 H, H5], 7.70 [d, J(NH,CH) = 8.8 Hz, 1 H, NH], 5.51–
5.37 [m, 1 H, CH], 3.55 [dd, J(CH2,CH2) = 17.7 Hz, J(CH2,CH) = 4.0 Hz, 1
H, CH2], 3.40 [dd, J(CH2,CH2) = 17.7 Hz, J(CH2,CH) = 9.7 Hz, 1 H, CH2].
13C NMR (101 MHz, DMSO-d6): δ = 189.83 [C=O], 153.88 [C2], 146.07–
145.78 [m, CF], 144.42–144.10 [m, CF], 143.55–143.31 [m, CF], 141.56
[C6], 139.00–138.65 [m, CF], 136.52–136.16 [m, C–F], 133.64 [C5],
133.49 [C3], 126.01 [q, 1J(C,F) = 283.0 Hz, CF3], 113.99–113.63 [m, CF],
47.15 [q, 2J(C,F) = 30.8 Hz, CH], 43.49 [CH2].
HPLC (0.1% TFA; 0 min, 4% B → 15 min, 100% B, flow: 1 mL/min): tR =
12.68 min, λ = 214 nm.
4,4,4-Trifluoro-1-(1-methyl-1H-indol-3-yl)-3-(pyrazin-2-ylami-
no)butan-1-one (3i)
According to the general procedure, 1b (100 mg, 0.45 mmol) was dis-
solved in dry CH2Cl2 (7 mL), treated with LHMDS (1.0 M solution in
toluene, 1.04 mL, 1.04 mmol), and reacted with 1-(1-methyl-1H-in-
dol-3-yl)ethan-1-one (117 mg, 0.68 mmol). After stirring at r.t. (2 h),
aqueous
workup,
flash
chromatography
[CH2Cl2 → CH2Cl2/(CH2Cl2/MeOH, 10:1), 7:3] and recrystallization
(chex), the β-amino ketone (105 mg, 0.30 mmol, 67%) was obtained as
a colorless solid; mp 198 °C; Rf = 0.17 (chex/EtOAc, 1:1).
1H NMR (400 MHz, DMSO-d6): δ = 8.46 [s,
J(H7in,H6in) = 7.6 Hz, H, H7in], 8.03 [dd, J(H6,H5) = 2.8 Hz,
1 H, H2in], 8.12 [d,
1
J(H6,H3) = 1.5 Hz, 1 H, H6], 7.98 [d, J(H3,H6) = 1.5 Hz, 1 H, H3], 7.79
[d, J(H5,H6) = 2.8 Hz, 1 H, H5], 7.54 [m, 2 H, NH, H4in], 7.32–7.25 [m, 1
H, H5in], 7.21 [td, J(H6in,H7in/H5in) = 7.6 Hz, 4J(H6in,H4in) = 1.0 Hz, 1 H,
H6in], 5.59–5.41 [m, 1 H, CH], 3.89 [s, 3 H, NCH3], 3.45 [dd, J(CH2,CH2) =
16.5 Hz, J(CH2,CH) = 9.8 Hz, 1 H, CH2], 3.26 [dd, J(CH2,CH2) = 16.5 Hz,
J(CH2,CH) = 3.5 Hz, 1 H, CH2].
13C NMR (101 MHz, CDCl3): δ = 188.98 [C=O], 154.06 [C2], 141.51
[C6], 138.37 [C2in], 137.39 [CquatN], 133.11 [C3], 132.92 [C5], 126.53
[q, 1J(C,F) = 283.0 Hz, CF3] 125.75 [C3in], 123.21 [C5in], 122.46 [C6in],
121.47 [C7in], 115.00 [Cquat], 110.81 [C4in], 47.42 [q, 2J(C,F) = 30.1 Hz,
CH], 37.64 [CH2], 33.35 [CH3].
19F NMR (376 MHz, DMSO-d6): δ = –74.68 [d, J(CF3,CH) = 7.8 Hz, CF3],
–140.87 to –141.17 [m, F2, F6], –149.30 [tt, J(F4,F3) = J(F4,F5) =
22.2 Hz, J(F4,F2) = J(F4,F6) = 4.4 Hz, F4], –160.93 to –161.21 [m, F3,
F5].
HRMS (ESI+): m/z calcd for C14H8F8N3O+ [M + H]+: 386.0534; found:
386.0534.
19F NMR (376 MHz, DMSO-d6): δ = –74.34 [d, J(CF3,CH) = 8.0 Hz, CF3].
HRMS (ESI+): m/z calcd for C17H16F3N4O+ [M + H]+: 349.1271; found:
349.1273.
HPLC-MS (0.05% formic acid; 0 min, 0% B → 2.0 min, 100% B, flow: 3.3
mL/min): tR = 1.74 min, λ = 220 nm.
HPLC-MS (0.05% formic acid; 0 min, 0% B → 2.0 min, 100% B, flow: 3.3
mL/min): tR = 1.60 min, λ = 220 nm.
4,4,4-Trifluoro-1-(furan-2-yl)-3-(pyrazin-2-ylamino)butan-1-one
(3h)
(E)-6,6,6-Trifluoro-1-phenyl-5-(pyrazin-2-ylamino)hex-1-en-3-
one (3j)
According to the general procedure, 1b (100 mg, 0.45 mmol) was dis-
solved in dry CH2Cl2 (7 mL), treated with LHMSD (1.0 M solution in
toluene, 1.04 mL, 1.04 mmol), and reacted with 2-acetylfuran (75 mg,
0.68 mmol). After stirring at r.t. (2 h), aqueous workup, and column
chromatography (chex/EtOAc, 1.5:1 → 1:1), the β-amino ketone 3h
(75 mg, 0.26 mmol, 58%) was obtained as a light yellow oil; Rf = 0.32
(chex/EtOAc, 1:1).
According to the general procedure, 1b (100 mg, 0.45 mmol) was dis-
solved in dry CH2Cl2 (7 mL), treated with LHMDS (1.0 M solution in
toluene, 1.04 mL, 1.04 mmol), and reacted with (E)-4-phenylbut-3-
en-2-one (99 mg, 0.68 mmol). After stirring at r.t. (2 h), aqueous
workup, and column chromatography (chex/EtOAc, 3:1 → 1:1), the β-
amino ketone (92 mg, 0.29 mmol, 64%) was obtained as a yellow oil;
Rf = 0.55 (chex/EtOAc, 1:1).
1H NMR (400 MHz, DMSO-d6): δ = 8.03 [dd, J(H6,H5) = 2.8 Hz,
J(H6,H3) = 1.5 Hz, 1 H, H6], 7.99 [d, J(H3,H6) = 1.5 Hz, 1 H, H3], 7.80
[d, J(H5,H6) = 2.8 Hz, 1 H, H5], 7.74–7.70 [m, 2 H, H2ph, H6ph], 7.67 [d,
J(Ha,Hb) = 16.3 Hz, 1 H, Ha], 7.53 [d, J(NH,CH) = 8.5 Hz, 1 H, NH], 7.47–
7.42 [m, 3 H, H3ph, H4ph, H5ph,], 6.96 [d, J(Ha,Hb) = 16.3 Hz, 1 H, Hb],
5.48–5.31 [m, 1 H, CH], 3.32–3.24 [m, 1 H, CH2], 3.19 [dd, J(CH2,CH2)
= 17.3 Hz, J(CH2,CH) = 3.6 Hz, 1 H, CH2].
1H NMR (800 MHz, DMSO-d6): δ = 8.02 [dd, J(H6,H5) = 2.8 Hz,
J(H6,H3) = 1.5 Hz,
1 H, H6], 8.00 [dd, J(H5furan,H4furan) = 1.7 Hz,
J(H5furan,H3furan) = 0.7 Hz, 1 H, H5furan], 7.95 [d, J(H3,H6) = 1.5 Hz, 1 H,
H3], 7.80 [d, J(H5,H6) = 2.8 Hz, 1 H, H5], 7.57 [d, J(NH,CH) = 8.5 Hz, 1
H, NH], 7.52 [dd, J(H3furan,H4furan) = 3.6 Hz, J(H3furan,H5furan) = 0.7 Hz 1
H,
H3furan],
6.73
[dd,
J(H4furan,H3furan) = 3.6 Hz,
J(H4furan,H5furan) = 1.7 Hz, 1 H, H4furan], 5.47–5.29 [m, 1 H, CH], 3.43–
3.37 [m, 1 H, CH2], 3.31 [dd, J(CH2,CH2) = 17.1 Hz, J(CH2,CH) = 3.8 Hz, 1
H, CH2].
13C NMR (101 MHz, DMSO-d6): δ = 183.44 [C=O], 153.91 [C2], 151.57
[C2furan], 148.36 [C5furan], 141.45 [C6], 133.15 [C3, C5], 129.19 [q,
1J(C,F) = 282.8 Hz, CF3], 119.42 [C3furan], 112.92 [C4furan], 47.02 [q,
2J(C,F) = 30.5 Hz, CH], 36.95 [CH2].
13C NMR (101 MHz, DMSO-d6): δ = 195.11 [C=O], 154.02 [C2], 143.33
[Ca], 141.45 [C6], 134.32 [C1ph], 133.18 [C3], 133.05 [C5], 130.88
[C4ph], 129.16 [C3ph
,
C5ph], 128.68 [C2ph
,
C6ph], 126.31 [q,
1J(C,F) = 282.8 Hz, CF3] 126.10 [Cb], 47.20 [q, 2J(C,F) = 30.3 Hz, CH].
19F NMR (376 MHz, DMSO-d6): δ = –74.50 [d, J(CF3,CH) = 7.9 Hz, CF3].
HRMS (ESI+): m/z calcd for C16H15F3N3O+ [M + H]+: 322.1162; found:
322.1160.
19F NMR (376 MHz, DMSO-d6): δ = –74.52 [d, J(CF3,CH) = 7.9 Hz, CF3].
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

I
S. Wunder et al.
Paper
Synthesis
4,4,4-Trifluoro-2-methyl-1-phenyl-3-(pyrazin-2-ylamino)butan-
1-one (3k)
acetonitrile (202 mg, 1.09 mmol). After stirring at r.t. (2.5 h), aqueous
workup, column chromatography (chex/EtOAc, 5:1 → 3:1), and wash-
ing with toluene, the β-amino ketone 3m (148 mg, 0.41 mmol, 60%)
was obtained as a colorless solid (mixture of diastereomers).
1H NMR (400 MHz, DMSO-d6): δ = 8.33 [d, J(H3ar,H4ar) = 9.6 Hz, 1 H,
H3ar], 8.18 [d, J(H3,H6) = 1.5 Hz, 1 H, H3], 8.09 [dd, J(H6,H5) = 2.7 Hz,
J(H6,H3) = 1.5 Hz, 1 H, H6], 7.94 [d, J(H5,H6) = 2.7 Hz, 1 H, H5], 7.65
[s, 2 H, NH, H5ar], 7.53 [t, J(H4ar,H3ar/H5ar) = 8.1 Hz, 1 H, H4ar], 6.22–
6.07 [m, 1 H, CH], 5.51 [d, J(CHCN,CH) = 10.5 Hz, 1 H, CHCN].
Following the general procedure, 1b (100 mg, 0.45 mmol) was dis-
solved in dry CH2Cl2 (7 mL), treated with LHMDS (1.0 M solution in
toluene, 1.04 mL, 1.04 mmol), and reacted with propiophenone
(0.09 mL, 0.68 mmol). After stirring at r.t. (2 h), aqueous workup, and
column chromatography (chex/EtOAc, 3:1 → 2:1), the β-amino ketone
3k (95 mg, 0.31 mmol, 68%) was obtained as a colorless solid (mix-
ture of diastereomers); mp 95 °C; Rf = 0.37 (chex/EtOAc, 2:1).
1H NMR (400 MHz, DMSO-d6): δ = 8.05–7.98 [m, 4 H, H6, H3, H2ph
,
13C NMR (75 MHz, DMSO-d6): δ = 152.60 [C2], 140.63 [C6], 135.21
[C1ph], 133.83 [C5], 132.89 [C3], 131.79 [C2ph, C6ph], 129.30 [C4ph],
128,21 [q, 1J(C,F) = 283.9 Hz, CF3], 126.23 [C3ph, C5ph], 114.98 [C≡N],
50.71 [q, 2J(C,F) = 30.2 Hz, CCF3], 32.00 [CCN].
H6ph], 7.80 [d, J(H5,H6) = 2.8 Hz, 1 H, H5], 7.71–7.65 [m, 1 H, H4ph],
7.60–7.53 [m, 3 H, H3ph, H5ph, NH], 5.36–5.23 [m, 1 H, CH], 4.17 [dq,
J(CHCH3,CH) = 14.2 Hz, J(CHCH3,CH3) = 7.0 Hz 1 H, CHCH3], 1.25 [dd,
J(CH3,CHCH3) = 7.0 Hz, J(CH3,CF3) = 1.1 Hz 3 H, CH3].
13C NMR (101 MHz, DMSO-d6): δ = 199.81 [C=O], 153.69 [C2], 141.17
[C6], 135.21 [C1ph], 133.65 [C5], 133.12 [C4ph], 132.96 [C3], 128.90
[C3ph, C5ph], 128.43 [C2ph, C6ph], 126.13 [q, 1J(C,F) = 284.3 Hz, CF3],
52.21 [q, 2J(C,F) = 28.8 Hz, CH], 26.32 [CHCH3], 14.60 [d,
4J(C,F) = 1.9 Hz, CH3].
19F NMR (471 MHz, DMSO-d6): δ = –71.63 [br s, CF3].
+
HR-EI-MS: m/z calcd for
C
14H9Cl2F3N4 [M]+: 360.0156; found:
360.0177.
HPLC-MS (0.05% formic acid; 0 min, 0% B → 2.0 min, 100% B, flow: 3.3
mL/min): tR = 1.68 min, 1.73 min, λ = 220 nm.
19F NMR (376 MHz, DMSO-d6): δ = –69.65 [dd, J(CF3,CH) = 8.4 Hz,
J(CF3,CH3) = 1.1 Hz, CF3].
HRMS (ESI+): m/z calcd for C15H15F3N3O+ [M + H]+: 310.1162; found:
Diethyl 2-[2,2,2-Trifluoro-1-(pyrazin-2-ylamino)ethyl]malonate
(3n)
According to the general procedure, 1b (150 mg, 0.68 mmol) was dis-
solved in dry CH2Cl2 (7 mL), treated with LHMDS (1.0 M solution in
toluene, 1.42 mL, 1.42 mmol), and reacted with diethyl malonate
(0.16 mL, 1.02 mmol). After stirring at r.t. (2 h), TLC and LC-MS con-
trol showed that large amounts of starting material remained. The re-
action mixture was cooled to –78 °C before LHMDS (1.0 M solution in
toluene, 0.68 mL, 0.68 mmol) was added. Stirring was continued at
–78 °C (10 min), diethyl malonate (0.1 mL, 0.68 mmol) was added,
and the reaction mixture was stirred at 40 °C (2 h). Subsequent aque-
ous workup and column chromatography (chex/EtOAc, 3:1) furnished
the desired β-amino ketone 3n (134 mg, 0.40 mmol, 59%) as a light
yellow oil; Rf = 0.31 (chex/EtOAc, 2:1).
1H NMR (300 MHz, DMSO-d6): δ = 8.09 [d, J(H3,H6) = 1.5 Hz, 1 H, H3],
8.07 [dd, J(H6,H5) = 2.7 Hz, J(H6,H3) = 1.5 Hz, 1 H, H6], 7.87 [d,
J(H5,H6) = 2.7 Hz, 1 H, H5], 7.71 [d, J(NH,CH) = 9.5 Hz, 1 H, NH], 5.73–
5.59 [m, 1 H, CH], 4.23–3.94 [m, 4 H, 2 × CH2], 1.16 [t, J(CH3,CH2) =
7.1 Hz, 3 H, CH3], 1.01 [t, J(CH3,CH2) = 7.1 Hz, 3 H, CH3].
310.1160.
HPLC (0.1% TFA; 0 min, 4% B → 15 min, 100% B, flow: 1 mL/min): tR =
15.79 min, 15.97 min, λ = 214 nm.
4,4,4-Trifluoro-2,2-dimethyl-1-phenyl-3-(pyrazin-2-ylamino)bu-
tan-1-one (3l)
Following the general procedure, 1b (100 mg, 0.45 mmol) was dis-
solved in dry CH2Cl2 (7 mL), treated with LHMDS (1.0 M solution in
toluene, 1.04 mL, 1.04 mmol), and reacted with 2-methyl-1-phenyl-
propan-1-one (0.1 mL, 0.68 mmol). After stirring at r.t. (3 h), aqueous
workup, and column chromatography (chex/EtOAc, 3:1 → 2:1), the β-
amino ketone 3l (32 mg, 0.10 mmol, 22%) was obtained as a light yel-
low solid; mp 130 °C; Rf = 0.29 (chex/EtOAc, 2:1).
1H NMR (400 MHz, DMSO-d6): δ = 8.20 [d, J(H3,H6) = 1.5 Hz, 1 H, H3],
8.00 [dd, J(H6,H5) = 2.8 Hz, J(H6,H3) = 1.5 Hz, 1 H, H6], 7.82 [d,
J(H5,H6) = 2.8 Hz, 1 H, H5], 7.75–7.68 [m, 1 H, H4ph], 7.67–7.61 [m, 2
H, H2ph, H6ph], 7.58–7.51 [m, 1 H, NH], 7.47 [m, 2 H, H3ph, H5ph], 6.01
[m, 1 H, CH], 1.40 [s, 3 H, CH3], 1.27 [s, 3 H, CH3].
13C NMR (101 MHz, DMSO-d6): δ = 206.17 [C=O], 154.05 [C2], 141.02
[C6], 137.80 [C1ph], 133.52 [C5], 133.14 [C4ph], 131.20 [C3], 128.36
[C3ph, C5ph], 127.29 [C2ph, C6ph], 125.73 [q, 1J(C,F) = 284.7 Hz, CF3],
54.13 [q, 2J(C,F) = 27.6 Hz, CH], 49.48 [C(CH3)2], 24.02 [CH3], 20.37 [d,
4J(C,F) = 1.1 Hz, CH3].
13C NMR (75 MHz, DMSO-d6): δ = 165.19 [C=O], 164.99 [C=O], 153.23
[C2], 141.06 [C6], 133.57 [C5], 133.31 [C3], 124.90 [q,
1J(C,F) = 283.5 Hz, CF3], 61.97 [CH2], 61.70 [CH2], 51.66 [CH(CO2Et)2],
49.70 [q, 2J(C,F) = 30.5 Hz, CH], 13.63 [CH3], 13.51 [CH3].
19F NMR (282 MHz, DMSO-d6): δ = –72.79 [d, J(CF3,CH) = 7.9 Hz, CF3].
+
HR-EI-MS: m/z calcd for
C
13H16F3N3O4 [M]+: 335.1093; found:
335.1104.
19F NMR (376 MHz, DMSO-d6): δ = –67.66 [d, J(CF3,CH) = 8.9 Hz, CF3].
HRMS (ESI+): m/z calcd for C16H17F3N3O+ [M + H]+: 324.1318; found:
HPLC-MS (0.05% formic acid; 0 min, 0% B → 2.0 min, 100% B, flow: 3.3
mL/min): tR = 1.62 min, λ = 220 nm.
324.1318.
HPLC (0.1% TFA; 0 min, 4% B → 15 min, 100% B, flow: 1 mL/min): tR =
15.83 min, λ = 214 nm.
Ethyl 4,4,4-Trifluoro-3-(pyrazin-2-ylamino)butanoate (3o)
Following the general procedure, 1b (90 mg, 0.41 mmol) was dis-
solved in dry CH2Cl2 (7 mL), treated with LHMDS (1.0 M solution in
toluene, 0.94 mL, 0.94 mmol), and reacted with EtOAc (0.06 mL,
0.62 mmol). After stirring at r.t. (1 h), aqueous workup, and flash
chromatography (chex → chex/EtOAc, 3:1), the β-amino ester 3o
(27 mg, 0.10 mmol, 25%) was obtained as a light yellow oil; Rf = 0.15
(chex/EtOAc, 2:1).
2-(2,6-Dichlorophenyl)-4,4,4-trifluoro-3-(pyrazin-2-ylamino)bu-
tanenitrile (3m)
Following the general procedure, 1b (150 mg, 0.68 mmol) was dis-
solved in dry CH2Cl2 (7 mL), treated with LHMDS (1.0 M solution in
toluene, 1.56 mL, 1.56 mmol), and reacted with 2,6-dichlorophenyl-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

J
S. Wunder et al.
Paper
Synthesis
1H NMR (400 MHz, DMSO-d6): δ = 8.12–7.91 [m, 2 H, H6, H3], 7.82 [d,
J(H5,H6) = 2.3 Hz, 1 H, H5], 7.65 [d, J(NH,CH) = 8.9 Hz, 1 H, NH], 5.40–
5.18 [m, 1 H, CH], 4.03 [m, 2 H, OCH2], 2.92 [dd, J(CH2,CH2) = 16.2 Hz,
J(CH2,CH) = 4.2 Hz, 1 H, CH2], 2.72 [dd, J(CH2,CH2) = 16.2 Hz, J(CH2,CH) =
10.0 Hz, 1 H, CH2], 1.06 [t, J(CH3,CH2) = 7.1 Hz, 3 H, CH3].
13C NMR (101 MHz, DMSO-d6): δ = 168.76 [C=O], 153.64 [C2], 141.15
[C6], 133.11 [C5], 133.06 [C3], 125.57 [q, 1J(C,F) = 283.2 Hz, CF3], 60.47
[OCH2], 47.83 [q, 2J(C,F) = 30.7 Hz, CH], 33.58 [CH2], 13.76 [CH3].
(7) (a) Gauthier, J. Y.; Chauret, N.; Cromlish, W.; Desmarais, S.;
Duong, L. T.; Falgueyret, J.-P.; Kimmel, D. B.; Lamontagne, S.;
Léger, S.; LeRiche, T.; Li, C. S.; Massé, F.; McKay, D. J.; Nicoll-Grif-
fith, D. A.; Oballa, R. M.; Palmer, J. T.; Percival, M. D.; Riendeau,
D.; Robichaud, J.; Rodan, G. A.; Rodan, S. B.; Seto, C.; Thérien, M.;
Truong, V.-L.; Venuti, M. C.; Wesolowski, G.; Young, R. N.;
Zamboni, R.; Black, W. C. Bioorg. Med. Chem. Lett. 2008, 18, 923.
(b) Black, W. C.; Bayly, C. I.; Davis, D. E.; Desmarais, S.; Falguyret,
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19F NMR (376 MHz, DMSO-d6): δ = –74.89 [d, J(CF3,CH) = 7.9 Hz, CF3].
+
HR-EI-MS: m/z calcd for
C
10H12F3N3O2 [M]+: 263.0882; found:
263.0898.
(8) (a) Pevear, D. C.; Tull, T. M.; Seipel, M. E.; Groarke, J. M. Antimi-
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HPLC-MS (0.05% formic acid; 0 min, 0% B → 2.0 min, 100% B, flow: 3.3
mL/min): tR = 1.43 min, λ = 220 nm.
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Acknowledgment
Support of the work by the Excellence Cluster Center of Integrated Pro-
tein Science Munich (CIPSM) and the GRK 2062 Molecular Principles of
Synthetic Biology is gratefully acknowledged. The authors thank Antje
Schöneberg and Doris Weidenkopf-Look (Merck) for laboratory sup-
port and Christian von der Heyden and Markus Knoth (Merck) for
NMR support and fruitful discussions.
(12) (a) Robak, M. T.; Herbage, M. A.; Ellman, J. A. Chem. Rev. 2010,
110, 3600. (b) Kukhar, V. P.; Sorochinsky, A. E.; Soloshonok, V. A.
Future Med. Chem. 2009, 1, 793. (c) Sorochinsky, A. E.;
Soloshonok, V. A. J. Fluorine Chem. 2010, 131, 127. (d) Liu, J.; Hu,
J. Future Med. Chem. 2009, 1, 875.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1561324.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J