Synthesis of 3,3,3-trifluoroethyl isocyanate, carbamate and ureas. Anticancer activity evaluation of N-(3,3,3-trifluoroethyl)-N′-substituted ureas

Article abstract of DOI:10.1016/j.jfluchem.2015.06.005

A new method is described for producing 3,3,3-trifluoroethyl isocyanate from perfluoroisobutene (PFIB). Isocyanate was used for synthesis of carbamates and ureas. A series of trifluoroethyl-substituted ureas has been tested in the National Cancer Institute (NCI, Bethesda, USA) by the NCI-60 DTP Human Tumor Cell Line Screening Program at a single high dose (10^-5 M). The moderate anticancer activity was shown against some types of cancer on the individual human cell lines for leukemia, non-small cell lung cancer and renal cancer.

Full text of DOI:10.1016/j.jfluchem.2015.06.005

Accepted Manuscript
Title: Synthesis of 3,3,3-trifluoroethyl isocyanate, carbamate
and ureas. Anticancer activity evaluation of
N-(3,3,3-trifluoroethyl)-N’-substituted ureas
Author: Elena L. Luzina Anatoliy V. Popov
PII:
S0022-1139(15)00158-X
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.jfluchem.2015.06.005
FLUOR 8578
To appear in:
FLUOR
Received date:
Revised date:
Accepted date:
19-5-2015
4-6-2015
6-6-2015
Please cite this article as: E.L. Luzina, A.V. Popov, Synthesis of 3,3,3-
trifluoroethyl isocyanate, carbamate and ureas. Anticancer activity evaluation of
N-(3,3,3-trifluoroethyl)-N’-substituted ureas, Journal of Fluorine Chemistry (2015),
http://dx.doi.org/10.1016/j.jfluchem.2015.06.005
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*Graphical Abstract - Pictogram
Page 1 of 26

*Graphical Abstract - Synopsis
Graphical Abstract
Synthesis of 3,3,3-trifluoroethyl isocyanate, carbamate and ureas. Anticancer
activity evaluation of N-(3,3,3-trifluoroethyl)-N'-substituted ureas
Elena L. Luzina and Anatoliy V. Popov
3,3,3-Trifluroethyl isocyanate was prepared from perfluoroisobutene. A 3,3,3-trifluroethyl-
substituted carbamate and 22 ureas were synthesized. From them 18 ureas were subjected to
anticancer screening by NCI.
Page 2 of 26

*Highlights (for review)
Highlights
 3,3,3-Trifluoroethyl isocyanate was synthesized by a preparative pathway.
 Novel N-3,3,3-trifluoroethyl-substituted ureas and a carbamate were obtained.
 Anticancer activity of the synthesized ureas was evaluated by the NCI.
 The activity was demonstrated against individual cancer cell lines.
Page 3 of 26

*Manuscript
Click here to view linked References
Synthesis of 3,3,3-trifluoroethyl isocyanate, carbamate and ureas.
Anticancer activity evaluation of N-(3,3,3-trifluoroethyl)-N'-
substituted ureas
Elena L. Luzina a and Anatoliy V. Popov b, *
aInstitute of Physiologically Active Compounds, Severnyi pr. 1, Chernogolovka, Moscow region,
142432, Russia, e-mail: luzina@ipac.ac.ru
bUniversity of Pennsylvania, Perelman School of Medicine, Department of Radiology, 3620
Hamilton Walk, Philadelphia, PA 19104, USA, e-mail: avpopov@mail.med.upenn.edu
Abstract
A new method is described for producing 3,3,3-trifluoroethylisocyanate from perfluoroisobutene
(PFIB). Isocyanate was used for synthesis of carbamates and ureas. A series of trifluoroethyl-
substituted ureas has been tested in the National Cancer Institute (NCI, Bethesda, USA) by the
NCI-60 DTP Human Tumor Cell Line Screening Program at a single high dose (10-5 M). The
mioderate anticancer activity was shown against some types of cancer on the individual human
cell lines for leukemia, non-small cell lung cancer and renal cancer.
Keywords: perfluoroisobutene, 3,3,3-trifluoroethylisocyanate; 3,3,3-trifluoroethyl ureas;
anticancer activity; synthesis
*Corresponding author: Anatoliy V. Popov, Tel.: 1(215) 746-8761; Fax: 1(215) 746-8764
e-mail: avpopov@mail.med.upenn.edu
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Introduction
The search for new effective drugs relies on the continued development of synthetic
methodologies to address the many problems associated with the design of new pharmaceutical
agents. One approach to new drugs is the incorporation of CF3 groups into molecules of potential
drug candidates (e.g. aromatic or heterocyclic systems) or synthesis of new drug candidate from
highly-reactive fluorinated reagents [1-3]. Recently we have found that polyfluorinated ureas
containing different substituents show anticancer activity [4-8], and we described ureas with two
geminal CF3 groups in polyfluoroalkyl moieties. It would therefore be interesting to synthesize
previously-unexplored monotrifluoromethyl-containing compounds trifluoromethyl-substituted
ureas, and investigate their anticancer activity.
Herein, we report a new method of synthesizing 3,3,3-trifluoroethylisocyanate from
perfluoroisobutene (PFIB) and the subsequent preparation of a number of N-(3,3,3-
trifluoroethyl)-N'-substituted ureas and a carbamate. The anticancer activity of the ureas is also
evaluated.
This article is an extension of our publications united by a common idea of developing
new physiologically active fluorinated compounds from perfluoroisobutene 1, a toxic by-product
of tetrafluoroethene and hexafluoropropene manufacturing [9, 10]. Our work covering the
development of new synthetic methods for preparing mono-, bis- and tris- trifluoromethyl(alkyl)-
containing compounds and their precursors has spanned nearly 20 years [4-8, 11-17].
2. Results and discussion.
2.1. Chemistry.
The preparation of 3,3,3-trifluoroethylisocyanate 8 is shown in Scheme 1. Isocyanate 8 was
prepared starting from the key starting material perfluoroisobutene (PFIB) 1. Hydrolysis of
perfluoroisobutene 1 into hexaflouroisobutyric acid 2 [4, 9] followed by treatment with
phosphorus pentachloride led to chloroanhydride 3 [4, 18]. The reaction of chloride 3 with
ethanol led to ester 4 which was converted into ethyl 3,3,3-trifluoropropionate 5 by treatment
Page 5 of 26

with the mixture Et3N/H2O (triethylamine/water) [19]. An alternative multigram synthesis of this
ester 5 involved the conversation of 4 by using of AcOK (potassium acetate) as a base [20].
3,3,3-Trifluoropropionic acid 6 was obtained by sulfuric acid mediated hydrolysis of ester 5
(alternative preparative ways: hydrolysis of ester 5 in aq. HBr [21] or three stage synthesis from
1-chloro-3,3,3-trifluoropropene [22], see also references therein). Acid 6 was transformed into
chloroanhydride 7 by the treatment with PCl5 according to [23] that is a modified method
reported in [24]. Previously, 3,3,3-trifluoroisocyanate 8 was synthesized from 3,3,3-
trifluoroethylamine and phosgene [25-27], by thermal degradation of N-diphenyl-N'-(3,3,3-
trifluoroethyl) urea [28, 29]. It was also synthesized using a Curtius reaction of chloroanhydride
7 and sodium azide [30], but isocyanate 8 was not isolated. We obtained isocyanate 8 with 60%
yield using a Curtius reaction with sodium azide in the presence of catalytic amount of
trimethylsilylazide ([NaN3]0:[Me3SiN3]0 = 1:0.016, mol/mol), similar to our previously reported
procedure for preparation of bis(trifluoromethyl)alkyl azides [4]. Ureas 10a-u, 12, and carbamate
14 were synthesized by addition of primary aliphatic or aromatic amines 9a-u, morpholine 11 or
alcohol 12 to isocyanate 8. Two methods were used for the preparation of the above ureas and
carbamate. While the reactions of well soluble amines 9a-e, 9h-u, 11 or alcohol 13 with
isocyanate 8 were carried out at rt (see Experimental 4.7.1), ureidation of poorly soluble amines
9f,g demanded elevated temperature and a catalyst, trimethyl amine (Experimental 4.7.2).
Page 6 of 26

Scheme 1. Synthesis of 3,3,3-trifluoroethyl- isocyanate 8, carbamate 14 and ureas 10a-u starting
from perfluoroisobutene 1.
The synthesized polyfluorinated carbamate 14 and ureas 10a-u and 12 are solids, stable at rt for
more than 2 years without noticeable changes and were obtained with high yields – 80-95%.
2.2. Biological activity
Biological activity of the newly synthesized compounds was evaluated using a variety of
prediction methods (Lipinski rules and Gelovani parameters [31-33], PASS Online [34-38],
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experimental studies (NCI primary test for anticancer activity) and the COMPARE analysis [39-
41]. The results of these analyses can be found in the SI in the biological activity evaluation
section.
2.2.1. The Lipinski and Gelovani parameters.
All 23 synthesized compounds 10a-u, 12 and 14 are in agreement with Lipinski rules of five [31,
32], which establish criteria for new potential drug candidates (for our molecules 198 < MW
<378; 0.42 < CLogP < 2.9; number of H-bond donors < 5; number of H-bond acceptors < 10). A
potential drug candidate should not violate more than one of the above rules. Gelovani
parameters were additionally considered (number of atoms from 20 to 70, molar refractivity
(MR) from 40 to 130 cm3/mol, polar surface area (PSA < 140 Å2) [33] (see also [42]). The
results of these calculations are presented in Supplementary Information (SI) Table S1.
2.2.2. Prediction prognosis using PASS Online
To investigate the biological potential of compounds 10a-u, 12 and 14, the PASS program was
implemented. PASS (Prediction of Activity Spectra for Substances) is a software product
designed as a tool for evaluating the general biological potential of an organic, drug-like
molecule. PASS provides simultaneous predictions of many types of biological activity based on
the structure of the organic compounds [34-38].
Predicted probability ‘‘to be active’’ (Pa) of different types of biological activity,
pharmacological effects and mechanisms revealed from low to moderate Pa values. For a
detailed analysis of the synthesized compounds, see SI Tables S2-S7.
2.2.3. Anticancer activity at one dose (10-5 M concentration).
Compounds 10a-r were tested by the National Cancer Institute (NCI, Bethesda, USA) on
60 human cancer cell lines organized into subpanels derived from nine different human cancer
types: leukemia, melanoma, lung, colon, renal, ovarian, breast, prostate and CNS, at one dose
(10-5 M concentration) in a primary anticancer assay [43-47].
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The single-dose data is graphed as the mean of the percent growth of the treated cells, relative to
the no-drug control, and relative to the time zero number of cells. This allows for detection of
both growth inhibition (values between 0 and 100) and cytotoxicity (values less than 0). The
screening begins with the evaluation of all compounds against the 60 cell lines at a single dose of
10-5 M (the methodology is presented in SI). The output from the single dose screen was used for
the COMPARE analysis [39-41].
For a detailed analysis of NCI screening of the synthesized compounds 10a-r, see SI Tables S8-
S9.
2.2.4. COMPARE analysis
Since advanced target identification studies were beyond the scope of this article, for the first
assumption of molecular mechanism we used an accessible on-line tool called the NCI
COMPARE analysis [39-41]. This analysis has been performed for tested compounds 10a –10r
(see SI Tables S10-S12) in order to investigate whether there is a resemblance to the anticancer
drugs from either the NCI standard agent database [39-41], or the NCI active synthetic and
natural compounds (present in publicly-available databases). This is also used to predict putative
mechanisms of action. The COMPARE analysis hypothesis is that compounds may have the
same mechanism of action as known agents if the data pattern correlates well with the pattern of
compounds belonging to the standard agent database.
The analysis revealed that possible mechanisms of action of these ureas include: alkylating
agents (10b, 10f, 10j, 10n, 10p, 10r), DNA antimetabolites (10a-g, 10i, 10k, 10m-o, 10q, 10r),
RNA/DNA antimetabolites (10c, 10h, 10k, 10o), topoisomerase II inhibitor (10m) and
antimitotic agents (10o, 10j). Some compounds may exhibit several mechanisms of action (10b,
10c 10f, 10j, 10k, 10m-o, 10r). For a detailed COPARE analysis of synthesized compounds 10a-
r, see SI Tables S10-S12.
3. Conclusion
Page 9 of 26

In this paper we reported a new preparative method of synthesis for 3,3,3-
trifluoroethylisocyanate from perfluoroisobutene (PFIB). 22 new trifluoromethyl-containing
ureas and a carbamate were obtained. Their potential biological activity was predicted using the
Lipinski rules, Gelovani parameters and the PASS program. The trifluoroethylsubstituted ureas
10a-r were tested in the National Cancer Institute (NCI, Bethesda, USA) NCI-60 DTP Human
Tumor Cell Line Screen Program at a single high dose (10-5 M) and the mechanism of action was
evaluated with the COMPARE analysis. Synthesized compounds 10a-r showed anticancer
activity on individual cell lines. Activity was notable on individual cell lines against leukemia,
non-small cell lung cancer and renal cancer
4. Experimental
4.1. General.
The 1H and 19F NMR spectra were recorded on Bruker DXP at 200 and 188 MHz,
respectively, in CDCl3, acetone-d6 and Me2SO-d6 using tetramethylsilane (TMS) as an internal
standard and CFCl3 as an external standard. Chemical shifts are reported in ppm units with the
use of δ scale. Mass-spectra were recorded on a Finnigan 4021 spectrometer. The elemental
analyses (C, H, F, N) were performed in the laboratory of analytic chemistry of IPAC RAS.
HPLC analysis was performed as described elsewhere [48]. Melting points were measured in
open capillary tubes and are uncorrected. Perfluoroisobutene 1 was obtained by pyrolysis of
octafluorocyclobutane [9]. The preparative procedures for the syntheses of 3,3,3-trifluoro-2-
(trifluoromethyl)propanoic acid 2 and 3,3,3-trifluoro-2-(trifluoromethyl)propanoyl chloride 3
were published in our article [4].
4.2. Ethyl 3,3,3-trifluoro-2-(trifluoromethyl)propanoate 4.
610.2 g (2.84 mol) of chloroanhydride 3 was added, drop by drop, to boiling dry ethanol (196.59
g, 4.26 mol). Atfer the addition the reaction mixture was refluxed for 1 h, then cooled until rt and
washed with cold water several times until neutral pH. Organic layer was dryed over MgSO4,
Page 10 of 26

and then distilled. Yield 87% (522.7 g), b.p. 100-102 °C. 1H and 19F NMR spectra correspond to
the literature data.[49, 50].
4.3. Ethyl 3,3,3-trifluoropropanoate 5 (adopted from [19], scaled up).
A solution of Et3N (708.4 g, 7 mol) and water (84 g, 4.67 mol) was added, drop by drop, to hot
(~90 °C, water bath) ester 4 (522.2 g, 2.33 mol) under rigorous agitation with a mechanical
stirrer. The reaction mixture was heated with water bath (100 °C) for additional 4 h, and then
cooled to rt. Next, 1.5 L of cold water (4 °C) was added to the reaction flask. The obtained
mixture was thoroughly agitated, then separated. Water fraction was exctracted with Et2O
(3x450 ml). The combined organic fractions were washed with 5% HCl until acidic pH of water
layer, dryed over MgSO4, and distilled. Trifluoropropionate 5 was isolated with a high yield
(82.7%, 301 g, b.p. 104-108 °C). 1H and 19F NMR spectra correspond to the literature data [51,
52].
4.4. 3,3,3-Trifluoropropionic acid 6.
301 g (1.93 mol) of ester 5 and 2.0 L of 50% sulfuric acid were stirring at 90 C during 20 h. 400
g of NaCl was added and dissolved, then acid 6 was extracted from the resulted mixture with
diethyl ether (3 x 900 ml). The ether solution was dried over MgSO4, concentrated and the
residue was distilled. Yield 150.2 g (61%) of acid 6. B.p. 142-145 C (literature data 153 C
[53]). 1H NMR (CDCl3): δ 3.76 (q, 2H, 3JHF = 9.8 Hz, CH2), 11.75 (s, 1H, OH). 19F NMR
(CDCl3): δ –63.88 (t, 3JFH = 9.8 Hz).
4.5. 3,3,3-Trifluoropropionyl chloride 7.
76.6 g (0.6 mol) of acid 6 was added slowly dropwise to 125 g (0.6 mol) of phosphorus
pentachloride (PCl5) under cooling with an ice bath. Then the mixture was warmed on a water
bath (65 °C) until complete dissolution of PCl5 and very slowly distilled. Yield 86.7 g (99%) of
chloroanhydride 7. B.p. 70-75 C. 1H NMR (CDCl3): δ 3.84 (q, 3JHF = 9.2 Hz). 19F NMR
(CDCl3): δ –64.02 (t, 3JFH = 9.2 Hz).
4.6. 3,3,3-Trifluoroethylisocyanate 8.
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In 3-necked flask equipped with a dropping funnel, a thermometer and an effective condenser,
112.3 g (0.77 mol) of chloroanhydride 7 was added dropwise to a mixture of sodium azide (59.8
g, 0.92 mol), 2 ml trimethylsilylazide (0.015 mol), 1g triethylbutylammonium bromide in 200 ml
of dibutyl ether and 100 ml diglyme with intensive stirring at temperature no more 35 C and
stirred 3 h. Then the mixture was slowly heated to release a large amount of nitrogen. After
complete nitrogen excretion the mixture was heated on a boiling water bath during 1 h and
distilled with an effective deflegmator. Yield 57 g (60%) of isocyanate 8. B.p. 58-63 C. 1H
NMR (CDCl3): δ 3.80 (q, 3JHF = 8.3 Hz). 19F NMR (CDCl3): δ –73.82 (t, 3JFH = 8.3 Hz).
4.7.1. General procedure for the synthesis of compounds 10a-e, 10h-u, 12, 14.
To a solution of 1 mmol of primary amine 9a-e,h-u, morpholine 11 or alcohol 13 in 10
ml of dry diethyl ether or dry benzene 1 mmol of isocyanate 8 was added. The mixture was
stirred during 4 h at rt and left overnight. The resulting precipitate was filtered and recrystallized
from benzene. HPLC analysis revealed single peaks for all tested compounds.
4.7.1.1. 1-Phenyl-3-(2,2,2-trifluoroethyl)urea (10a). Yield 98 %, m.p. 151-153 °C. 1H NMR
(DMSO-d6): δ 3.86 (dq, 2H, 3JHF = 10 Hz, 3JHH = 6 Hz, CF3CH2), 6.62 (t, 1H, 3JHH = 6 Hz,
CH2NH), 6.90 (t, 1H, 3JHH = 7 Hz, CHAr), 7.20 (t, 2H, 3JHH = 7 Hz, CHAr), 7.38 (d, 2H, 3JHH = 7
Hz, CHAr), 8.53 (s, 1H, NH). 19F NMR (DMSO-d6): δ –71.48 (t, 3JFH = 10 Hz). EI-MS (m/z):
218 (M+). Anal. Calcd. for C9H9F3N2O: C, 49.55%; H, 4.16%; F, 26.12%; N, 12.84%; Found: C,
49.53%; H, 4.21%; F, 26.37%; N, 12.60%.
4.7.1.2. 1-(Pyridin-2-yl)-3-(2,2,2-trifluoroethyl)urea (10b). Yield 96 %, m.p. 160-161 °C. 1H
NMR (DMSO-d6): δ 3.96 (dq, 2H, 3JHF = 10 Hz, 3JHH = 7 Hz, CF3CH2), 6.90 (t, 1H, 3JHH = 7 Hz,
CH2NH), 7.20 (d, 1H, 3JHH = 7 Hz, CHAr), 7.66 (t, 1H, 3JHH = 7 Hz, CHAr), 8.14 (t, 1H, 3JHH = 7
Hz, CHAr), 8.60 (d, 1H, 3JHH = 7 Hz, CHAr), 9.50 (s, 1H, NH). 19F NMR (DMSO-d6): δ –71.02 (t,
3JFH = 10 Hz). EI-MS (m/z): 219 (M+). Anal. Calcd. for C8H8F3N3O: C, 43.84%; H, 3.68%; F,
26.01%; N, 19.17%; Found: C, 43.68%; H, 3.55%; F, 26.12%; N, 19.29%.
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4.7.1.3. 1-(Pyridin-3-yl)-3-(2,2,2-trifluoroethyl)urea (10c). Yield 94 %, m.p. 197-199 °C. 1H
NMR (DMSO-d6): δ 3.76 (dq, 2H, 3JHF = 10 Hz, 3JHH = 7 Hz, CF3CH2), 6.78 (t, 1H, 3JHH = 7 Hz,
CH2NH), 7.20 (dd, 1H, 3JHH = 7 Hz, 4JHH = 2 Hz, CHAr), 7.92 (d, 1H, 3JHH = 7 Hz, CHAr), 8.12
(d, 1H, 4JHH = 2 Hz, CHAr), 8.48 (s, 1H, CHAr), 8.78 (s, 1H, NH). 19F NMR (DMSO-d6): δ -71.10
(t, 3JFH = 10 Hz). EI-MS (m/z): 219 (M+). Anal. Calcd. for C8H8F3N3O: C, 43.84%; H, 3.68%; F,
26.01%; N, 19.17%; Found: C, 43.58%; H, 3.59%; F, 26.14%; N, 19.32%.
4.7.1.4. 1-(Pyridin-4-yl)-3-(2,2,2-trifluoroethyl)urea (10d). Yield 99 %, m.p. 150-151°C.
1H NMR (acetone-d6): δ 4.02 (dq, 2H, 3JHF = 10 Hz, 3JHH = 7 Hz, CF3CH2), 6.70 (t, 1H, 3JHH = 7
Hz, CH2NH), 7.48 (d, 2H, 3JHH = 6 Hz, CHAr), 8.36 (d, 2H, 3JHH = 6 Hz, CHAr), 8.74 (s, 1H,
NH). 19F NMR (DMSO-d6): δ –70.92 (t, 3JFH = 10 Hz). EI-MS (m/z): 219 (M+). Anal. Calcd. for
C8H8F3N3O: C, 43.84%; H, 3.68%; F, 26.01%; N, 19.17%; Found: C, 43.72; H, 3.76%; F,
25.93%; N, 19.03%.
4.7.1.5. 1-(6-Methylpyridin-2-yl)-3-(2,2,2-trifluoroethyl)urea (10e). Yield 98 %, m.p. 145-147
°C. 1H NMR (DMSO-d6): δ 2.42 (s, 3H, CH3), 3.98 (dq, 2H, 3JHF = 9 Hz, 3JHH = 7 Hz, CF3CH2),
6.94 (d, 1H, 3JHH = 7 Hz, CHAr), 7.12 (d, 1H, 3JHH = 7 Hz, CHAr), 7.52 (t, 1H, 3JHH = 7 Hz,
CHAr), 8.94 (br. s, 1H, CH2NH), 9.38 (s, 1H, NH). 19F NMR (DMSO-d6): δ –71.04 (t, 3JFH = 9
Hz). EI-MS (m/z): 234 (M+ + 1). Anal. Calcd. for C9H10F3N3O: C, 46.36%; H, 4.32%; F,
24.44%; N, 18.02%; Found: C, 46.22%; H, 4.38%; F, 24.62%; N, 17.88%.
4.7.1.6. 1-(5-Methylisoxazol-3-yl)-3-(2,2,2-trifluoroethyl)urea (10h). Yield 98%, m.p. 181-182
°C. 1H NMR (DMSO-d6): δ 2.30 (s, 3H, CH3), 3.88 (dq, 2H, 3JHF = 9 Hz, 3JHH = 6 Hz, CF3CH2),
6.35 (s, 1H, =CH), 6.82 t (1H, 3JHH = 6 Hz, CH2NH), 9.38 (s, 1H, NH). 19F NMR (DMSO-d6): δ
–70.90 (t, 3JFH = 9 Hz). EI-MS (m/z): 223 (M+). Anal. Calcd. for C7H8F3N3O2: C, 37.68%; H,
3.61%; F, 25.54%; N, 18.83%; Found: C, 37.70%; H, 3.45%; F, 25.64%; N, 18.96%.
4.7.1.7. 1-(2,2,2-Trifluoroethyl)-3-(5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)urea (10i). Yield 90
%, m.p.164-165 °C 1H NMR (DMSO-d6): δ 4.02 (dq, 2H, 3JHF = 10 Hz, 3JHH = 7 Hz, CF3CH2),
7.55 (t, 1H, 3JHH = 7 Hz, CH2NH), 12.04 (s, 1H, NH). 19F NMR (DMSO-d6): δ –70.90 (t, 3F,
Page 13 of 26

3JHF = 10 Hz), 18.20 (s, 3F). EI-MS (m/z): 294 (M+). Anal. Calcd. for C6H4F6N4OS: C, 24.50%;
H, 1.37%; F, 38.75%; N, 19.05%; Found: C, 24.29%; H, 1.28%; F, 38.62%; N, 19.15%.
4.7.1.8. 1-(5-(Ethylthio)-1,3,4-thiadiazol-2-yl)-3-(2,2,2-trifluoroethyl)urea (10j). Yield 95%,
m.p. 215-216°C. 1H NMR (DMSO-d6): δ 1.34 (t, 3H, CH3, 3JHH = 7 Hz), 3.30 (q, 2H, 3JHH = 7
Hz, CH2S), 4.02 (dq, 2H, 3JHF = 9 Hz, 3JHH = 6 Hz, CF3CH2), 6.85 (t, 1H, 3JHH = 6 Hz, CH2NH),
10.88 (br.s, 1H, NH). 19F NMR (DMSO-d6): δ –71.02 (t, 3JFH = 9 Hz). EI-MS (m/z): 286 (M+).
Anal. Calcd. for C7H9F3N4OS2: C, 29.37%; H, 3.17%; F, 19.91%; N, 19.57%; Found: C,
29.56%; H, 3.45%; F, 19.82%; N, 19.76%.
4.7.1.9. 1-(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-3-(2,2,2-
trifluoroethyl)urea (10k). Yield 86 %, m.p. 231-233 °C. 1H NMR (DMSO-d6): δ 2.20 (s, 3H,
CH3C), 3.08 (s, 3H, CH3N), 3.86 (dq, 2H, 3JHF = 9 Hz, 3JHH = 6 Hz, CF3CH2), 6.82 (t, 1H, 3JHH
6 Hz, CH2NH), 7.28 (t, 1H, 3JHH = 7 Hz, CHAr), 7.38 (d, 2H, 3JHH = 7 Hz, CHAr), 7.40 (s, 1H,
NH),7.48 (m, 2H, CHAr). 19F NMR (DMSO-d6): δ –70.84 (t, 3JFH = 9 Hz). EI-MS (m/z): 328
(M+). Anal. Calcd. for C14H15F3N4O2: C, 51.22%; H, 4.61%; F, 17.36%; N, 17.07%; Found: C,
51.28%; H, 4.48%; F, 17.60%; N, 17.17%.
=
4.7.1.10. 1-(Benzo[d]thiazol-2-yl)-3-(2,2,2-trifluoroethyl)urea (10l). Yield 95%, m.p. 308-309
°C. 1H NMR (DMSO-d6): δ 3.95 (dq, 2H, 3JHF = 10 Hz, 3JHH = 6 Hz, CF3CH2), 7.15 (t, 1H, 3JHH
= 7 Hz, CHAr), 7.22 (t, 1H, 3JHH = 6 Hz, CH2NH), 7.30 (t, 1H, 3JHH = 8 Hz, CHAr), 7.58 (d, 1H,
3JHH = 8 Hz, CHAr), 7.74 (d, 1H, 3JHH = 7 Hz, CHAr), 10.72 (s, 1H, NH). 19F NMR (DMSO-d6): δ
–70.93 (t, 3JFH = 10 Hz). EI-MS (m/z): 275 (M+). Anal. Calcd. for C10H8F3N3OS: C, 43.64%; H,
2.93%; F, 20.71%; N, 15.27%; Found: C, 43.69; H, 2.76%; F, 20.79%; N, 15.21%.
4.7.1.11. 1-(4-Methylbenzo[d]thiazol-2-yl)-3-(2,2,2-trifluoroethyl)urea (10m). Yield 70%, m.p.
185-186 °C. 1H NMR (DMSO-d6): δ 2.27 (s, 3H, CH3), 3.88 (dq, 2H, 3JHF = 9 Hz, 3JHH = 6 Hz,
CF3CH2), 7.21 (t, 1H, 3JHH = 6 Hz, CH2NH), 7.32 (d, 1H, 3JHH = 6 Hz, CHAr), 7.35 (s, 1H,
CHAr), 7.93 (s, 1H, NH). 8.15 (d, 1H, 3JHH = 6 Hz, CHAr). 19F NMR (DMSO-d6): δ –70.98 (t,
Page 14 of 26

3JFH = 9 Hz). EI-MS (m/z): 289 (M+). Anal. Calcd. for C11H10F3N3OS: C, 45.67%; H, 3.48%; F,
19.70%; N, 14.53%; Found: C, 45.46; H, 3.54%; F, 19.92%; N, 14.69%.
4.7.1.12. 1-(4,6-Dimethylbenzo[d]thiazol-2-yl)-3-(2,2,2-trifluoroethyl)urea (10n). Yield 94 %,
m.p. 291-293 °C. 1H NMR (DMSO-d6): δ 2.35 (s, 3H, CH3), 2.60 (s, 3H, CH3), 3.77 (dq, 2H,
3JHF = 9 Hz, 3JHH = 6 Hz, CF3CH2), 6.84 (s, 1H, CHAr), 7.15 (t, 1H, 3JHH = 6 Hz, CH2NH), 7.35
(s, 1H, CHAr), 10.80 (s, 1H, NH). 19F NMR (DMSO-d6): δ –70.99 (t, 3JFH = 9 Hz). EI-MS (m/z):
303 (M+). Anal. Calcd. for C12H12F3N3OS: C, 47.52%; H, 3.99%; F, 18.79%; N, 13.85%; Found:
C, 47.36; H, 3.74%; F, 18.92%; N, 13.69%.
4.7.1.13. 1-(4-Chlorobenzo[d]thiazol-2-yl)-3-(2,2,2-trifluoroethyl)urea (10o). Yield 54%, m.p.
245-246 °C. 1H NMR (DMSO-d6): δ 3.87 (dq, 2H, CF3CH2, 3JHF = 9 Hz, 3JHH = 6 Hz), 7.29 (dd,
1H, 3JHH = 9 Hz, 4JHH = 2 Hz, CHAr), 7.42 (d, 1H, 4JHH = 2 Hz, CHAr), 7.60 (t, 1H, 3JHH = 6 Hz,
CH2NH), 8.21 (s, 1H, NH), 8.25 (d, 1H, 3JHH = 9 Hz, CHAr). 19F NMR (DMSO-d6): δ –70.99 (t,
3JFH = 9 Hz). EI-MS (m/z): 309 (M+). Anal. Calcd. for C10H7ClF3N3OS: C, 38.78%; H, 2.28%;
F, 18.40%; N, 13.57%; Found: C, 38.66; H, 2.44%; F, 18.62%; N, 13.39%.
4.7.1.14. 1-(Furan-2-ylmethyl)-3-(2,2,2-trifluoroethyl)urea (10p). Yield 90 %, m.p. 120-122 °C.
1H NMR (DMSO-d6): δ 3.70 (dq, 2H, 3JHF = 10 Hz, 3JHH = 7 Hz, CF3CH2), 4.24 (d, 2H, 3JHH = 6
Hz, CH2N), 6.10 (d, 1H, 3JHH = 4 Hz, CHAr), 6.30-6.50 (m, 3H, 2CHAr + CF3CH2NH), 7.36 (s,
1H, NH). 19F NMR (DMSO-d6): δ –70.96 (t, 3JFH = 10 Hz). EI-MS (m/z): 222 (M+). Anal. Calcd.
for C8H9F3N2O2: C, 43.25%; H, 4.08%; F, 25.65%; N, 12.61%; Found: C, 43.50%; H, 4.35%; F,
25.78%; N, 12.42%.
4.7.1.15. 1-(3,4-Dimethoxyphenethyl)-3-(2,2,2-trifluoroethyl)urea (10q). Yield 84 %, m.p. 135-
136 °C. 1H NMR (DMSO-d6): δ 2.67 (t, 2H, 3JHH = 7 Hz, CH2Ar), 3.29 (q, 2H, 3JHH = 7 Hz,
CH2CH2N), 3.70 (m +2s, 8H, CF3CH2 + CH3O), 5.83 (t, 1H, 3JHH = 7 Hz, CH2CH2NH), 6.35 (t,
1H, 3JHH = 6 Hz, CF3CH2NH), 6.70 (m, 3H, CHAr). 19F NMR (DMSO-d6): δ –71.35 (t, 3JFH = 9
Hz). EI-MS (m/z): 306 (M+). Anal. Calcd. for C13H17F3N2O3: C, 50.98%; H, 5.68%; F, 18.61%;
N, 9.15%; Found: C, 50.76; H, 3.76%; F, 18.87%; N, 9.04%.
Page 15 of 26

4.7.1.16. 2-(3,4-Dimethoxybenzoyl)-N-(2,2,2-trifluoroethyl)hydrazine-1-carboxamide (10r).
Yield 77%, m.p. 198-199 °C. 1H NMR (DMSO-d6): δ 4.85 (s+m, 8H, CH3O+ CF3CH2), 7.02 (d,
1H, 3JHH = 7 Hz, CHAr), 7.16 (t, 1H, 3JHH = 6 Hz, CH2NH), 7.56 (s+d, 2H, 3JHH = 7 Hz, CHAr),
8.28 (s, 1H, NH), 10.14 (s, 1H, NH). 19F NMR (DMSO-d6): δ –70.13 (t, 3JFH = 9 Hz). EI-MS
(m/z): 322 (M+ + 1). Anal. Calcd. for C12H14F3N3O4: C, 44.86%; H, 4.39%; F, 17.74%; N,
13.08%; Found: C, 44.72%; H, 4.44%; F, 17.62%; N, 17.15%.
4.7.1.17. 2-(2-Bromobenzoyl)-N-(2,2,2-trifluoroethyl)hydrazine-1-carboxamide (10s). Yield
73%, m.p.148-150 °C. 1H NMR (DMSO-d6): δ 3.86 (dq, 2H, CF3CH2, 3JHF = 9 Hz, 3JHH 6 Hz),
6.82 t (1H, CH2NH, 3JHH = 6 Hz), 7.24-7.45 (m, 2H, CHAr), 7.46-7.70 (m, 2H, CHAr), 8.48 (s,
1H, NH), 10.08 (s, 1H, NH). 19F NMR (DMSO-d6): δ –70.96 (t, 3JFH = 9 Hz). EI-MS (m/z): 399
(M+). Anal. Calcd. for C10H9BrF3N3O2: C, 35.32%; H, 2.67%; F, 16.76%; N, 12.36%; Found: C,
35.60; H, 2.41%; F, 16.74%; N, 12.22%.
4.7.1.18. 1-Isobutyl-3-(2,2,2-trifluoroethyl)urea (10t).Yield 99 %, m.p. 103-105 °C. 1H NMR
(DMSO-d6): δ 0.86 (d, 6H, CH3, 3JHH = 7 Hz), 1.63 (sept, 1H, CH, 3JHH = 7 Hz), 2.86 (t, 2H,
CHCH2, 3JHH = 7 Hz), 3.76 dq (2H, CF3CH2, 3JHF = 10 Hz, 3JHH = 7 Hz), 5.98 (t, 1H, NH, 3JHH
7 Hz), 6.28 (t, 1H, NH, 3JHH = 7 Hz). 19F NMR (DMSO-d6): δ –71.16 (t, 3JFH = 10 Hz). EI-MS
(m/z): 199 (M+ + 1). Anal. Calcd. for C7H13F3N2O: C, 42.42%; H, 6.61%; F, 28.76%; N,
14.13%; Found: C, 42.50%; H, 6.49%; F, 28.57%; N, 14.30%.
=
4.7.1.19. 1-(4-Chlorobenzyl)-3-(2,2,2-trifluoroethyl)urea (10u). Yield 97%, m.p. 158-159 °C. 1H
NMR (acetone-d6): δ 3.77 (dq, 2H, CF3CH2, 3JHF = 9 Hz, 3JHH = 6 Hz), 4.25 (d, 2H, CH2Ar, 3JHH
= 6 Hz), 6.43 (br. s, 2H, CH2NH), 7.26 (s, 4H, CHAr). 19F NMR (acetone-d6): δ –71.29 (t, 3JFH
9 Hz). EI-MS (m/z): 267 (M+). Anal. Calcd. for C10H10ClF3N2O: C, 45.04%; H, 3.78%; F,
13.30%; N, 10.51%; Found: C, 45.16; H, 3.72%; F, 13.82%; N, 10.27%.
=
4.7.1.20. N-(2,2,2-trifluoroethyl)morpholine-4-carboxamide (12). Yield 99%, m.p. 118-119 °C.
1H NMR (DMSO-d6): δ 3.34 (m, 4H, CH2N), 3.60 (m, 4H, CH2O), 3.92 (dq, 2H, CF3CH2, 3JHF
=
9 Hz, 3JHH = 6 Hz), 6.60 (br. s, 1H,NH). 19F NMR (DMSO-d6): δ –71.03 (t, 3JFH = 9 Hz).EI-MS
Page 16 of 26

(m/z): 212 (M+). Anal. Calcd. for C7H11F3N2O2: C, 39.63%; H, 5.23%; F, 26.86%; N, 13.20%;
Found: C, 39.56%; H, 3.45%; F, 26.78%; N, 13.16%.
4.7.1.21. 4-Fluorobenzyl (2,2,2-trifluoroethyl)carbamate (14). Yield 98 %, m.p. 58-60 °C. 1H
NMR (acetone-d6): δ 3.83 (dq, 2H, CF3CH2, 3JHF = 9 Hz, 3JHH = 6 Hz), 5.10 (s, 3H, CH2NH),
3
7.02 (t, 2H, CHAr, JHF = 9 Hz), 7.46 (m, 2H, CHAr). 19F NMR (acetone-d6): δ -113.08 (s, 1F), -
71.36 (t, 3F, 3JFH = 9 Hz). EI-MS (m/z): 251 (M+ + 1). Anal. Calcd. for C10H9F4NO2: C, 47.82%;
H, 3.61%; F, 30.25%; N, 5.58%; Found: C, 47.65; H, 3.43%; F, 30.29%; N, 5.64%.
4.5.2. General procedure for the synthesis of compound 10f, 10g
A solution of 1 mmol of isocyanate 8 in 5 ml of benzene was added to 1 mmol of amine in 10 ml
of dry benzene and 0.2 ml of saturated ether solution of catalyst trimethylamine in a 50 ml glass
ampoule. This ampoule was sealed and heated at 100 °C for 1.5-2 h. The ampoule was opened,
the solvent was evaporated, and the residue was recrystallized from benzene.
4.5.2.1. 1-(Pyrimidin-2-yl)-3-(2,2,2-trifluoroethyl)urea (10f). Yield 86 %, m.p. 190-191°C. 1H
NMR (DMSO-d6): δ 3.96 (dq, 2H, 3JHF = 9 Hz, 3JHH = 7 Hz, CF3CH2), 7.05 (t, 1H, 3JHH = 7 Hz,
CHAr), 8.58 (d, 2H, 3JHH = 7 Hz, CHAr), 9.50 (t, 1H, 3JHH = 7 Hz, CH2NH), 10.05 (s, 1H, NH).
19F NMR (DMSO-d6): δ –70.74 (t, 3JFH = 9 Hz). EI-MS (m/z): 221 (M+ + 1). Anal. Calcd. for
C7H7F3N4O: C, 38.19%; H, 3.20%; F, 25.89%; N, 25.45%; Found: C, 38.02%; H, 3.38%; F,
25.72%; N, 25.28%.
4.5.2.2. N-(5-Methylisoxazol-3-yl)-4-(3-(2,2,2-trifluoroethyl)ureido)benzenesulfonamide (10g).
Yield 86 %, m.p. 247-248 °C. 1H NMR (DMSO-d6): δ 2.20 (s, 3H, CH3), 3.85 (dq, 2H, 3JHF = 9
Hz, 3JHH = 6 Hz, CF3CH2), 6.04 (s, 1H, =CH), 6.82 t (1H, 3JHH = 6 Hz, CH2NH), 7.66 (d, 2H,
3JHH = 7 Hz, CHAr), 7.76 (d, 2H, 3JHH = 7 Hz, CHAr), 9.08 (s, 1H, NH), 11.08 (br. s, 1H, NH). 19F
NMR (DMSO-d6): δ –71.01 (t, 3JFH = 9 Hz). EI-MS (m/z): 378 (M+). Anal. Calcd. for
C13H13F3N4O4S: C, 41.27%; H, 3.46%; F, 15.07%; N, 14.81%; Found: C, 41.36; H, 3.24%; F,
15.22%; N, 14.62%.
Acknowledgements
Page 17 of 26

The authors thank the National Cancer Institute (NCI) (Bethesda, MD, USA) for screening our
compounds in human cancer cell lines, Prof. J.G. Gelovani (University of Texas M. D. Anderson
Cancer Center) for permission to use his rules in publications and Dr. S.P. Arlauckas (University
of Pennsylvania) for a fruitful discussion. AVP’s research reported in this publication was
supported by the National Center for Advancing Translational Sciences of the National Institutes
of Health under award number UL1TR000003. The content is solely the responsibility of the
authors and does not necessarily represent the official views of the National Institutes of Health.
Page 18 of 26

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