2,2,2-Trifluoroethyl Oxalates in the One-Pot Parallel Synthesis of Hindered Aliphatic Oxamides

Article abstract of DOI:10.1002/ejoc.201501579

A simple parallel synthesis approach to unsymmetrical N¹,N²-substituted aliphatic oxamides using methyl (2,2,2-trifluoroethyl) oxalate and bis(2,2,2-trifluoroethyl) oxalate was developed. The method was validated on a 52-membered set of the oxamides, derived mainly from hindered primary and secondary aliphatic amines, and gave the products with a high overall success rate in moderate yields.

Full text of DOI:10.1002/ejoc.201501579

DOI: 10.1002/ejoc.201501579
Full Paper
Library Synthesis
2,2,2-Trifluoroethyl Oxalates in the One-Pot Parallel Synthesis of
Hindered Aliphatic Oxamides
Andrey V. Bogolubsky,[a] Yurii S. Moroz,*[b] Pavel K. Mykhailiuk,*[a,c] Sergey E. Pipko,[b,d]
Alexander V. Grishchenko,[d] Anton V. Zhemera,[a] Anzhelika I. Konovets,[a,e]
Roman A. Doroschuk,[c] Yurii V. Dmytriv,[a] Olga A. Zaporozhets,[c] and
Andrey Tolmachev[a,b]
Dedicated to the 25th anniversary of Enamine Ltd.
Abstract: A simple parallel synthesis approach to unsymmetri- the oxamides, derived mainly from hindered primary and sec-
cal N1,N2-substituted aliphatic oxamides using methyl (2,2,2-tri-
fluoroethyl) oxalate and bis(2,2,2-trifluoroethyl) oxalate was de-
veloped. The method was validated on a 52-membered set of
ondary aliphatic amines, and gave the products with a high
overall success rate in moderate yields.
Introduction
oxamides.[13]
A logical continuation of the last project
would be the development of a method for the creation of
unsymmetrical N1,N2-substituted aliphatic oxamide motifs
bearing diverse substituents. Such motifs are found in medici-
nal[14–18] and synthetic organic chemistry[19–30] (Figure 1), but
quick access to sized libraries of N1,N2-substituted aliphatic ox-
amides remains unknown.
The “Escape from Flatland” concept has become an important
part of modern drug discovery, as recent publications have
placed complexity and three-dimensionality among the major
descriptors for predicting the success of drug-candidate mol-
ecules.[1–3] The concept involves the substitution of a “flat” aro-
matic moiety in a molecule with a saturated fragment, rich in
sp3-hybridized carbon atoms, to positively influence important
drug-related properties:[4–7] such a change decreases lipophilic-
ity and toxicity, and increases solubility, permeability, and oral
absorption. The development of suitable methods for the as-
sembly of molecules from “saturated” fragments is an impor-
tant goal within this context. We have contributed to this task
by designing parallel synthesis approaches to aliphatic deriva-
tives of sulfonamides,[8] ureas,[9] secondary amines,[10,11] sulf-
ides, sulfoxides, sulfones,[12] and N1-aryl-N2-aliphatic-substituted
Our typical strategy in achieving the synthesis of diverse sets
of compounds is based on a parallel synthesis. The criteria for
the parallel synthesis are as follows: i) a one-pot experimental
design with simple set-up and work-up steps; ii) use of readily
available substrates to give diversity to compound libraries; and
iii) applicability of the method to various substrates.
The usual approach to unsymmetrical N1,N2-substituted ali-
phatic oxamides has been a stepwise aminolysis of ethyl chlor-
oxoacetate[26,29,31,32] (1a) or diethyl oxalate (1b) (Figure 2).[33,34]
The procedure satisfies our criteria, but closer examination re-
veals that reagents 1a and 1b are incompatible with the parallel
synthesis. The aminolysis of 1a occurs vigorously with aliphatic
amines, and requires a dropwise addition of the reactants,
maintaining a low temperature, to give pure ester monoamides.
The aminolysis of 1b was successfully achieved with reactive
amines, but it failed with sterically hindered amine sub-
strates.[35] The solution to the “too reactive – too inert” dilemma
could involve the use of a moderately reactive reagent.
[a] Enamine Ltd.,
78 Chervonotkatska Street, Kyiv 02094, Ukraine
E-mail: Pavel.Mykhailiuk@mail.enamine.net
Pavel.Mykhailiuk@gmail.com
http://www.enamine.net/
[b] ChemBioCenter, Kyiv National Taras Shevchenko University,
61 Chervonotkatska Street, Kyiv 02094, Ukraine
E-mail: ysmoroz@gmail.com
[c] Department of Chemistry, Kyiv National Taras Shevchenko University,
64 Volodymyrska Street, Kyiv 01601, Ukraine
[d] UkrOrgSyntez Ltd. (UORSY),
29 Schorsa Street, Kyiv 01133, Ukraine
http://www.uorsy.net/
[e] The Institute of High Technologies, Kyiv National Taras Shevchenko
University,
Our previous experience with unsymmetrical aliphatic
ureas[9] revealed that switching from ethyl chloroformate and
diethyl carbonate to the bis(2,2,2-trifluoroethyl) analog resulted
in a high chemoselectivity in the stepwise aminolysis, and thus
enabled a one-pot parallel synthesis. Indeed, the moderately
reactive bis(2,2,2-trifluoroethyl) carbonate has proved its effi-
ciency with different aliphatic amines, affording ureas in 30–
4 Glushkov Street, Building 5, Kyiv 03187, Ukraine
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/ejoc.201501579.
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Figure 1. Aliphatic oxamides in medicinal and organic chemistry.
Figure 2. Comparison of reagents 1a and 1b in “flask” and parallel syntheses of aliphatic oxamides.
90 % isolated yield. We have now expanded this strategy to the should we use in the parallel synthesis? and ii) which aliphatic
synthesis of aliphatic oxamides, introducing 2,2,2-trifluoroethyl amines are we able to use with our approach? Consequently, in
oxalate derivatives as valuable alternatives to the commonly the first part of the study, we aimed to identify an optimal
used reagents. In this paper, we describe the development of a oxalate reagent, in the second part, we aimed to find the limits
one-pot parallel synthesis procedure, and its application to the of the method. For the oxalate reagents, we chose three avail-
synthesis of a 52-membered set of unsymmetrical N1,N2-substi- able 2,2,2-trifluoroethyl derivatives for testing: ethyl (2,2,2-tri-
tuted oxamides.
fluoroethyl) oxalate (1c), methyl (2,2,2-trifluoroethyl) oxalate
(1d), and bis(2,2,2-trifluoroethyl) oxalate (1e), with 1b as a refer-
ence (Figure 3). The effectiveness of the aminolysis increases
with a decrease of the pKa value of the alcohol leaving group
Results and Discussion
The one-pot method we envisaged includes two types of rea- (the pKa values for ethanol, methanol, and 2,2,2-trifluoroethanol
gents: amines and an oxalate, and we initially aimed to answer are 16, 15.5, and 12.5, respectively).[36–38] The reactivity of these
two questions: i) which 2,2,2-trifluoroethyl oxalate derivative reagents, therefore, should increase from 1b to 1e. For the
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Figure 3. Tested reagents 1b–1e.
Figure 4. Diversity reagents 2 selected for the optimization of the reaction conditions.
amines, we chose 36 aliphatic amines from our internal data- or 2{11} (1 equiv.) was added, and the reaction mixture was
base, and utilized 11 of these for optimization of the reaction heated at 100 °C for 6 h. We used two different work-up proce-
conditions (chemset 2, Figure 4, Figure S1 in the Supporting dures, depending on the state of the reaction mixtures. If a
Information). In the optimization study, we focused on sterically precipitated product formed, it was collected by filtration, and
hindered amines, because they have been major contributors dried in an oven. In other cases, extraction with CHCl3 was car-
to failed aminolysis experiments.[39] We divided the amine sub- ried out. The product content in the crude samples was deter-
1
strates into hindered primary (group 1, 2{1–4}) and hindered mined by using LC–MS or H NMR spectroscopy. Samples with
secondary amines (group 2, 2{5–9}), but also included two un- purities below 90 % were subjected to flash chromatography.
1
hindered or reactive amines (group 3, 2{10–11}) to test more All synthesized compounds were characterized by H and 13C
combinations. Phenyl-containing amines were chosen for easy NMR spectroscopy and LC–MS to confirm their identity and pu-
identification by LC–MS.
rity.
A combinatorial approach often gives compounds in low iso-
lated yields, despite a high product content in the crude sam-
ples after the reaction. The low yields are a result of the use of
a single method of purification that is optimal for most of the
compounds, but not for the whole set. Thus, analysis based on
isolated yields might result in incorrect conclusions about the
effectiveness of a studied reaction. Therefore, we used product
content in the crude samples as the main parameter in analyz-
ing our data.
Optimization of the Reaction Conditions: When Hindered
Meets Reactive
The oxalate reagent has to support: i) chemoselective formation
of an ester monoamide but not symmetrical bisamide side-
products in the first aminolysis; and ii) efficient conversion of
the ester monoamide into the product in the second
aminolysis. To identify the optimal oxalate derivative, we set up
72 reactions (18 per oxalate) on a millimolar scale, introducing
The experiments revealed two scenarios depending on the
hindered amines 2{1–9} (i.e., groups 1 and 2) in the first type of amine used. Reactions involving hindered primary ali-
aminolysis, and unhindered amines 2{10–11} (i.e., group 3) in phatic amines (Table 1, Figures S1–S32) were successful with
the second aminolysis (Table 1). We used a one-pot procedure unsymmetrical reagents 1c and 1d, resulting in a 70–96 % prod-
similar to that reported for unsymmetrical aliphatic ureas.[9] uct content. Reagent 1b was less efficient than 1c and 1d under
Briefly, a sealed vial with an acetonitrile solution (1 mL) of the the same conditions, and the experiments with 1e failed, and
first amine 2 (1 equiv.) and the oxalate (1 equiv.) was kept at gave mainly symmetrical side-products. The isolated yields for
room temperature for 12 h with occasional shaking. Then, 2{10} oxamides 3{1–4, 10–11} were higher in the reactions with rea-
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Table 1. Identifying the optimal oxalate reagent. Case 1: group 1 and group 3 amines.
[a] Product content was determined by LC–MS or 1H NMR spectroscopy. [b] Low product content or complex mixture in the crude sample made purification
impossible.
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gents 1c and 1d than in the reactions with 1b. We were not oxamides when a combination of primary and reactive amines
able to isolate compounds 3{1, 10–11}, 3{2, 10–11}, and 3{3, 11} is used (procedure A in the Experimental Section).
in the experiments with 1e.
Reactions involving hindered secondary aliphatic amines
(Table 2, entries 1–10) were successful with reagent 1e and
failed with 1b, 1c, and 1d. LC–MS analysis showed a 54–97 %
product content in the experiments with 1e, which afforded
isolated yields at least 2.5 times higher than those obtained
with the other oxalate reagents. The reactions with 1b, 1c, and
1d resulted mainly in the formation of the side-products includ-
ing benzyl or 1-phenylpiperazenyl monoamide esters, bis-
(benzyl) or bis(1-phenylpiperazenyl) oxamides, and the unre-
acted amines. The product content for most experiments with
1c and 1d was less than 20 %, and for 1b it was less than
5 % (Figures S32–S67). This made purification of the products
impractical.
The formation of the ester monoamide is a critical step under
the parallel synthesis conditions. This reaction requires the
amine and the oxalate to have balanced reactivities to ensure
complete reaction, and to avoid the formation of the symmetri-
cal side-products. The electron-withdrawing 2,2,2-trifluoroethyl
groups might tune the reactivity of the studied oxalates. This
effect supported the chemoselective formation of the ester
monoamides from reagents 1c and 1d with hindered primary
aliphatic amines 2{1–4}; while 1e underwent complete amino-
lysis to give the symmetrical bisamides. Analysis of the crude
product mixtures obtained in the synthesis of 3{1–4, 10–11}
clearly proved this conclusion. Also, the result of the following
experiment supports our idea: substitution of an ethyl group
Group 2 amines 2{5–9} required a more reactive carbonyl
with a 2,2,2-trifluoroethyl group positively affected the first substrate for the aminolysis to go to completion. Therefore, hin-
aminolysis, and as a result the reactions with 1c and 1d gave dered secondary amines would react with 1e more effectively
higher isolated yields than those with 1b. The combined data, than with 1b–1d (which are too inert for these amines) to give
therefore, allowed to identify oxalate 1c or 1d as the optimal the corresponding ester monoamides. The experimental data
reagent for the parallel synthesis of N1,N2-substituted aliphatic supported this conclusion, showing a 100 % success rate in the
Table 2. Identifying the optimal oxalate reagent. Case 1: group 2 and group 3 amines.
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Table 2. (Continued).
[a] Product content was determined by LC–MS or 1H NMR spectroscopy. [b] Low product content or complex mixture in the crude sample made purification
impossible.
reactions with 1e, 33 % in the reactions with 1c and 1d, and group 1 or group 2 amine as the second amine substrate. For
less than 5 % in the reactions with 1b. These data allowed us chemset 4.1, we ran the reactions with oxalate 1d because it
to identify oxalate 1e as the optimal reagent for the parallel
synthesis of N1,N2-substituted aliphatic oxamides when hin-
dered secondary amines are used together with reactive amines
(procedure B in the Experimental Section).
gave higher yields than the ethyl analog in the optimization
experiments. In chemset 5.1, we utilized hindered secondary
amine 2{8} as the first amine substrate, and a group 1 or
group 2 amine as the second amine substrate. For chemset
5.1, we ran the reactions with oxalate 1e under the modified
conditions for the second aminolysis to ensure full conversion
of the ester monoamides into the products (vide infra).
Evaluation of the Optimized Conditions
LC–MS analysis of the crude mixtures of chemset 4.1 re-
vealed high product content for the experiments with amines
2{1–2} and 2{4–5}, and these reactions gave moderate isolated
yields. But the experiments with more hindered amines 2{6–9}
failed, and gave the methyl ester monoamides in most cases.
Increasing the duration of the second aminolysis — heating for
12 h at 100 °C — had no effect on the efficacy of the conversion
of the intermediate. A simple solution to resolve this issue was
Encouraged by the outcome of the initial experiments, we went
on to explore the limitations (if any) of our approach.
Case 1: When hindered meets hindered. As the low reactivity
of the ester monoamides might result in low or no yield, we
designed two series of experiments in which both the amine
substrates were hindered (Table 3, entries 1–8, chemset 4.1;
Table 4, entries 1–8, chemset 5.1). In chemset 4.1, we utilized
hindered primary amine 2{3} as the first amine substrate, and a
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Table 3. Identifying the limits of the parallel synthesis approach: hindered primary amine as the first amine substrate.
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Table 3. (Continued).
[a] Product content was determined by LC–MS or 1H NMR spectroscopy. The products of entries 1, 2, 3, 5, 7, 13, 14, 21 are mixtures of stereoisomers. [b] Low
product content or complex mixture in the crude sample made purification impossible.
to switch to procedure B; the 2,2,2-trifluoroethyl ester monoam-
Case 3: When heteroaryl, substituted, or functionalized is in-
ides are more reactive than their methyl analogs. Using the volved. We evaluated our approach using aliphatic amines con-
latter approach, we obtained the desired oxamides in moderate taining functionalities frequently used in medicinal chemistry:
yields (Table 4, entries 3 and 9–12).
substituted phenyl rings (Table 3, entries 9–12, 19, and 20), five-
and six-membered heterocycles (Table 3, entries 10, 12, and
17–24), hydroxyl groups (Table 3, entries 9, 13, and 14), and
morpholine moieties (Table 3, entries 11, 16, 21, and 23). Posi-
tive results were obtained in all experiments, and this allowed
us to conclude that: i) our method can be used with various
phenyl- and heteroaryl-containing amine substrates; ii) the in-
troduction of electron-withdrawing or electron-donating
groups into the ring has no significant influence on the yields;
and iii) our method tolerates amines containing additional func-
tional groups.
LC–MS analysis of the crude mixtures of chemset 5.1 re-
vealed positive results in the reactions with the primary and
less hindered secondary acyclic amine 2{5} (Table 4, entries 1–
5). Experiments with more hindered secondary amines failed,
and afforded the corresponding ester monoamides (Table 4,
entries 6–8). Increasing the duration of the second aminolysis
to 36 h was unsuccessful.
Case 2: When highly hindered meets reactive. We carried out
reactions with two tBu-containing amines 2{18} and 2{19} as
the first amine substrate, and two “reactive” amines 2{11} and
2{29} as the second amine substrate. The experiments were suc-
cessful with highly hindered primary amine 2{18} (Table 3,
entries 15 and 16), but failed with highly hindered secondary
amine 2{19}, which resulted in no reaction (Table 4, entries 13
and 14).
Our results allowed to establish the following guidelines (Fig-
ure 5) for the use of 2,2,2-trifluoroethyl oxalates for the one-
pot parallel synthesis of N1,N2-substituted aliphatic oxamides:
i) procedure A, based on ethyl (2,2,2-trifluoroethyl) oxalate (1c)
or methyl (2,2,2-trifluoroethyl) oxalate (1d), is preferable if the
Therefore, a one-pot approach to N1,N2-substituted aliphatic first amine substrate is a primary amine, and the second amine
oxamides involving poorly reactive aliphatic amines remains substrate is not highly hindered; and ii) procedure B, based on
challenging,[40,41] and represents a potential limitation of our bis(2,2,2-trifluoroethyl) oxalate (1e), is preferable if the first
approach.
amine substrate is a hindered secondary amine.
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Table 4. Identifying the limits of the parallel synthesis approach: hindered secondary amine as the first amine substrate.
[a] Product content was determined by LC–MS or 1H NMR spectroscopy. The products of entries 1, 2, 3, 4, 6, 10 are mixtures of stereoisomers. [b] Low product
content or complex mixture in the crude sample made purification impossible.
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Figure 5. The choice of oxalate reagent depends on the first amine substrate.
Practical Application: When Reactive Meets Reactive
Experimental Section
General Remarks: All chemicals and solvents were obtained from
Enamine, and were used without further purification. Ethyl (2,2,2-
trifluoroethyl) oxalate, methyl (2,2,2-trifluoroethyl) oxalate, and
bis(2,2,2-trifluoroethyl) oxalate were synthesized according to previ-
ously reported procedures.[42,43] 1H and 13C NMR spectra were ac-
quired with Bruker Avance DRX 400 and Bruker Avance DRX 500
spectrometers, using [D6]DMSO as a solvent, and tetramethylsilane
(TMS) as an internal standard. IR spectra were recorded with a Per-
kin–Elmer Spectrum BX II instrument. Elemental analysis was carried
out with a Vario MICRO Cube elemental microanalyzer (Elementar).
Melting points were determined with a Buchi melting-point appara-
tus. LC–MS data were acquired with an Agilent 1100 HPLC system
equipped with diode-array and mass-selective detectors, using a
Zorbax SB-C18 column, 4.6 mm × 15 mm; eluent A: acetonitrile/
water, 95:5, with 0.1 % TFA; eluent B: water with 0.1 % TFA. If the
product content in the crude material was below 90 %, the samples
were purified using a Companion Combi-Flash instrument with a
UV detector and a reusable LukNova column (gradient elution; elu-
ent A: CHCl3; eluent B: CHCl3/methanol, 7:3).
Can we use our approach if both the amine substrates are un-
hindered amines? We answered this question, carrying out four
parallel reactions to prepare the known biologically active com-
pound GNF-Pf-3529, the synthesis of which has not been re-
ported before, under conditions identical to those used for the
18 member set. These experiments were successful, and re-
vealed that the highest product content was obtained in the
reaction with 1d, which afforded GNF-Pf-3529 in 65 % isolated
yield (Figure 6, Figures S68–S71).
Optimized Procedures for the Parallel Synthesis of Unsymmetri-
Figure 6. The parallel synthesis of GNF-Pf-3529.
cal N1,N2-Substituted Aliphatic Oxamides
Procedure A: A sealed vial (8 mL) containing a mixture of methyl
(2,2,2-trifluoroethyl) oxalate (1 mmol) and 2-methyl-1-phenylprop-
an-1-amine 2{3} (1 mmol) in acetonitrile (1 mL) was shaken at room
temperature for 12 h. Then, 1-phenylpropan-1-amine 2{2} (1 mmol)
was added, and the reaction vial was heated at 100 °C for 12 h to
ensure full conversion of the ester monoamide. The product precipi-
tated out upon cooling to room temperature. The precipitate was
Conclusions
We have developed a simple, one-pot parallel synthesis ap-
proach to N1,N2-substituted aliphatic oxamides. The approach
uses a stepwise aminolysis of 2,2,2-trifluoroethyl oxalates: collected by filtration, then it was suspended in acetonitrile
(1.5 mL), and the mixture was placed in an ultrasonic bath for
30 min. The product was collected by filtration, and dried in an
oven to give N1-(2-methyl-1-phenylpropyl)-N2-(1-phenylpropyl)ox-
methyl (2,2,2-trifluoroethyl) oxalate and bis(2,2,2-trifluoroethyl)
oxalate. The nature of first amine substrate determines the
choice of oxalate reagent. We have established reaction condi-
tions, and evaluated our method on a 52-membered set of new
oxamides. The oxamides were prepared on multi-milligram
scale from structurally varied aliphatic amines, including hetero-
aryl-containing and functionalized substrates. We believe that
the developed approach will become a useful tool for synthetic
and medicinal chemists, and will allow to expand the variety of
aliphatic oxamides.
amide (223 mg, 66 %) as a whitish solid, m.p. 173–175 °C. IR (KBr):
1
ν = 3299, 3035, 2970, 2930, 2872, 1650, 1510, 1213 cm–1. H NMR
˜
(400 MHz, [D6]DMSO): δ = 0.63 (m, 3 H, CH3), 0.79 (m, 3 H, CH3),
0.91 (m, 3 H, CH3), 1.79 (m, 2 H, CH2), 2.17 (m, 1 H, CH), 4.38 (m, 1
H, CH), 4.68 (m, 1 H, CH), 7.15–7.40 (m, 10 H, Ar), 9.0 (m, 2 H, NH)
ppm. 13C NMR (125.7 MHz, [D6]DMSO): δ = 12.3, 20.0, 28.3, 31.9,
55.1, 60.3, 126.8, 126.9, 127.0 (2), 127.1, 127.5, 127.6, 128.2, 128.3,
128.4, 142.1, 142.2, 142.9, 143.0, 159.6, 159.7, 159.8 ppm. MS (APSI):
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m/z = 361.3 [M + Na]+. C21H26N2O2 (338.4): calcd. C 74.53, H 7.74,
N 8.28; found C 74.68, H 7.89, N 8.11. The remaining compounds
from chemset 4 were synthesized under essentially identical condi-
tions.
R. A. Doroschuk, R. A. Doroschuk, L. N. Babichenko, A. I. Konovets, A.
Tolmachev, ACS Comb. Sci. 2015, 17, 348–354.
[13] A. V. Bogolubsky, Y. S. Moroz, P. K. Mykhailiuk, S. E. Pipko, A. V. Zhemera,
A. I. Konovets, O. O. Stepaniuk, I. S. Myronchuk, Y. V. Dmytriv, R. A. Doros-
chuk, O. A. Zaporozhets, A. Tolmachev, ACS Comb. Sci. 2015, 17, 615–
622.
Procedure B: An acetonitrile solution (1 mL) of bis(2,2,2-trifluoro-
ethyl) oxalate (1 mmol) and N-ethyl-1-(4-fluorophenyl)ethan-1-
amine 2{8} (1 mmol) was kept at room temperature for 12 h in a
sealed vial (8 mL). Then, N-methyl-1-phenylmethanamine 2{5}
(1 mmol) was added, and the resulting mixture was heated at
100 °C for 36 h to ensure full conversion of the ester monoamide.
Then, the solvent was evaporated in vacuo. The crude mixture was
dissolved in chloroform (3 mL), and the solution was washed with
HCOOH (10 %), and water. The organic phase was evaporated. The
crude product was purified by flash chromatography to give N1-
benzyl-N2-ethyl-N2-[1-(4-fluorophenyl)ethyl]-N1-methyloxamide
(144 mg, 42 %) as an oil. 1H NMR (500 MHz, [D6]DMSO): δ = 0.85
(m, 3 H, CH3), 1.55 (m, 3 H, CH3), 2.7–2.9 (m, 3 H, CH3), 3.12 (m, 2
H, CH2), 4.35–4.65 (m, 2 H, CH2), 4.88, 5.54 (m, 1 H, CH), 7.15–7.55
(m, 9 H, Ar) ppm. 13C NMR (125.7 MHz, [D6]DMSO): δ = 13.5 (2),
15.6, 15.7, 16.9 (2), 17.9, 30.8 (2), 34.4, 34.8, 35.7, 35.9, 48.5, 48.6,
50.7, 50.9, 52.6, 52.8, 55.2, 115.2 (2), 115.4 (2), 127.6, 127.8, 128 (m),
128.7 (m), 129.4 (m), 129.6 (m), 135.8 (m), 135.9 (m), 136.0, 136.6
(m), 160.6 (m), 162.6 (m), 164.3 (m), 164.9 (m), 165.1 ppm. MS (APSI):
m/z = 359.2 [M + OH]–. C20H23FN2O2 (342.4): calcd. C 70.15, H 6.77,
N 8.18; found C 69.92, H 6.93, N 8.01. The remaining compounds
from chemset 5 were synthesized under essentially identical condi-
tions.
[14] M. L. Bolognesi, A. Cavalli, V. Andrisano, M. Bartolini, R. Banzi, A. Anto-
nello, M. Rosini, C. Melchiorre, Farmaco 2003, 58, 917–928.
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Received: December 16, 2015
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