Bis(2,2,2-trifluoroethyl) carbonate as a condensing agent in one-pot parallel synthesis of unsymmetrical aliphatic ureas

Article abstract of DOI:10.1021/co500025f

One-pot parallel synthesis of unsymmetrical aliphatic ureas was achieved with bis(2,2,2-trifluoroethyl) carbonate. The procedure worked well for both the monosubstituted and functionalized alkyl amines and required no special conditions (temperature control, order, or rate of addition). A library of 96 diverse ureas was easily synthesized.

Full text of DOI:10.1021/co500025f

Research Article
pubs.acs.org/acscombsci
Bis(2,2,2-trifluoroethyl) Carbonate as a Condensing Agent in One-Pot
Parallel Synthesis of Unsymmetrical Aliphatic Ureas
Andrey V. Bogolubsky,† Yurii S. Moroz,*,†,‡ Pavel K. Mykhailiuk,*,†,§ Dmitry S. Granat,†,§
Sergey E. Pipko,‡ Anzhelika I. Konovets,†,∥ Roman Doroschuk,§ and Andrey Tolmachev†,‡
†Enamine Ltd., 23 Matrosova Street, Kyiv, 01103, 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
S
* Supporting Information
ABSTRACT: One-pot parallel synthesis of unsymmetrical aliphatic
ureas was achieved with bis(2,2,2-trifluoroethyl) carbonate. The
procedure worked well for both the monosubstituted and
functionalized alkyl amines and required no special conditions
(temperature control, order, or rate of addition). A library of 96
diverse ureas was easily synthesized.
KEYWORDS: bis(2,2,2-trifluoroethyl)carbonate, functionalized amines, unsymmetrical aliphatic ureas, one-pot approach,
parallel synthesis
alcohols). We therefore focused on the methods utilizing
carbonates, for example, diethyl carbonate, bis(phenyl)
carbonate and bis(p-nitrophenyl) carbonate.27−30 The typical
two-step procedure includes the interaction of a carbonate with
the first amine forming a carbamate, which further reacts with
the second amine to form the urea (Scheme 1). This method
allows for the synthesis of the trisubstituted Alk−N(H)−
C(O)−N(R)−Alk1 ureas because an N,N-disubstituted carba-
mate is not capable of forming the required intermediate.23,30
Initial experiments showed that nonactivated diethyl
carbonate had low reactivity. On the other hand, highly
reactive bis(phenyl) carbonate and bis(p-nitrophenyl) carbo-
nate required dropwise addition and temperature control to
prevent formation of symmetrical ureas. These drawbacks
violated the requirements specified above, thus limiting the
application of these carbonates in the parallel synthesis.
INTRODUCTION
■
Compounds with a motif of urea have found wide application
in organic, combinatorial, and medicinal chemistry, organo-
catalysis, and material science.1,2 Many drugs (e.g., cariprazine,
hetrazan, sorafenib) and agrochemicals (e.g., cumyluron,
cycluron, tebuthiuron) contain the fragment of urea (Figure
1). Our ongoing research on the urea-based bioactive molecules
focuses on the aliphatic compounds, Alk−N(R)−C(O)−
N(R1)−Alk1 (R, R1 = H, Alk); the saturated carbon atoms
provide more flexibility to the molecule allowing to effectively
explore a chemical space in three dimensions and reduce the
negative effects of the flat “aromatic” fragments (e.g., increasing
solubility, decreasing toxicity).3−9
To generate a library of the Alk−N(R)−C(O)−N(R1)−Alk1
ureas, we chose a parallel synthesis, which allows for preparing
large sets of organic compounds. We then examined existing
synthetic approaches looking for an optimal, cost- and time-
effective method, that would account for the following
requirements to parallel synthesis: (a) one-pot procedure
with an easy purification protocol; (b) moisture stable starting
reagents, which would allow creating highly diverse sets of
compounds; and (c) addition of all components concurrently
and without temperature control. These criteria made most
reported approaches inapplicable for the parallel synthesis:
phosgene,11,12 triphosgene13,14 are toxic reagents; gases CO2,15
De Aguirre and Collot18 previously reported that the rate of
urea formation from the carbamate depends on the pKa value
of the corresponding alcohol, for example, p-nitrophenol (pKa
≈ 7) > phenol (pKa ≈ 10) > ethanol (pKa ≈ 16). Relying on
this correlation, we proposed an alternative reagent, bis(2,2,2-
trifluoroethyl) carbonate (1). The pKa value of 2,2,2-
trifluoroethanol is ∼12, which is between phenol and ethanol
and provides moderate activity to reagent 1. This feature makes
bis(2,2,2-trifluoroethyl) carbonate a promising substitute to
other carbonates helping to overcome the associated draw-
backs. Herein, we demonstrate a successful application of
16
H2 are inconvenient in handling; many isocyanates17,18 and
carbamates19,20 are commercially unavailable; highly active 1,1′-
carbonyldiimidazole21,22 and chloroformates23−26 need special
care to prevent formation of the side products (symmetrical
ureas in case of highly nucleophilic alkyl amines or chlorinated
compounds in case of functionalized amines, e.g., amino
Received: February 19, 2014
Revised: March 27, 2014
Published: April 2, 2014
© 2014 American Chemical Society
303
dx.doi.org/10.1021/co500025f | ACS Comb. Sci. 2014, 16, 303−308

ACS Combinatorial Science
Research Article
Figure 1. Drugs and agrochemicals bearing the motif of urea.10
amines. Then, we conducted 96 parallel reactions [synthesis of
a full combinatorial set (>2700) was beyond the scope of this
work] in a one-pot two-step fashion.
Scheme 1. Preparation of Unsymmetrical Ureas Utilizing
Carbonates
Set-up of several experiments at the same time leads to errors
associated with measuring quantities of starting reagents,
reducing purity of the final product. To decrease effects of
these errors, reagent 1 was added in an excess (1.5 equiv) to the
amine. After completion of the reaction, the unreacted
bis(2,2,2-trifluoroethyl) carbonate was distilled off under
reduced pressure along with the solvent, while crude
trifluoroethyl carbamate remained in the tube. We, however,
found that volatile trifluoroethyl carbamates, derived from
lower amines (methyl-, propyl-, allyl-, etc.), were partially
removed along with the carbonate during the distillation, which
led to decreasing the overall yield. To overcome this problem,
the lower amines were introduced in the second step of the
procedure.
reagent 1 in the parallel synthesis of the unsymmetrical Alk−
N(H)−C(O)−N(R)−Alk1 ureas derived from mono and
functionalized alkyl amines.
RESULTS AND DISSCUSION
Bis(2,2,2-trifluoroethyl) carbonate (1) is formed along with
trifluoroethylchloroformate in approximately 1/3 ratio in the
■
Scheme 2. Synthesis of Bis(2,2,2-trifluoroethyl) Carbonate
The reaction between the formed alkyl carbamate and the
second amino component required a catalytic base (0.3 equiv of
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)) to proceed: the
weaker acidity of the NH proton of the alkyl trifluoroethyl
carbamates compared with the aryl derivatives prevents forming
the isocyanate intermediates with the second amine byitself.26
Second step involves extraction with CHCl3 and solvent
evaporation to afford the Alk−N(H)−C(O)−N(R)−Alk1 ureas
in moderate to high yields and high purity. Volatility of 2,2,2-
trifluoroethanol results in removal along with the solvent, which
is another advantage over the phenols. Additional purification
by flash chromatography was performed only in 35% of the
experiments. The impurities (in most cases unreacted amine 3)
were well separated from the product simplifying the
purification (Figures S1−S30, in the Supporting Information).
LC-MS analysis of the crude mixtures also confirmed the
absence of the symmetrical ureas, which supported our
suggestion on higher stability of trifluoroethyl carbamates
compared with phenyl and p-nitrophenyl analogues.
The identities and purities of the synthesized Alk−N(H)−
C(O)−N(R)−Alk1 ureas were confirmed by 1H and 13C NMR
spectroscopy and LC-MS analysis. The representative examples
are shown in Tables 1 and 2, and the full list is given in Tables
S1 and S2, in the Supporting Information.
The proposed approach allows synthesizing ureas from
mono and functionalized amines bearing amino group (entries
1−4, in Table 2), hydroxyl (alkyl and aryl) (entries 5−14, in
Table 2) groups, and pyrazole moieties (entries 15−20, in
Table 2), which are commonly utilized in drug design due to
Scheme 3. One-Pot Synthesis of Unsymmetrical Aliphatic
Ureas
reaction between triphosgene and trifluoroethanol (Scheme
2).26 The reagents can be easily separated by fractional
distillation under atmospheric pressure. Trifluoroethylchlor-
oformate can be converted to reagent 1 by the reaction with
trifluoroethanol in the presence of triethylamine as a base.
To determine and optimize the conditions of parallel
synthesis, we created a diverse library of ureas from primary
and secondary alkyl amines out of our database. We arbitrary
selected amines with variable structural motifs increasing
diversity of the library (Tables S1 and S2, in the Supporting
Information). While selecting amino substrates for the first step
of the procedure (Scheme 3), we omitted the secondary
304
dx.doi.org/10.1021/co500025f | ACS Comb. Sci. 2014, 16, 303−308

ACS Combinatorial Science
Research Article
Table 1. Representative Examples of Ureas Derived from Monofunctional Amines 2
a
Isolated yield.
their ability to interact with a target protein through formation
of H-bonds or other electrostatic contacts. The average yields
were lower for the ureas synthesized from amino alcohols
(entries 15−38, in Table S2, in the Supporting Information)
and alkyl amino phenols (entries 39−55, in Table S2, in the
Supporting Information) than those for other types of amines.
The proposed method failed in the reactions where 2- or 3-
amino alcohols were introduced as the first amino component,
because of the formation of cyclic carbamates. Condensation of
these alcohols with the trifluoroethyl carbamates in the second
step resolved the issue, as well as showed a potency of
preparing ureas derived from two functionalized amines (e.g.,
entries 6, 11, and 15, in Table 2). The average yields for the
trisubstituted ureas were comparable to those for the
disubstituted; therefore, the catalytic base was the main driving
force in the second step of the reaction.
that smoothly reacts with alkyl amines, requires no special
conditions (temperature control, order or rate of addition), and
demonstrates high regioselectivity to form the trifluoroethyl
carbamates, but not symmetrical ureas. The obtained
carbamates can be further converted to ureas only in the
presence of the catalytic base. The proposed approach easily
gave the diverse library of unsymmetrical ureas derived from
mono- and functionalized amines. Potential limitation of the
approach: interaction of reagent 1 with lower amines or 2-, 3-
amino alcohols, can be resolved by introducing these substrates
in the second step. Understanding the potency of the urea-
based compounds in combinatorial and medicinal chemistry,
we believe that the reported herein procedure allows expanding
variety of saturated compounds with the Alk−N(H)−C(O)−
N(R)−Alk1 functionality.
ASSOCIATED CONTENT
■
In conclusion, current study demonstrates the simple and
effective one-pot parallel synthesis of unsymmetrical ureas with
the Alk−N(H)−C(O)−N(R)−Alk1 functionality (R = H, Alk).
The procedure employs bis(2,2,2-trifluoroethyl) carbonate (1)
S
* Supporting Information
Details of experimental procedures, full list of the synthesized
1
ureas, H, 13C NMR, and LC-MS spectra for the selected
305
dx.doi.org/10.1021/co500025f | ACS Comb. Sci. 2014, 16, 303−308

ACS Combinatorial Science
Research Article
Table 2. Representative Examples of Ureas Derived from Amines 2 Bearing Additional Functionality
306
dx.doi.org/10.1021/co500025f | ACS Comb. Sci. 2014, 16, 303−308

ACS Combinatorial Science
Research Article
Table 2. continued
a
Isolated yield.
AUTHOR INFORMATION
Corresponding Authors
*E-mail: ysmoroz@mail.enamine.net.
■
synthesized compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
307
dx.doi.org/10.1021/co500025f | ACS Comb. Sci. 2014, 16, 303−308

ACS Combinatorial Science
Research Article
(18) De Aguirre, I.; Collot, J. Isocyanates Bloques: Etude Cinetique
Et Thermodynamique. Bull. Soc. Chim. Belges 1989, 98, 19−30.
(19) Gallou, I.; Eriksson, M.; Zeng, X.; Senanayake, C.; Farina, V.
Practical Synthesis of Unsymmetrical Ureas from Isopropenyl
Carbamates. J. Org. Chem. 2005, 70, 6960−6963.
*E-mail: Pavel.Mykhailiuk@mail.enamine.net; Pavel.
Mykhailiuk@gmail.com.
Notes
The authors declare no competing financial interest.
(20) Ichikawa, Y.; Nishiyama, T.; Isobe, M. Stereospecific Synthesis
of Urea-Tethered Neoglycoconjugates Starting from Glucopyranosyl
Carbamates. Tetrahedron 2004, 60, 2621−2627.
REFERENCES
■
(1) Vishnyakova, T. P.; Golubeva, I. A.; Glebova, E. V. Substituted
Ureas. Methods of Synthesis and Applications. Russ. Chem. Rev. 1985,
54, 249−261.
(21) Li, Z.; Nakagawa, O.; Koga, Y.; Taniguchi, Y.; Sasaki, S.
Synthesis of New Derivatives of 8-oxoG-Clamp for Better Under-
standing the Recognition Mode and Improvement of Selective Affinity.
Bioorg. Med. Chem. 2010, 18, 3992−3998.
(22) Kaur, K.; Jain, M.; Khan, S. I.; Jacob, M. R.; Tekwani, B. L.;
Singh, S.; Singh, P. P.; Jain, R. Synthesis, Antiprotozoal, Antimicrobial,
B-Hematin Inhibition, Cytotoxicity and Methemoglobin (MetHb)
Formation Activities of bis(8-Aminoquinolines). Bioorg. Med. Chem.
2011, 19, 197−210.
(23) Azad, S.; Kumamoto, K.; Uegaki, K.; Ichikawa, Y.; Kotsuki, H. A
New Practical Method for the Synthesis of Unsymmetrical Ureas via
High-Pressure-Promoted Condensation of 2,2,2-Trichloroethyl Carba-
mates (Troc-Carbamates) with Amines. Tetrahedron Lett. 2006, 47,
587−590.
(24) Agarkov, A.; Gilbertson, S. R. Preparation of a Library of
Unsymmetrical Ureas Based on 8-Azabicyclo[3.2.1]octane Scaffold. J.
Comb. Chem. 2008, 10, 655−657.
(25) Kitteringham, J.; Shipton, M. R.; Voyle, M. A Simple Method
for the Synthesis of Unsymmetrical Ureas. Synth. Commun. 2000, 30,
1937−1943.
(26) Bogolubsky, A. V.; Ryabukhin, S. V.; Pipko, S. E.; Lukin, O.;
Shivanyuk, A.; Mykytenko, D.; Tolmachev, A. A Facile Synthesis of
Unsymmetrical Ureas. Tetrahedron 2011, 67, 3619−3623.
(27) Souers, A. J.; Gao, J.; Wodka, D.; Judd, A. S.; Mulhern, M. M.;
Napier, J. J.; Brune, M. E.; Bush, E. N.; Brodjian, S. J.; Dayton, B. D.;
et al. Synthesis and Evaluation of Urea-Based Indazoles as Melanin-
Concentrating Hormone Receptor 1 Antagonists for the Treatment of
Obesity. Bioorg. Med. Chem. Lett. 2005, 15, 2752−2757.
(28) Yoon, J.; Choi, H.; Lee, H. J.; Ryu, C. H.; Park, H.; Suh, Y.; Oh,
U.; Jeong, Y. S.; Choi, J. K.; Park, Y.-H.; et al. Chain-Branched Acyclic
Phenethylthiocarbamates as Vanilloid Receptor Antagonists. Bioorg.
Med. Chem. Lett. 2003, 13, 1549−1552.
(2) Gallou, I. Unsymmetrical Ureas. Synthetic Methodologies and
Application in Drug Design. Org. Prep. Proced. Int. 2007, 39, 355−383.
(3) Burke, M. D.; Schreiber, S. L. A Planning Strategy for Diversity-
Oriented Synthesis. Angew. Chem., Int. Ed. Engl. 2004, 43, 46−58.
(4) Lovering, F.; Bikker, J.; Humblet, C. Escape from Flatland:
Increasing Saturation as an Approach to Improving Clinical Success. J.
Med. Chem. 2009, 52, 6752−6756.
(5) Ritchie, T. J.; Macdonald, S. J. F. The Impact of Aromatic Ring
Count on Compound DevelopabilityAre Too Many Aromatic Rings
a Liability in Drug Design? Drug Discovery Today 2009, 14, 1011−
1020.
̀
(6) Yang, Y.; Engkvist, O.; Llinas, A.; Chen, H. Beyond Size,
Ionization State, and Lipophilicity: Influence of Molecular Topology
on Absorption, Distribution, Metabolism, Excretion, and Toxicity for
Druglike Compounds. J. Med. Chem. 2012, 55, 3667−3677.
(7) Ritchie, T. J.; Macdonald, S. J. F.; Young, R. J.; Pickett, S. D. The
Impact of Aromatic Ring Count on Compound Developability:
Further Insights by Examining Carbo- and Hetero-Aromatic and
-Aliphatic Ring Types. Drug Discovery Today 2011, 16, 164−171.
(8) Morley, A. D.; Pugliese, A.; Birchall, K.; Bower, J.; Brennan, P.;
Brown, N.; Chapman, T.; Drysdale, M.; Gilbert, I. H.; Hoelder, S.;
et al. Fragment-Based Hit Identification: Thinking in 3D. Drug
Discovery Today 2013, 18, 1221−1227.
(9) Ishikawa, M.; Hashimoto, Y. Improvement in Aqueous Solubility
in Small Molecule Drug Discovery Programs by Disruption of
Molecular Planarity and Symmetry. J. Med. Chem. 2011, 54, 1539−
1554.
(10) Gaulton, A.; Bellis, L. J.; Bento, A. P.; Chambers, J.; Davies, M.;
Hersey, A.; Light, Y.; McGlinchey, S.; Michalovich, D.; Al-Lazikani, B.;
et al. ChEMBL: A Large-Scale Bioactivity Database for Drug
Discovery. Nucleic Acids Res. 2012, 40, D1100−D1107.
(11) Gibson, F. S.; Park, M. S.; Rapoport, H. Bis[[4-(2,2-Dimethyl-
1,3-Dioxolyl)]methyl]- Carbodiimide (BDDC) and Its Application to
Residue-Free Esterifications, Peptide Couplings, and Dehydrations. J.
Org. Chem. 1994, 59, 7503−7507.
(29) Ballini, R.; Fiorini, D.; Maggi, R.; Righi, P.; Sartori, G.; Sartorio,
R. TBD-Catalysed Solventless Synthesis of Symmetrically N,N′-
Substituted Ureas from Primary Amines and Diethyl Carbonate.
Green Chem. 2003, 5, 396−398.
(30) Saliu, F.; Rindone, B. Organocatalyzed Synthesis of Ureas from
Amines and Ethylene Carbonate. Tetrahedron Lett. 2010, 51, 6301−
6304.
(12) Mitchell, M. A.; Kelly, R. C.; Wicnienski, N. A.; Hatzenbuhler,
N. T.; Williams, M. G.; Petzold, G. L.; Slightom, J. L.; Siemieniak, D.
R. Synthesis and DNA Crosslinking by a Rigid CPI Dimer. J. Am.
Chem. Soc. 1991, 113, 8994−8995.
́
́ ́
(13) Maya, I.; Lopez, O.; Maza, S.; Fernandez-Bolanos, J. G.;
̃
Fuentes, J. A Facile Access to Ureido Sugars. Synthesis of Urea-
Bridged B-Cyclodextrins. Tetrahedron Lett. 2003, 44, 8539−8543.
(14) Sanna, V.; Pintus, G.; Roggio, A. M.; Punzoni, S.; Posadino, A.
M.; Arca, A.; Marceddu, S.; Bandiera, P.; Uzzau, S.; Sechi, M. Targeted
Biocompatible Nanoparticles for the Delivery of (−)-Epigallocatechin
3-Gallate to Prostate Cancer Cells. J. Med. Chem. 2011, 54, 1321−
1332.
(15) Peterson, S. L.; Stucka, S. M.; Dinsmore, C. J. Parallel Synthesis
of Ureas and Carbamates From Amines and CO2 under Mild
Conditions. Org. Lett. 2010, 12, 1340−1343.
(16) Mohy El Dine, T.; Chapron, S.; Duclos, M.-C.; Duguet, N.;
Popowycz, F.; Lemaire, M. One-Pot, Solvent-Free Access to
Unsymmetrical Ureas by Palladium-Catalysed Reductive Alkylation
Using Molecular Hydrogen. Eur. J. Org. Chem. 2013, 2013, 5445−
5454.
́
(17) Gillies, E. R.; Frechet, J. M. J. Synthesis and Self-Assembly of
Supramolecular Dendritic “Bow-Ties”: Effect of Peripheral Function-
ality on Association Constants. J. Org. Chem. 2004, 69, 46−53.
308
dx.doi.org/10.1021/co500025f | ACS Comb. Sci. 2014, 16, 303−308