2,2,2-Trifluoroethyl Chlorooxoacetate-Universal Reagent for One-Pot Parallel Synthesis of N1-Aryl-N2-alkyl-Substituted Oxamides

Article abstract of DOI:10.1021/acscombsci.5b00091

A one-pot parallel synthesis of N¹-aryl-N²-alkyl-substituted oxamides with 2,2,2-trifluoroethyl chlorooxoacetate was developed. The synthesis of a library of 45 oxamides revealed higher efficiency of this reagent over the known ethyl chlorooxoacetate. The reagent was successfully used to prepare the known oxamide-containing HIV entry inhibitors.

Full text of DOI:10.1021/acscombsci.5b00091

Research Article
pubs.acs.org/acscombsci
2,2,2-Trifluoroethyl ChlorooxoacetateUniversal Reagent for One-
Pot Parallel Synthesis of N1‑Aryl‑N2‑alkyl-Substituted Oxamides
Andrey V. Bogolubsky,† Yurii S. Moroz,*,†,‡ Pavel K. Mykhailiuk,*,†,§ Sergey E. Pipko,‡
Anton V. Zhemera,† Anzhelika I. Konovets,†,∥ Olena O. Stepaniuk,†,$ Inna S. Myronchuk,†,$
Yurii V. Dmitriv,† Roman A. Doroschuk,§ Olga A. Zaporozhets,§ and Andrey Tolmachev†,‡
†Enamine, Ltd., 78 Chervonotkatska Street, Kyiv, 02094, Ukraine
‡ChemBioCenter, Kyiv National Taras Shevchenko University, 61 Chervonotkatska Street, Kyiv, 02094, Ukraine
§Department of Chemistry, Kyiv National Taras Shevchenko University, 64 Volodymyrska Street, Kyiv, 01601, Ukraine
∥The Institute of High Technologies, Kyiv National Taras Shevchenko University, 4 Glushkov Street, Building 5, Kyiv, 03187,
Ukraine
$National Technical University of Ukraine “Kyiv Politechnic Institute”, 37 Peremohy Avenue, Kyiv, 03056, Ukraine
S
* Supporting Information
ABSTRACT: A one-pot parallel synthesis of N1-aryl-N2-alkyl-
substituted oxamides with 2,2,2-trifluoroethyl chlorooxoacetate
was developed. The synthesis of a library of 45 oxamides
revealed higher efficiency of this reagent over the known ethyl
chlorooxoacetate. The reagent was successfully used to prepare
the known oxamide-containing HIV entry inhibitors.
KEYWORDS: N1-aryl-N2-alkyl-substituted oxamides, parallel synthesis, one-pot approach, ethyl chlorooxoacetate,
2,2,2-trifluoroethyl chlorooxoacetate
INTRODUCTION
■
The “Escape from Flatland”1−4 concept has gained considerable
attention in designing new scaffolds and compound libraries for
drug discovery. Following the concept, we have developed
parallel synthesis methods to various drug-like compounds and
building blocks with a saturated skeleton including aliphatic
sulfonamides,5 unsymmetrical aliphatic ureas6 and aliphatic
secondary amines.7,8 One of our recent projects to implement
the concept was focused on an N1-aryl-N2-alkyl-substituted
oxamide motif. This fragment has found its application in
medicinal and synthetic organic chemistry: potential human
immunodeficiency virus (HIV-1) entry inhibitors9−12 and
antimalarial drugs,13−15 N-heterocyclic carbene (NHC) pre-
Figure 1. Application of N1-alkyl-N2-aryl-substituted oxamides.9−25
catalysts including modifications of the Grubbs’ second
generation catalyst,16−25 and other bioactive compounds26−30
are derivatives of the unsymmetrical oxamides (Figure 1).
various substrates and provide diversity to a library.6−8
Systematic examination of the available literature revealed
that the common synthetic strategy to N1-aryl-N2-alkyl-
substituted oxamides utilized a stepwise aminolysis of ethyl
chlorooxoacetate (1a).22,24,31 The ester chloride reacts with an
aryl amine to produce an ester monoamide that undergoes the
second aminolysis directly or via activation of an acid
Despite growing interest in sized libraries of these oxamides,
suitable methods for their parallel synthesis have remained
unknown.
Our typical development procedure involves: experimental
design followed by test reactions to optimize conditions, and
validation of a method on a series of experiments at the Parallel
Synthesis Department. The requirements to the experimental
design included (1) use of simple reaction set up (preferably in
a one-pot fashion) and work up procedures and (2) use of
“universal” starting reagents which could be applicable to
Received: June 9, 2015
Revised: August 18, 2015
© XXXX American Chemical Society
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monoamide formed upon saponification of the ester mono-
amide (Scheme 1). The above strategy was initially selected for
the one-pot syntheses of unsymmetrical ureas and 4-substituted
semicarbazides.6,35,36
To confirm our hypothesis and to evaluate the one-pot
strategy in the parallel synthesis of N1-aryl-N2-alkyl-substituted
oxamides, we performed the experiments with reagents 1a and
1b utilizing various amines. The current report describes our
results on the method evaluation and presents the comparative
study of the efficacy of the above ester chlorides under the
parallel synthesis conditions.
Scheme 1. General Approach to N1-Aryl-N2-alkyl-Substituted
Oxamides
RESULTS AND DISCUSSION
■
Method Development. We arbitrary selected 14 aryl
(reagent chemset 2) and 45 alkyl (reagent chemset 3) amines
from our internal database for the test experiments. Amines 2
contained the common fragments in the N1-aryl-N2-alkyl-
substituted oxamide motif - derivatives of aniline, quinoline,
pyrazole, and pyridine (Figure 2). Since the aminolysis of ester
monoamides was a critical step, diversity reagents 3 comprised
structurally different substrates: 10 primary, 15 secondary cyclic
and 20 secondary acyclic alkyl amines (Tables 1−3). Then, we
created a random 45 member library of the oxamides (Tables
1−3) and performed 90 parallel reactions utilizing ester
chlorides 1a (set A) and 1b (set B). The library would allow
to evaluate all selected alkyl fragments which completely
satisfied the purpose of the work and the synthesis of all
possible variants (630!) was unnecessary. We conducted the
experiments on a millimolar scale because most biochemical
assays require milligram quantities of test compounds.
the method development: it would support simple set up
without special reaction conditions (inert atmosphere, cooling
upon addition of reagents, etc.); it would allow creation of
diverse sets by varying amines; performing the direct aminolysis
of the ester monoamide would enable the one-pot procedure.
But use of reagent 1a limited the one-pot method to primary
alkyl amines because ethyl ester monoamides reacted poorly
with hindered amines. Therefore, the strategy needed
modification to satisfy all the requirements to the parallel
synthesis design.
The aminolysis of esters depends on the pKa value of the
leaving alcohol group:32 the lower pKa value results in higher
efficiency of the reaction. In this context, 2,2,2-trifluoroethyl
chlorooxoacetate (1b) (Scheme 2) could be a more reactive
The synthesis was performed as a two-step procedure
(Scheme 2). Briefly, to an acetonitrile solution of amine 2 (1
equiv) and a base, N,N-diisopropylethylamine, (1.5 equiv or 2.7
equiv for free aryl amines or aryl amine hydrochlorides) in a
sealed 8 mL vial was added chlorooxoacetate ester 1a or 1b (1
equiv). The obtained mixture was left shaking at room
temperature for 30 min (Figure S1). Then, amine 3 (1
equiv) was added to the vial and the mixture was heated in an
oven at 100 °C for 6 h (Figure S2). The aforementioned
conditions were sufficient for both aminolysis steps. A simple
work up, treatment with a CHCl3-water (3/4, v/v) mixture
with subsequent separation and evaporation of the organic
phase, resulted in crude product 4. We analyzed the crude
samples with LC-MS (Figures S3−S56) and subjected to
purification those having less than 90% product content.
Identities and purities of the synthesized compounds were
Scheme 2. One-Pot Synthesis of N1-Aryl-N2-alkyl-Substituted
Oxamides
alternative to 1a (the pKa values of 2,2,2-trifluoroethanol and
ethanol are 12.5 and 16, respectively)33,34 which would enable
the one-pot strategy under the parallel synthesis conditions.
Our previous experience with the 2,2,2-trifluoroethyl deriva-
tives, bis(2,2,2-trifluoroethyl) carbonate and 2,2,2-trifluoroethyl
chloroformate, revealed that moderate reactivity of these
reagents compared with the ethyl and the phenyl or the p-
nitrophenyl analogs supported efficient stepwise aminolysis in
1
further confirmed by means of H and 13C NMR spectroscopy
and LC-MS.
To compare reagents 1a and 1b in the synthesis, we arranged
the experimental results based on the type of the alkyl amines
Figure 2. Diversity reagents 2.
B
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Table 1. Results of the Parallel Synthesis of N1-Aryl-N2-alkyl-Substituted Oxamides Derived from Primary Alkyl Amines
#
*
§
Product content was determined by LC-MS. Isolated yield. Mixture of isomers, 54/46, trans/cis.
and examined two parameters: amount of the product in the
crude samples and the isolated yields.
amines, and the acid monoamides (Figures S15, S17, and S21).
The low product content complicated the purification or made
it impossible for compounds 4{3,13}, 4{3,14}, 4{3,16},
4{3,18}, 4{3,19}, 4{3,22}, and 4{3,24} from this set. The
isolated yields in set A were below 55%. For set B, all the
experiments succeeded in the products with more than 65%
product content. The isolated yields in set B ranged from low
to high. Overall, the values of the yields were substantially
higher for the experiments in set B than those in set A.
Acyclic Secondary Alkyl Amines. Similarly to the experi-
ments with the cyclic alkyl amines, reagent 1a was inefficient in
the parallel synthesis of the oxamides derived from the acyclic
secondary amino substrates. The LC-MS analysis of the crude
samples in set A showed complex mixtures with the average
product content close to 21% (Table 3 and Figures S33−S56).
The identified impurities were amines 3, the acid monoamides
(for example, 4{2,29} and 4{14,44}), the ester monoamides
(for example, 4{6,33} and 4{11,42}), or mixtures of both
monoamides (for example, 4{2,28} and 4{9,37}). The product
content was above 35% only in 5 experiments with less
hindered amines 3. The isolated yields in set A were below
20%, most reactions resulted in no product because the low
Primary Alkyl Amines. Both reagents showed similar
efficiencies in the experiments with the hindered primary
alkyl amines, for example, 4{1,1}, 4{2,3}, and 4{10,9}, in Table
1, resulting in the high purity products without a need for
chromatography step. The yields for these samples ranged from
30% to 82%. But reagent 1a was less efficient than 1b in the
experiments with the hindered primary alkyl amines, for
example, 4{1,2}, 4{4,5}, and 4{5,6}: the LC-MS analysis of set
A revealed complex mixtures with lower product contents
(<50%) compared with those for set B (>85%) and identified
the ester monoamides as main impurities (Figures S5 and S7).
Consequently, the isolated yields in these reactions were
substantially higher in set B than those in set A.
Cyclic Secondary Alkyl Amines. The LC-MS of the crude
mixtures of set A showed more than 50% product content only
in the experiments with the less hindered and more reactive
alkyl amines, for example, 4{1,12}, 4{6,15}, and 4{13,25}
(Table 2). For most cases with these amines, the product
content in set A was below 30% with an average value close to
13%. We identified the impurities to be the starting alkyl
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Table 2. Results of the Parallel Synthesis of N1-Aryl-N2-alkyl-Substituted Oxamides Derived from Cyclic Secondary Alkyl
Amines
#
*
§
†
Product content was determined by LC-MS. Isolated yield. Mixture of isomers, 70/30, trans/cis. Mixture of isomers, 96/4, trans/cis.
D
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Table 3. Results of the Parallel Synthesis of N1-Aryl-N2-alkyl-Substituted Oxamides Derived from Acyclic Secondary Alkyl
Amines
#
*
Product content was determined by LC-MS. Isolated yield.
E
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Figure 3. One-pot parallel synthesis of the known HIV entry inhibitors.
product content made the purification step impossible. The
employment of 1b was successful: the LC-MS analysis revealed
that 11 experiments resulted in more than 90% product
content; in other experiments, it ranged between 70% and 88%.
The isolated yields in set B were at least 3 times higher than
those for the same experiments in set A.
approach in the parallel synthesis of the known bioactive
oxamides, N1-(4-chlorophenyl)-N2-(2,2,6,6-tetramethylpiperi-
din-4-yl)oxamide and N1-(2,2,6,6-tetramethylpiperidin-4-yl)-
N2-(p-tolyl)oxamide, and obtained the products in higher
yields than those reported in the previously published
procedures.
The successful employment of 2,2,2-trifluoroethyl chloroox-
oacetate with different alkyl amino substrates allowed to suggest
it as the “universal” reagent for the parallel synthesis of N1-aryl-
N2-alkyl-substituted oxamides. We believe that the developed
approach would help synthetic and medicinal chemists in
expanding variety of the compounds with this structural motif.
The experimental data clearly confirmed the influence of the
leaving alcohol group on the activity of the ester monoamides.
The ethyl monoamides reacted with the strongly nucleophilic
primary alkyl amines and failed with the amines with hindered
amino group affording the complex mixtures which contained
the product and the intermediate, the ester monoamide, or the
side product, the acid monoamide. The inefficient aminolysis
resulted in the substantially lower isolated yields in set A than
those in set B. On the other hand, reagent 1b was effective in all
conducted experiments: its moderate reactivity allowed to
perform the first aminolysis with the aryl amines without
formation of symmetrical bisamides and was substantial to
complete the second aminolysis. Many experiments in set B
provided the products in high purity without the chromatog-
raphy purification. The above observations made 1b a
“universal” reagent for the parallel synthesis of N1-aryl-N2-
alkyl-substituted oxamides.
Practical Application. We additionally verified the method
on the known bioactive compounds: N1-(4-chlorophenyl)-N2-
(2,2,6,6-tetramethylpiperidin-4-yl)oxamide (NBD-556) and N1-
(2,2,6,6-tetramethylpiperidin-4-yl)-N2-(p-tolyl)oxamide (YYA-
021). The parallel synthesis of NBD-556 and YYA-021 was
accomplished in two sets (4 reactions) on a millimolar scale
under similar conditions to those applied to the synthesis of the
45-member library (Figure 3). For the crude samples of set A,
the LC-MS analysis showed 68 and 78% product content for
NBD-556 and YYA-021, respectively, identifying the unreacted
ester monoamide and bis-tolyl oxamide as main impurities
(Figures S57, S58, S61, and S62). For the samples of set B, the
product content was close to 100% (Figures S59, S60, S63, and
S64) which resulted in 67% and 62% isolated yields for NBD-
556 and YYA-021, respectively. These values were higher than
the reported in the literature (30−40%).12,37,38
EXPERIMENTAL PROCEDURES
■
All chemicals and solvents were obtained from commercially
available sources (Enamine, Sigma-Aldrich) and used without
further purification. 1H and 13C NMR spectra were acquired on
Bruker Avance DRX 500 spectrometer using DMSO-d6 as a
solvent and tetramethylsilane (TMS) as an internal standard. IR
spectra were recorded on PerkinElmer Spectrum BX II. Melting
points were determined on Buchi melting point apparatus and
are uncorrected. LC-MS data were recorded on Agilent 1100
HPLC equipped with diode-matrix and mass-selective detector,
column: Zorbax SB-C18, 4.6 mm × 15 mm. Eluent, A,
acetonitrile−water with 0.1% of TFA (95:5); B, water with
0.1% of TFA. The flash chromatography purification was
performed using Companion Combi-Flash instrument with
UV-detector and reusable LukNova column [gradient elution;
eluent, A, CHCl3; B, CHCl3/methanol (7:3, v:v)].
General Procedure for the Synthesis of N1-Aryl-N2-
alkyl-Substituted Oxamides. A mixture of ethyl chloroox-
oacetate (1a), set A, or 2,2,2-trifluoroethyl chlorooxoacetate
(1b), set B, (1 mmol), aniline 2{1} (1 mmol), and DIEA (1.5
or 2.7 mmol if the amine was in form of hydrochloride) in 2
mL of acetonoitrile was shaken in an 8 mL sealed vial at room
temperature for 30 min. Then, 3-amino-3-phenylpropan-1-ol
3{1} (1.1 mmol) was added and the reaction mixture was
heated at 100 °C for 6 h. After it was cooled to room
temperature, chloroform (3 mL) and water (4 mL) were added
sequentially, and the organic phase was washed with water (4
mL) twice, separated, and evaporated to yield oxamide 4{1,1}
in >98% purity according to the LC-MS analysis. Yield: 209 mg,
70% (set A)/215 mg, 72% (set B), white solid, mp 197−199
°C. IR (KBr): ν (cm−1) 3302, 1659, 1510, 1440,1053. 1H NMR
(500 MHz, DMSO-d6): δ = 1.95 (m, 1H, CH2), 2.10 (m, 1H,
CH2), 3.41 (m, 2H, CH2), 4.63 (br.s, 1H, OH), 5.05 (q, J = 8.1
Hz, 1H, CH), 7.12 (t, J = 7.2 Hz, 1H, Ar), 7.23 (t, J = 7.2 Hz,
1H, Ar), 7.33 (m, 4H, Ar), 7.39 (d, J = 7.6 Hz, 2H, Ar), 7.80 (d,
J = 7.1 Hz, 2H, Ar), 9.46 (d, J = 8.6 Hz, 1H, NH), 10.59 (s, 1H,
NH). 13C NMR (125.75 MHz, DMSO-d6): δ = 38.0, 50.9, 57.7,
120.4, 124.6, 126.8, 127.0, 128.4, 128.8, 137.7, 142.9, 158.8,
159.7. MS (APSI) m/z [M + H]+ calculated for C17H19N2O3:
299.1; found 299.2.
CONCLUSIONS
■
We have developed the one-pot parallel synthesis approach to
N1-aryl-N2-alkyl-substituted oxamides from the chlorooxoace-
tate esters. The reaction proceeded through the direct
aminolysis of the ester monoamide intermediate which required
good leaving alcohol group to interact with hindered amines.
The commonly utilized ethyl chlorooxoacetate limited the
approach because of the low reactivity and was substituted with
the alternative reagent, 2,2,2-trifluoroethyl chlorooxoacetate.
We validated the method on the 45 member library of N1-aryl-
N2-alkyl-substituted oxamides synthesized on a millimolar scale
utilizing both chlorooxoacetates. The obtained results con-
firmed higher efficiency of the 2,2,2-trifluoroethyl derivative
compared with the ethyl analog. The experiments with the
latter reagent failed in most cases. We additionally tested the
The remaining compounds in the library were synthesized
under the essentially identical conditions. If the product
F
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A.; et al. Design, Synthesis and Biological Evaluation of Small
Molecule Inhibitors of CD4-gp120 Binding Based on Virtual
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ASSOCIATED CONTENT
* Supporting Information
■
J.; Schon, A.; Princiotto, A. M.; Wu, X.; Mascola, J. R.; Freire, E.; et al.
̈
S
Structure-Based Design and Synthesis of an HIV-1 Entry Inhibitor
Exploiting X-Ray and Thermodynamic Characterization. ACS Med.
Chem. Lett. 2013, 4, 338−343.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acscombs-
ci.5b00091.
(12) Curreli, F.; Choudhury, S.; Pyatkin, I.; Zagorodnikov, V. P.;
Bulay, A. K.; Altieri, A.; Kwon, Y. D.; Kwong, P. D.; Debnath, A. K.
Design, Synthesis, and Antiviral Activity of Entry Inhibitors That
Target the CD4-Binding Site of HIV-1. J. Med. Chem. 2012, 55, 4764−
4775.
1
Details of experimental set up; LC-MS data, H and 13C
NMR spectra, and analytical data for selected synthesized
compounds (PDF)
(13) Plouffe, D.; Brinker, A.; McNamara, C.; Henson, K.; Kato, N.;
Kuhen, K.; Nagle, A.; Adrian, F.; Matzen, J. T.; Anderson, P.; et al. In
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Silico Activity Profiling Reveals the Mechanism of Action of
Antimalarials Discovered in a High-Throughput Screen. Proc. Natl.
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Lavandera, J.-L.; Vanderwall, D. E.; Green, D. V. S.; Kumar, V.; Hasan,
S.; et al. Thousands of Chemical Starting Points for Antimalarial Lead
Identification. Nature 2010, 465, 305−310.
AUTHOR INFORMATION
Corresponding Authors
*E-mail: ysmoroz@mail.enamine.net; ysmoroz@gmail.com.
*E-mail: Pavel.Mykhailiuk@mail.enamine.net; Pavel.
Mykhailiuk@gmail.com.
■
Notes
The authors declare no competing financial interest.
(15) Meister, S.; Plouffe, D. M.; Kuhen, K. L.; Bonamy, G. M. C.;
Wu, T.; Barnes, S. W.; Bopp, S. E.; Borboa, R.; Bright, A. T.; Che, J.;
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ACKNOWLEDGMENTS
Dedicated to the 25th anniversary of Enamine Ltd.
■
ABBREVIATIONS
HIV-1, human immunodeficiency virus; NHC, N-heterocyclic
carbene; DIEA, N,N-diisopropylethylamine
■
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