Synthesis of 1-aroyl(1-arylsulfonyl)-4-bis(trifluoromethyl)alkyl semicarbazides as potential physiologically active compounds

Article abstract of DOI:10.1016/j.jfluchem.2013.01.033

1,1-Bis(trifluoromethyl)alkyl isocyanates obtained from perfluoroisobutene (PFIB) react with aroyl(arylsulfonyl)hydrazines. Twenty eight prospective biologically active polyfluorinated 1,4-substituted semicarbazides were synthesized. The structure of each

Full text of DOI:10.1016/j.jfluchem.2013.01.033

Journal of Fluorine Chemistry 148 (2013) 41–48
Contents lists available at SciVerse ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Synthesis of 1-aroyl(1-arylsulfonyl)-4-bis(trifluoromethyl)alkyl semicarbazides
as potential physiologically active compounds
Elena L. Luzina a, Anatoliy V. Popov b,
*
a Institute of Physiologically Active Compounds, Severnyi pr. 1, Chernogolovka, Moscow Region 142432, Russia
b University of Pennsylvania, Department of Radiology, 231 South 34th Street, Philadelphia, PA 19104, USA
A R T I C L E I N F O
A B S T R A C T
Article history:
1,1-Bis(trifluoromethyl)alkyl isocyanates obtained from perfluoroisobutene (PFIB) react with aroyl(ar-
ylsulfonyl)hydrazines. Twenty eight prospective biologically active polyfluorinated 1,4-substituted
semicarbazides were synthesized. The structure of each new product was confirmed by analytical and
spectroscopic methods. The Lipinski’s and Gelovani’s parameters were then calculated. Two adjustments
to the Lipinski rules of five are suggested for fluorinated drug candidates.
Received 18 January 2013
Received in revised form 30 January 2013
Accepted 31 January 2013
Available online 8 February 2013
ß 2013 Elsevier B.V. All rights reserved.
Keywords:
Polyfluoroalkyl isocyanates
Semicarbazides
Perfluoroisobutene
Lipinski rules
1. Introduction
than a normal methyl group [26,27]. Our recent studies suggest
that the anticancer properties of several polyfluoroalkyl-substi-
The current communication 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 manufactur-
ing [1,2]. 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 [3–13]. Among these methods is the preparative syntheses of
bis(trifluoromethyl)methyl-, ethyl- (2) or propyl- (3) isocyanates
tuted ureas are due to the presence of bis(trifluoromethyl)ethyl or -
propyl groups [3–5]. Ureas are more resistant to enzymatic
hydrolytic cleavage than amides. This fact makes substituted ureas
promising drug candidates [28,29]. That is why we have recently
focused on the synthesis of new fluoro-substituted compounds
containing the moiety –N–C(O)–N– [3–6]. Recently it was reported
that trifluoromethyl groups bring anticancer activity to substituted
ureas [30].
It has long been known that hydrazides are biologically active
compounds. For example isoniazid (isonicotinic acid hydrazide,
INH) [31] has been used for more than 50 years as the most
effective anti-tuberculous drug. Many semicarbazide compounds
containing sulfonyl moieties were found to be enzyme inhibitors
[32–34], showing antibacterial [35,36] and antiviral activity
[37,38]. In addition, several 1,4-disubstituted (non-fluorinated)
semicarbazides have demonstrated anticancer activity [39–49].
Here we present the synthesis of novel compounds which
combine the above-mentioned moieties in a single structure.
(Scheme
1 [3,6]), which are precursors of polyfluorinated
substituted ureas, carbamates and other derivatives [3,6].
Fluorinated organic molecules are known to perform a wide
range of biological functions [14–24] and fluorinated agents have
become a focus in the development of new therapies for cancer and
other diseases. In fact, approximately 20% of all currently approved
drugs contain at least one fluorine atom [21,25]. Fluorine can have
direct effects on the drug binding to the target site in the body, as it
is able to form strong interactions with hydrogen bond donors and
lipophilic sidechains, including aromatic groups [20,22,23]. The
trifluoromethyl group is one of the most lipophilic functional
groups known. Its electronegative nature also has dramatic effects
on the drug molecule’s electronic character and adds more bulk
2. Results and discussion
This report presents the preparation of 1-aroyl(1-arylsulfonyl)-
4-[1,1-bis(trifluoromethyl)alkyl] semicarbazides which, as single
structures or as fragments, may be biologically active with
anticancer activity or other cellular targets.
We obtained isocyanates 2, 3 from isobutene 1 as described in
our previous publications [3,6] (Scheme 1). The preparation of
* Corresponding author. Tel.: +1 215 746 8761; fax: +1 215 746 8764.
E-mail addresses: luzina@ipac.ac.ru (E.L. Luzina), avpopov@mail.med.upenn.edu,
anatoliy.popov@gmail.com (A.V. Popov).
0022-1139/$ – see front matter ß 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.jfluchem.2013.01.033

42
E.L. Luzina, A.V. Popov / Journal of Fluorine Chemistry 148 (2013) 41–48
Scheme 1. Preparation of bis(trifluoromethyl)alkyl isocyanates from perfluoroisobutene 1.
novel arylsulfonehydrazides 5i–w is shown in Scheme 2. All these
novel hydrazides are white crystalline substances. The yields are
from moderate to high, namely: 5v, k – 60–67%; 5q, p – 75–78%; 5l,
w, i – 84–89%; and 5o, t, r, h, j, s – 90–99%. Scheme 3 represents
synthesis of 1-aroyl-4-[1,1-bis(trifluoromethyl)alkyl] semicarba-
zides 7a–e, 8a–d and 1-arylsulfonyl-4-[1,1-bis(trifluoromethy-
l)alkyl] semicarbazides 9f, 10f–w.
All 28 synthesized polyfluorinated compounds 7a–e, 8a–d and
9f, 10f–w are white crystals, stable at rt for more than 1 year
without noticeable changes. 1-Aroyl-substitudes semicarbazides
Scheme 2. Synthesis of arylsulfonehydrazides 5i–w.

E.L. Luzina, A.V. Popov / Journal of Fluorine Chemistry 148 (2013) 41–48
43
Scheme 3. Synthesis of 1-aroyl-4-bis(trifluoromethyl)alkyl semicarbazides 7a–e, 8a–d and 1-arylsylfonyl-4-bis(trifluoromethyl)alkyl semicarbazides 9f, 10f–w.
were obtained with high yields: 7b, e – 75–78%; 8b, c, 7c – 83–85%;
and 7d, 8d, 7a, 8a – 90–98%. Yields of 1-arylsulfonyl-substitited
semicarbazides differ from relatively low to high: 10k, l, j – 31–
40%; 10q, v, w, r – 54–57%; 10j, i, m, u – 60–67%; 10t, n, s, o – 73–
75%; and 10f, 9f – 95–96%.
various molecular parameters including MW, number of H-bond
donors and acceptors, and hydrophobicity in order to maximize
the likelihood that compounds have acceptable absorption,
distribution, metabolism and excretion (ADME) properties. The
calculated parameters for the new potential drug candidates
(Table 1) are in agreement with the Lipinski rules of five [50,51]
(MW ꢀ 500; CLogP ꢀ 5; number of H-bond donors ꢀ 5; number of
Lipinski’s rule of five can be used to predict the ‘‘drug-likeness’’
of potential molecular targets [50,51]. This rule defines ranges for

44
E.L. Luzina, A.V. Popov / Journal of Fluorine Chemistry 148 (2013) 41–48
Table 1
Properties of the compounds 7a–e, 8a–d and 9f, 10f–w calculated with ChemBioDraw Ultra, v.13. The Lipinski’s and Gelovani’s parameters.
2
MR (cm3/mol)
Molecular formula (number
of atoms)
PSA (A )
˚
Compound
MW
CLogP
H-bond
donor
H-bond
Lipinski
acceptor
score of 4
7a
343.23
361.22
403.28
344.22
422.13
357.26
375.25
417.31
358.24
393.30
407.33
435.39
486.43
435.39
449.41
421.36
472.20
462.19
457.77
502.23
453.36
459.31
589.35
469.40
443.36
443.36
464.38
477.40
1.748
1.891
1.406
0.251
2.611
2.277
2.42
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
8
9
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
3
3
3
3
3
2
3
3
3
3
3
66.41
66.82
C12H11F6N3O2 (34)
C12H10F7N3O2 (34)
C14H15F6N3O4 (42)
C11H10F6N4O2 (33)
C12H10BrF6N3O2 (34)
C13H13F6N3O2 (37)
C13H12F7N3O2 (37)
C15H17F6N3O4 (45)
C12H12F6N4O2 (36)
C12H13F6N3O3S (38)
C13H15F6N3O3S (41)
C15H19F6N3O3S (47)
C18H20F6N4O3S (52)
C15H19F6N3O3S (47)
C16H21F6N3O3S (50)
C14H17F6N3O3S (44)
C12H12BrF6N3O3S (38)
C12H11Cl2F6N3O3S (38)
C13H14ClF6N3O4S (42)
C13H14BrF6N3O4S (42)
C14H17F6N3O5S (46)
C13H13F8N3O4S (42)
C16H15F12N3O5S (52)
C18H17F6N3O3S (48)
C16H15F6N3O3S (44)
C16H15F6N3O3S (44)
C15H18F6N4O4S (48)
C14H13F6N5O3S2 (43)
70.23
70.23
88.69
82.59
70.23
70.23
70.23
88.69
82.59
87.3
7b
7c
10
9
80.91
7d
64.88
7e
8
74.1
8a
8
71.01
8b
9
71.41
8c
1.935
0.78
10
9
85.51
8d
69.48
9f
2.069
2.598
3.596
3.438
3.526
3.925
3.097
2.962
3.405
2.871
3.021
2.107
2.464
3.693
3.987
3.273
3.273
2.3227
1.879
9
75.787
80.425
89.701
105.63
89.701
94.339
85.063
85.557
85.615
86.87
10f
10g
10h
10i
10j
10k
10l
10m
10n
10o
10p
10q
10r
10s
10t
10u
10v
10w
9
87.3
9
87.3
10
9
90.54
87.3
9
87.3
9
87.3
9
87.3
9
87.3
10
10
11
12
17
9
96.53
96.53
105.76
96.53
105.76
87.3
89.726
88.125
82.266
98.331
100.899
92.667
92.667
93.145
94.768
9
87.3
9
87.3
11
11
99.77
112.02
H-bond acceptors ꢀ 10). The Lipinski rule states that, in general, an
orally active drug has no more than one violation of the above
criteria. Only one compound 10r violates 2 Lipinski rules (score of
4, Table 1), although the applicability of these rules to poly-
fluorinated drug candidates, in our humble opinion, is question-
3. Conclusion
We demonstrated a simple approach to synthesize compounds
with potential biological activity. We showed, specifically, that the
interaction of bis(trifluoromethyl)alkyl isocyanates with aroyl- or
arylsulfonyl-hydrazines leads to variable 1-aroyl(or arylsulfonyl)-
4-[1,1-bis(trifluoromethyl)alkyl] semicarbazides, which were
obtained starting from perfluoroisobutene, a toxic industrial by-
product. Applicability of the Lipinski and Gelovani rules for
polyfluorinated small molecule drug candidates is discussed.
able. At least
2 corrections/adjustments have to apply for
polyfluorinated and especially trifluoromethyl-containing small
molecules. First, the rule MW ꢀ 500 dramatically reduces the
number of polyfluorinated (especially polytrifluoromethylated)
candidates. The fluorine atom is a classic bioisostere of the
hydrogen atom [52]. For this reason, we suggest treating fluorine
atoms as hydrogens for molecular weight calculation in the rules of
five.
4. Experimental
Second, the number of H-bond acceptors, calculated using the
tools incorporated into the structure-drawing programs, was over-
calculated in each of the products listed in Table 1. This
miscalculation ‘‘makes’’ trifluoromethyl-containing lipophilic
molecules ‘‘highly hydrophilic’’, thus misleading those less-
familiar with the field of fluorine organic chemistry. It is reported
that one trifluoromethyl group can form only one H-bond [53], so
we suggest considering one trifluoromethyl group as one H-bond
acceptor in the Lipinski rules. The use of these corrections will
dramatically increase the number of fluorinated drug candidates.
The difficulties mentioned above have led us to pay attention to
other calculated parameters that can be used to evaluate
polyfluorinated small molecules as potential drug candidates.
Recently, J.G. Gelovani formulated rules for potential small
molecule drug candidates [54] and granted us permission to use
his rules in publications [5]. His rules concerning the properties of
4.1. General methods
The 1H and 19F NMR spectra were recorded on Bruker DXP at
200 and 188 MHz, respectively, in CDCl3, DMSO-d6, acetone-d6
using tetramethylsilane (TMS) as an internal standard and
CF3COOH as an external standard. Chemical shifts are reported
in ppm units with the use of d scale. Mass-spectra were recorded on
a Finnigan 4021 spectrometer. The elemental analyses (C, H, F, N)
were performed in the laboratory of analytical chemistry of IPAC
RAS. Melting points were measured in open capillary tubes and are
uncorrected. HPLC analysis was performed as described elsewhere
[65]. The starting materials isocyanates 2 and 3 were prepared by
the Curtius reaction [3,6]. The starting sulfonohydrazides 5f–h and
hydrazides 6a–e are commercial and were used without additional
treatment. The products are named with ChemBioDraw Ultra, v.13
[66].
prospective small molecule drugs are (1) molecular polar surface
2
˚
area (PSA) [55–59] <140 A ; (2) molar refractivity (MR) [60–64]
within the range of 40–130 cm3/mol; (3) the number of atoms in
the molecule 20–70 (Table 1). One can now see that all 1,4-
disubstituted semicarbazides 7a–e, 8a–d and 9f, 10f–w are in
agreement with the Gelovani rules. We believe that these criteria
will help medicinal chemists to better evaluate pharmacological
potency of polyfluoro organic compounds.
4.1.1. General procedure for the synthesis of compounds 7a–e and
8a–d
To a solution of 1 mmol of hydrazide 6a–e in 10 ml of dry
diethyl ether or dry benzene was added 1 mmol of isocyanate 2, 3.
The mixture was stirred for 4 h at rt and left overnight. The
resulting precipitate was filtered and recrystallized from benzene,

E.L. Luzina, A.V. Popov / Journal of Fluorine Chemistry 148 (2013) 41–48
45
or in some cases, solvent was evaporated and the residue was
crystallized from hexane.
(q, 2H, CH2, JHH = 7.0 Hz), 3.90 (s, 6H, CH3O), 7.02 (d, 1H, CHAr
J = 7.0 Hz), 7.46 (s, 1H, CHAr), 7.50 s (1H, NH), 7.65 (d, 1H, CHAr
J = 7.0 Hz), 8.12 (s, 1H, NH), 10.30 (s, 1H, NH). 19F NMR (DMSO-d6):
6.04 s. EI-MS (m/z): 418 [M+1]+. Anal. calcd. for C15H17F6N3O4: C,
43.17; H, 4.11; F, 27.32; N, 10.07; O, 15.34; found: C, 43.32; H, 4.03; F,
27.50; N, 9.98.
,
,
d
4.1.1.1. 2-Benzoyl-N-(1,1,1,3,3,3-hexafluoro-2-methylpropan-2-yl)hy-
drazine-1-carboxamide (7a). Yield 95%, m.p. 190–191 8C. 1H NMR
(DMSO-d6):
3H, CHAr), 7.86 (d, 2H, CHAr, JHH = 7.0 Hz), 8.26 (s, 1H, NH), 10.22
(s, 1H, NH). 19F NMR (DMSO-d6): 5.64 s. EI-MS (m/z): 343 [M]+.
d 1.96 (s, 3H, CH3), 7.22 (s, 1H, NH), 7.40–7.60 (m,
d
4.1.1.9. 2-Isonicotinoyl-N-(1,1,1-trifluoro-2-(trifluoromethyl)butan-
2-yl)hydrazine-1-carboxamide (8d). Yield 91%, m.p. 198–200 8C. 1H
Anal. calcd. for C12H11F6N3O2: C, 41.99; H, 3.23; F, 33.21; N,
12.24; O, 9.32; found: C, 42.12; H, 3.12; F, 33.45; N, 12.42.
NMR (DMSO-d6):
d 1.07 (t, 3H, CH3, JHH = 7.0 Hz), 2.40 (q, 2H, CH2,
JHH = 7.0 Hz), 7.27 (s, 1H, NH), 7.92 (d, 2H, CHAr, JHH = 7.1 Hz), 8.32
(s, 1H, NH), 8.72 (d, 2H, CHAr, JHH = 7.1 Hz), 10.55 (s, 1H, NH). 19F
4.1.1.2. 2-(4-Fluorobenzoyl)-N-(1,1,1,3,3,3-hexafluoro-2-methylpro-
pan-2-yl)hydrazine-1-carboxamide (7b). Yield 75%, m.p. 191–
NMR (DMSO-d6):
12H12F6N4O2: C, 40.23; H, 3.38; F, 31.82; N, 15.64; O, 8.93; found:
d
6.02 s. EI-MS (m/z): 359 [M+1]+. Anal. calcd. for
193 8C. 1H NMR (DMSO-d6):
d
1.98 (s, 3H, CH3), 7.30 (m, 3H,
C
NH + CHAr), 8.00 (m, 2H, CHAr), 8.32 (s, 1H, NH), 10.42 (s, 1H, NH).
C, 40.17; H, 3,52; F, 32.02; N, 15,42.
19F NMR (DMSO-d6):
d 5.04 (s, 6F, CF3); 36.96 (m, 1F, CFAr). EI-MS
(m/z): 361 [M]+. Anal. calcd. for C12H10F7N3O2: C, 39.90; H, 2.79; F,
4.1.2. General procedure for the synthesis of compounds 5i–w
To solution of 1 mmol of arylsulfonyl chloride 4i–w in 10 ml of
THF, 1.1 mmol of hydrazine-hydrate in 10 ml THF were added drop
wise at 0–5 8C with stirring. After stirring 1–2 h at rt 20 ml of water
were added, the precipitate was filtered, dried and crystallized from
benzene or hexane. HPLC analysis revealed single peaks for all tested
compounds.
36.82; N, 11.63; O, 8.86; found: C, 40.02; H, 2.64; F, 36.90; N, 11.68.
4.1.1.3. 2-(3,4-Dimethoxybenzoyl)-N-(1,1,1,3,3,3-hexafluoro-2-methyl-
propan-2-yl)hydrazine-1-carboxamide (7c). Yield 82%, m.p. 184–
186 8C. 1H NMR (acetone-d6):
d 1.92 (s, 3H, CH3), 3.88 (s, 3H,
CH3O), 3.92 (s, 3H, CH3O), 7.08 (d, 1H, CHAr, J = 7.1 Hz), 7.45 (s, 1H,
NH), 7.58 (s, 1H, CHAr), 7.60 (d, 1H, CHAr, J = 7.1 Hz), 8.32 (s, 1H, NH),
10.30 (s, 1H, NH). 19F NMR (acetone-d6):
d
6.04 s. EI-MS (m/z): 403
4.1.2.1. 4-Isopropylbenzenesulfonohydrazide (5i). Yield 89%, m.p.
[M]+. Anal. calcd. for C14H15F6N3O4: C, 41.70; H, 3.75; F, 28.27; N,
10.42; O, 15.87; found: C, 41.86; H, 3.74; F, 28.36; N, 10.44.
48–51 8C. 1H NMR (DMSO-d6):
d
1.30 (d, 6H, JHH = 7.2 Hz, CH3CH),
3.02 (septet, 6H, JHH = 7.2 Hz, CH3CH), 7.42 (d, 2H, JHH = 7.9 Hz,
H
Ar), 7.78 (d, 2H JHH = 7.9 Hz, CHAr), 8.13 (s, 1H, NH). EI-MS (m/z):
4.1.1.4. N-(1,1,1,3,3,3-hexafluoro-2-methylpropan-2-yl)-2-isonicoti-
noylhydrazine-1-carboxamide (7d). Yield 90%, m.p. 192–194 8C. 1H
215 [M+1]+. Anal. calcd. for C9H14N2O2S: C, 50.45; H, 6.59; N, 13.07;
O, 14.93; S, 14.96; found: C, 50.64; H, 6,72; N, 13.02.
NMR (DMSO-d6):
d 1.92 (s, 3H, CH3), 7.77 (s, 1H, NH), 7.72 (d, 2H,
CHAr, JHH = 7.1 Hz), 8.38 (s, 1H, NH), 8.68 (d, 2H, CHAr, JHH = 7.1 Hz),
4.1.2.2. 4-(tert-Butyl)benzenesulfonohydrazide (5j). Yield 97%, m.p.
10.68 (s, 1H, NH). 19F NMR (DMSO-d6):
d
5.66 s. EI-MS (m/z): 345
72–75 8C. 1H NMR (DMSO-d6):
d 1.34 (s, 9H, CH3C), 7.60 (d, 1H,
[M+1]+. Anal. calcd. for C11H10F6N4O2: C, 38.38; H, 2.93; F, 33.12; N,
16.28; O, 9.30; found: C, 38.48; H, 2.84; F, 33.35; N, 16.02.
JHH = 8.6 Hz, HAr), 7.84 (d, 1H, JHH = 8.6 Hz, HAr), 8.50 (s, 1H, NH). EI-
MS (m/z): 229 [M+1]+. Anal. calcd. for C10H16N2O2S: C, 52.61; H,
7.06; N, 12.27; O, 14.02; S, 14.04; found: C, 52.82; H, 6.96; N, 12.38.
4.1.1.5. 2-(2-Bromobenzoyl)-N-(1,1,1,3,3,3-hexafluoro-2-methylpro-
pan-2-yl)hydrazine-1-carboxamide (7e). Yield 77%, m.p. 148–
4.1.2.3. 3,5-Dimethylbenzenesulfonohydrazide (5k). Yield 67%, m.p.
150 8C. 1H NMR (DMSO-d6):
d
1.94 (s, 3H, CH3), 7.25 (s, 1H, NH),
7.30–7.50 (m, 3H, CHAr), 7.76 (d, 1H, CHAr, JHH = 7.0 Hz), 8.42 (s, 1H,
NH), 10.26 (s, 1H, NH). 19F NMR (DMSO-d6):
5.76 s. EI-MS (m/z):
82–84 8C. 1H NMR (DMSO-d6):
d 2.40 (s, 6H, CH3), 6.75 (s, 1H, HAr),
7.54 s (2H, HAr), 8.30 (s, 1H, NH). EI-MS (m/z): 201 [M+1]+. Anal.
calcd. for C8H12N2O2S: C, 47.98; H, 6.04; N, 13.99; O, 5.98; S, 16.01;
found: C, 48.05; H, 6.18; N, 14.10.
d
423 [M+1]+. Anal. calcd. for C12H10BrF6N3O2: C, 34.14; H, 2.39; Br,
18.93; F, 27.00; N, 9.95; O, 7.58; found: C, 34.32; H, 2.48; F, 26.92;
N, 10.04.
4.1.2.4. 4-Bromobenzenesulfonohydrazide (5l). Yield 84%, m.p. 87–
89 8C. 1H NMR (DMSO-d6):
d 7.69 (d, 1H, JHH = 8.8 Hz, HAr), 7.75 (d,
4.1.1.6. 2-Benzoyl-N-(1,1,1-trifluoro-2-(trifluoromethyl)butan-2-yl)hy-
drazine-1-carboxamide (8a). Yield 98%, m.p. 193–195 8C. 1H NMR
1H, JHH = 8.8 Hz, HAr), 8.30 (s, 1H, NH). EI-MS (m/z): 252 [M+1]+.
Anal. calcd. for C6H7BrN2O2S: C, 28.70; H, 2.81; Br, 31.82; N, 11.16;
O, 12.74; S, 12.77; found: C, 28.66; H, 2.93; N, 11.02.
(DMSO-d6):
d 1.06 (t, 3H, CH3, JHH = 7.0 Hz), 2.48 (q, 2H, CH2,
JHH = 7.0 Hz) 7.18 (s, 1H, NH), 7.40–7.60 (m, 3H, CHAr), 7.90 (d, 2H,
CHAr, JHH = 7.0 Hz), 8.20 (s, 1H, NH), 10.26 (s, 1H, NH). 19F NMR
4.1.2.5. 3,4-Dichlorobenzenesulfonohydrazide (5m). Yield 98%, m.p.
107–109 8C. 1H NMR (DMSO-d6):
d 7.66 (d, 1H, JHH = 8.2 Hz, HAr),
(DMSO-d6):
d
5.84 s. EI-MS (m/z): 357 [M]+. Anal. calcd. for
C
13H13F6N3O2: C, 43.71; H, 3.67; F, 31.91; N, 11.76; O, 8.96; found:
7.74 (dd, 1H, JHH = 8.2, 1.8 Hz, HAr), 7.78 (s, 1H, NH), 7.92 (d, 1H,
JHH = 1.8 Hz, HAr,). EI-MS (m/z): 241 [M]+. Anal. calcd. for
C6H6Cl2N2O2S: C, 29.89; H, 2.51; Cl, 29.41; N, 11.62; O, 13.27; S,
13.30; found: C, 30.02; H, 2.36; N, 11.78.
C, 43.82; H, 3.75; F, 32.05; N, 11.84.
4.1.1.7. 2-(4-Fluorobenzoyl)-N-(1,1,1-trifluoro-2-(trifluoromethyl)-
butan-2-yl)hydrazine-1-carboxamide (8b). Yield 83%, m.p. 188–
190 8C. 1H NMR (DMSO-d6):
d
0.99 (t, 3H, CH3, JHH = 7.0), 2.32 (q,
2H, CH2, JHH = 7.0 Hz) 6.92 (s, 1H, NH), 7.30 (m, 2H, CHAr), 7.94 (s,
1H, NH), 8.04 (m, 2H, CHAr), 9.60 (s, 1H, NH). 19F NMR (DMSO-d6):
4.1.2.6. 5-Chloro-2-methoxybenzenesulfonohydrazide
(5n). Yield
97%, m.p. 110–112 8C. 1H NMR (DMSO-d6):
d
3.95 (s, 3H, CH3O),
d
7.19 (d, 1H, JHH = 8.8 Hz, HAr), 7.52 (dd, 1H, JHH = 8.8, 2.8 Hz, HAr),
7.72 (d, 1H, JHH = 2.8 Hz, HAr), 7.95 (s, 1H, NH). EI-MS (m/z): 237
[M+1]+. Anal. calcd. for C7H9ClN2O3S: C, 35.52; H, 3.83; Cl, 14.98; N,
11.84; O, 20.28; S, 13.55; found: C, 35.68; H, 3.72; N, 11.88.
5.74 (s, 6F, CF3); 36.64 (m, 1F, CFAr). EI-MS (m/z): 376 [M+1]+. Anal.
calcd. for C13H12F7N3O2: C, 41.61; H, 3.22; F, 35.44; N, 11.20; O,
8.53; found: C, 41.75; H, 3.16; F, 35,26; N, 11.32.
4.1.1.8. 2-(3,4-Dimethoxybenzoyl)-N-(1,1,1-trifluoro-2-(trifluoro-
4.1.2.7. 5-Bromo-2-methoxybenzenesulfonohydrazide
(5o). Yield
3.93 (s, 3H,
methyl)butan-2-yl)hydrazine-1-carboxamide (8c). Yield 85%, m.p.
90%, m.p. 136–138 8C (dec). 1H NMR (DMSO-d6):
d
187–189 8C. 1H NMR (DMSO-d6):
d
0.99 (t, 3H, CH3, JHH = 7.0 Hz), 2.32
CH3O), 7.11 (d, 1H, JHH = 8.8 Hz, HAr), 7.67 (dd, 1H, JHH = 8.8, 2.0 Hz,

46
E.L. Luzina, A.V. Popov / Journal of Fluorine Chemistry 148 (2013) 41–48
HAr), 7.82 (d, 1H, JHH = 2.0 Hz, HAr). EI-MS (m/z): 281 [M]+. Anal.
calcd. for C7H9BrN2O3S: C, 29.91; H, 3.23; Br, 28.42; N, 9.96; O,
17.07; S, 11.41; found: C, 30.02; H, 3.38; N, 10.12.
4.1.3.1. N-(1,1,1,3,3,3-hexafluoro-2-methylpropan-2-yl)-2-tosylhy-
drazine-1-carboxamide (9f). Yield 96%, m.p. 144–145 8C. 1H NMR
(acetone-d6):
1H, NH), 7.40 (m, 2H, CHAr), 7.80 (m, 2H, CHAr), 8.10 (s, 1H, NH),
8.40 (br. s, 1H, NH). 19F NMR (acetone–d6):
1.00 s. EI-MS (m/z):
d 1.90 (s, 3H, CH3CCF3), 2.50 (s, 3H, CH3Ar), 6.61 (s,
4.1.2.8. 2,5-Dimethoxybenzenesulfonohydrazide (5p). Yield 78%,
d
m.p. 98–100 8C. 1H NMR (DMSO-d6):
d
3.82 (s, 3H, CH3O), 3.90 (s,
394 [M+1]+. Anal. calcd. for C12H13F6N3O3S: C, 36.67; H, 3.34; F,
27.86; N, 10.49; O, 13.77; S, 7.87; found: C, 36.65; H, 3.33; F,
28.98; N, 10.68.
3H, CH3O), 7.22 (m, 2H, HAr), 7.31 (d, 1H, JHH = 2.6 Hz, HAr), 7.74 (s, 1H,
NH). EI-MS (m/z): 233 [M+1]+. Anal. calcd. for C8H12N2O4S: C, 41.37;
H, 5.21; N, 12.06; O, 27.55; S, 13.81; found: C, 41.52; H, 5.38; N, 12.29.
4.1.3.2. 2-Tosyl-N-(1,1,1-trifluoro-2-(trifluoromethyl)butan-2-yl)hy-
4.1.2.9. 4-(Difluoromethoxy)benzenesulfonohydrazide
75%, m.p. 72–74 8C. 1H NMR (DMSO-d6):
3.83 (s, 2H, NH2),
7.16 (t, 1H, JHF = 73.3 Hz, CHF2), 7.28 (d, 2H, JHH = 7.0 Hz, HAr), 7.86
(d, 2H, JHH = 7.0 Hz, HAr), 8.22 (s, 1H, NH). 19F NMR (DMSO-d6):
ꢁ5.71 (d, 2F, JFH = 73.3 Hz, CF2). EI-MS (m/z): 239 [M+1]+. Anal.
calcd. for C7H8F2N2O3S: C, 35.29; H, 3.39; F, 15.95; N, 11.76; O,
20.15; S, 13.46; found: C, 35.46; H, 3.51; F, 16.12; N, 11.94.
(5q). Yield
drazine-1-carboxamide (10f). Yield 95%, m.p. 90–92 8C. 1H NMR
(DMSO-d6): d 0.87 (t, 3H, CH3, JHH = 7.0 Hz), 2.24 (q, 2H, CH2,
d
JHH = 7.0 Hz), 2.42 (s, 3H, CH3CAr), 6.70 (s, 1H, NH), 7.26 (d, 2H,
CHAr, JHH = 7.0 Hz), 7.67 (d, 2H, CHAr, JHH = 7.0 Hz), 8.26 (s, 1H, NH),
d
9.44 (s, 1H, NH). 19F NMR (DMSO-d6):
d 4.03 s. EI-MS (m/z): 408
[M+1]+. Anal. calcd. for C13H15F6N3O3S: C, 38.33; H, 3.71; F, 27.98;
N, 10.32; O, 11.78; S, 7.87; found: C, 38.42; H, 3.63; F, 27.86; N,
10.44.
4.1.2.10. 2,5-bis(2,2,2-Trifl uoroethoxy)benzenesulfonohydrazide
(5r). Yield 94%, m.p. 118–120 8C. 1H NMR (DMSO-d6):
d
4.62 (q,
2H, JHF = 8.6 Hz, CH2O), 4.72 (q, 2H, JHF = 8.6 Hz, CH2O), 7.28 (m, 2H,
Ar), 7.42 (s, 1H, HAr). 19F NMR (DMSO-d6):
4.30 (t, 3F, JFH = 8.6,
4.1.3.3. 2-(Mesitylsulfonyl)-N-(1,1,1-trifluoro-2-(trifluoromethyl)bu-
tan-2-yl)hydrazine-1-carboxamide (10g). Yield 40%, m.p. 116–
117 8C. 1H NMR (DMSO-d6):
d 0.76 (t, 3H, JHH = 7.2 Hz, CH3CH2),
2.26 (q, 2H, JHH = 7.2 Hz, CH2), 2.30 (s, 3H, CH3), 2.60 (s, 6H, CH3),
H
d
CF3CH2), 5.01 (t, 3F, CF3CH2, JFH = 8.6 Hz). EI-MS (m/z): 383 [M+1]+.
Anal. calcd. for: C10H10F6N2O4S: C, 34.56; H, 3.16; F, 29.82; N, 7.33;
O, 16.74; S, 8.39; found: C, 32.48; H, 2.92; F, 31.05; N, 7.73.
6.62 (s, 1H, NH), 6.91 (s, 2H, HAr), 8.32 (s, 1H, NH), 9.20 (s, 1H, NH).
19F NMR (DMSO-d6):
d
5.08 s. EI-MS (m/z): 436 [M+1]+. Anal.
calcd. for C15H19F6N3O3S: C, 41.38; H, 4.40; F, 26.18; N, 9.65; O,
11.02; S, 7.36; found: C, 41.32; H, 4.50; F, 26.22; N, 9.71.
4.1.2.11. [1,10-Biphenyl]-2-sulfonohydrazide (5s). Yield 99%, m.p.
84–86 8C. 1H NMR (DMSO-d6):
d 3.79 (br. s, 2H, NH2), 7.27–7.47 (m,
6H, HAr), 7.48–7.67 (m, 2H, HAr), 8.00 (dd, 1H, JHH = 7.4, 1.6 Hz, HAr).
EI-MS (m/z): 249 [M+1]+. Anal. calcd. for C12H12N2O2S: C, 58.05; H,
4.87; N, 11.28; O, 12.89; S, 12.91; found: C, 58.17; H, 4.98; N, 11.36.
4.1.3.4. 2-((5-(Dimethylamino)naphthalen-1-yl)sulfonyl)-N-(1,1,1-
trifluoro-2-(trifluoromethyl)butan-2-yl)hydrazine-1-carboxamide
(10h). Yield 68%, m.p. 141–143 8C. 1H NMR (CDCl3):
d 0.74 (t, 3H,
JHH = 7.0 Hz, CH3,), 2.16 (q, 2H, JHH = 7.0 Hz, CH,), 2.89 (s, 6H,
CH3N), 5.64 (s, 1H, NH), 6.53 (s, 1H, NH), 6.94 (s, 1H, NH), 7.22 (d,
1H, JHH = 7.4 Hz, HAr), 7.50–7.69 (m, 2H, HAr), 8.28 (m, 2H, HAr),
4.1.2.12. Naphthalene-1-sulfonohydrazide (5t). Yield 92%, m.p.
108–110 8C. 1H NMR (DMSO-d6):
d 7.51–7.70 (m, 4H, HAr), 7.97
(d, 1H, JHH = 7.8 Hz, HAr), 8.15 (m, 2H, HAr), 8.51 (s, 1H, NH), 8.69 (d,
1H, JHH = 8.2 Hz, HAr). EI-MS (m/z): 223 [M+1]+. Anal. calcd. for
8.65 (d, 1H, JHH = 8.4 Hz, HAr). 19F NMR (CDCl3):
d 5.08 s. EI-MS (m/
z): 487 [M+1]+. Anal. calcd. for C18H20F6N4O3S: C, 44.45; H, 4.14;
F, 23.43; N, 11.52; O, 9.87; S, 6.59; found: C, 44.60; H, 4.02; F,
23.54; N, 11.38.
C
10H10N2O2S: C, 54.04; H, 4.53; N, 12.60; O, 14.40; S, 14.43; found:
C, 54.18; H, 4,66; N, 12.34.
4.1.2.13. Naphthalene-2-sulfonohydrazide (5u). Yield 94%, m.p.
4.1.3.5. 2-((4-Isopropylphenyl)sulfonyl)-N-(1,1,1-trifluoro-2-(tri-
134–136 8C. 1H NMR (DMSO-d6):
d
3.80 (br s, 2H, NH2), 7.64 (m,
fluoromethyl)butan-2-yl)hydrazine-1-carboxamide (10i). Yield 66%,
m.p. 126–128 8C. 1H NMR (DMSO-d6):
d 0.82 (t, 3H, JHH = 7.2 Hz,
2H,CHAr), 7.84–8.14(m, 4H, CHAr), 8.33(s, 1H, CHAr), 8.46(s, 1H, NH).
EI-MS (m/z): 223 [M+1]+. Anal. calcd. for C10H10N2O2S: C, 54.04; H,
4.53; N, 12.60; O, 14.40; S, 14.43; found: C, 53.94; H, 4.44; N, 12.36.
CH3CH2,), 1.29 (d, 6H, JHH = 7.0 Hz, CH3CH), 2.28 (q, 2H,
JHH = 7.2 Hz, CH2), 3.02 (sept, 6H, JHH = 7.0 Hz, CH3CH), 6.72 (s,
1H, NH), 7.40 (d, 2H, JHH = 7.9 Hz, HAr), 7.78 (d, 2H, JHH = 7.9 Hz,
4.1.2.14. 4-Methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfono-
hydrazide (5v). Yield 59(60) %, m.p. 116–118 8C. 1H NMR (DMSO-
H d
Ar), 8.39 (br. s, 1H, NH), 9.43 (s, 1H, NH). 19F NMR (DMSO-d6):
5.10 s. EI-MS (m/z): 436 [M+1]+. Anal. calcd. for C15H19F6N3O3S: C,
41.38; H, 4.40; F, 26.18; N, 9.65; O, 11.02; S, 7.36; found: C, 41.46;
H, 4.52; F, 26.04; N, 9.74.
d6):
d 2.94 (s, 3H, CH3N), 3.32 (m, 2H, CH2N), 4.31 (m, 2H, CH2O),
6.75 (d, 1H, JHH = 8.3 Hz, HAr), 7.04 (m, 2H, HAr), 7.94 (s, 1H, NH). EI-
MS (m/z): 244 [M+1]+. Anal. calcd. for C9H13N3O3S: C, 44.43; H,
5.39; N, 17.27; O, 19.73; S, 13.18; found: C, 44.56; H, 5.48; N, 17.32.
4.1.3.6. 2-((4-(tert-Butyl)phenyl)sulfonyl)-N-(1,1,1-trifluoro-2-(tri-
fluoromethyl)butan-2-yl)hydrazine-1-carboxamide (10j). Yield 60%,
4.1.2.15. 4-(1,2,3-Thiadiazol-4-yl)benzenesulfonohydrazide
m.p. 148–150 8C. 1H NMR (DMSO-d6):
d 0.89 (t, 3H, JHH = 7.2 Hz,
(5w). Yield 87%, m.p. 156–158 8C. 1H NMR (DMSO-d6):
d
7.97 (d,
CH3CH2), 1.32 (s, 9H, CH3C), 2.34 (q, 2H, JHH = 7.2 Hz, CH2), 5.92 (s,
1H, NH), 6.89 (br. s, 1H, NH), 6.97 (s, 1H, NH), 7.57 (s, 2H,
JHH = 8.6 Hz, HAr), 7.82 (d, 2H, JHH = 8.6 Hz, CHAr). 19F NMR (DMSO-
2H, JHH = 8.2 Hz, HAr), 8.34 (d, 3H, JHH = 8.2 Hz, NH + HAr), 9.66 (s,
1H, HAr). EI-MS (m/z): 257 [M+1]+. Anal. calcd. for C8H8N4O2S2: C,
37.49; H, 3.15; N, 21.86; O, 12.48; S, 25.02; found: C, 37.69; H, 3.01;
N, 21.59.
d6):
16H21F6N3O3S: C, 42.76; H, 4.71; F, 25.36; N, 9.35; O, 10.68; S,
d
5.04 s. EI-MS (m/z): 450 [M+1]+. Anal. calcd. for
C
7.13; found: C, 42.68; H, 4.82; F, 25.52; N, 9.44.
4.1.3. General procedure for the synthesis of compounds 9f and 10f–w
To the stirred solution of 1 mmol of sulfonohydrazide 5f–v in
5 ml dry benzene, 1.1 mmol of isocyanate 2 or 3 in 5 ml benzene was
added drop wise and stirred at rt during 1 h. The volatile were
evaporated and residue was crystallized from petroleum ether:-
benzene 1:1 (v/v). HPLC analysis revealed single peaks for all tested
compounds.
4.1.3.7. 2-((3,5-Dimethylphenyl)sulfonyl)-N-(1,1,1-trifluoro-2-(tri-
fluoromethyl)butan-2-yl)hydrazine-1-carboxamide
(10k). Yield
31%, m.p. 121–123 8C. 1H NMR (CDCl3):
d
0.92 (t, 3H, JHH = 7.2 Hz,
CH3CH2), 2.36 (q, 2H, JHH = 7.2 Hz, CH2), 2.39 (s, 6H, CH3), 5.90 (s,
1H, NH), 6.60 (s, 1H, NH), 6.74 (s, 1H, HAr), 7.30 (s, 1H, NH), 7.52 (s,
2H, HAr). 19F NMR (CDCl3): 5.12 s. EI-MS (m/z): 422 [M+1]+. Anal.
d

E.L. Luzina, A.V. Popov / Journal of Fluorine Chemistry 148 (2013) 41–48
47
calcd. for C14H17F6N3O3S: C, 39.91; H, 4.07; F, 27.05; N, 9.9; O,
11.39; S, 7.61; found: C, 40.02; H, 4. 12; F, 27.18; N, 10.04.
4.1.3.14. 2-((2,5-bis(2,2,2-Trifluoroethoxy)phenyl)sulfonyl)-N-
(1,1,1-trifluoro-2-(trifluoromethyl)butan-2-yl)hydrazine-1-carbox-
amide (10r). Yield 57%, m.p. 58–60 8C. 1H NMR (DMSO-d6):
0.77
d
4.1.3.8. 2-((4-Bromophenyl)sulfonyl)-N-(1,1,1-trifluoro-2-(trifluoro-
(t, 3H, JHH = 7.0 Hz, CH3), 2.23 (q, 2H, JHH = 7.0 Hz, CH2), 4.54 (q,
2H, JHF = 8.6 Hz, CH2O), 4.72 (q, 2H, JHF = 8.8 Hz, CH2O), 6.80 (br. s,
1H, NH), 7.23 (m, 2H, HAr), 7.43 (d, 1H, JHH = 2.6 Hz, HAr), 8.45 (s,
methyl)butan-2-yl)hydrazine-1-carboxamide (10l). Yield 32%, m.p.
59–61 8C. 1H NMR (DMSO-d6):
d 0.86 (t, 3H, JHH = 7.2 Hz, CH3CH2),
2.32 (q, 2H, JHH = 7.2 Hz, CH2,), 6.76 (s, 1H, NH), 7.65 (d, 2H,
JHH = 8.6 Hz, HAr), 7.75 (d, 2H, JHH = 8.6 Hz, HAr), 8.40 (s, 1H, NH), 9.69
1H, NH), 8.97 (s, 1H, NH). 19F NMR (DMSO-d6):
d 4.29 (t, 3F,
JFH = 8.6 Hz, CF3CH2), 4.99 (t, 3F, CF3CH2, JFH = 8.8 Hz), 5.03 (s, 6F,
CF3C). EI-MS (m/z): 590 [M+1]+. Anal. calcd. for C16H15F12N3O5S:
C, 32.61; H, 2.57; F, 38.68; N, 7.13; O, 13.57; S, 5.44; found: C,
32.70; H, 2.62; F, 38.54; N, 7.01.
(s, 1H, NH). 19F NMR (DMSO-d6):
d
5.10 s. EI-MS (m/z): 473 [M+1]+.
Anal. calcd. forC12H12BrF6N3O3S: C, 30.52; H,2.56; Br, 16.92; F, 24.14;
N, 8.90; O, 10.16; S, 6.79; found: C, 30.48; H, 2.48, F, 24.24; N, 7.02.
4.1.3.9. 2-((3,4-Dichlorophenyl)sulfonyl)-N-(1,1,1-trifluoro-2-(tri-
4.1.3.15. 2-([1,10-Biphenyl]-2-ylsulfonyl)-N-(1,1,1-trifluoro-2-(tri-
fluoromethyl)butan-2-yl)hydrazine-1-carboxamide (10m). Yield
fluoromethyl)butan-2-yl)hydrazine-1-carboxamide
74%, m.p. 164–166 8C. 1H NMR (DMSO-d6):
(10s). Yield
0.83 (t, 3H,
66%, m.p. 62–64 8C. 1H NMR (DMSO-d6):
d
0.82 (t, 3H,
d
JHH = 7.2 Hz, CH3CH2), 2.26 (q, 2H, JHH = 7.2 Hz, CH2), 6.78
(s, 1H, NH), 7.62 (d, 1H, JHH = 8.4 Hz, HAr), 7.72 (dd, 1H,
JHH = 8.6, 1.9 Hz, HAr), 7.89 (d, 1H, JHH = 1.9 Hz, HAr), 8.42
(d, 1H, JHH = 2.6 Hz, NH), 9.84 (d, 1H, JHH = 2.6 Hz, NH). 19F
JHH = 7.4 Hz, CH3), 2.30 (q, 2H, JHH = 7.4 Hz, CH2), 6.74 (br. s,
1H, NH), 7.21–7.41 (m, 4H, HAr), 7.42–7.62 (m, 4H, HAr), 8.00 (d,
1H, JHH = 7.7 Hz, HAr), 8.33 (s, 1H, NH), 8.77 (s, 1H, NH). 19F NMR
(DMSO-d6):
18H17F6N3O3S: C, 46.06; H, 3.65; F, 24.28; N, 8.95; O, 10.23; S,
d
5.11 s. EI-MS (m/z): 470 [M+1]+. Anal. calcd. for
NMR (DMSO-d6):
d
5.06 s. EI-MS (m/z): 463 [M+1]+. Anal. calcd.
C
for C12H11Cl2F6N3O3S: C, 31.18; H, 2.40; Cl, 15.34; F, 24.66; N,
9.09; O, 10.38; S, 6.94; found: C, 31.02; H, 2.56; F, 24.43; N, 9.28.
6.83; found: C, 46.22; H, 3.54; F, 24.42; N, 9.03.
4.1.3.16. 2-(Naphthalen-1-ylsulfonyl)-N-(1,1,1-trifluoro-2-(trifluor-
4.1.3.10. 2-((5-Chloro-2-methoxyphenyl)sulfonyl)-N-(1,1,1-tri-
fluoro-2-(trifluoromethyl)butan-2-yl)hydrazine-1-carboxamide
omethyl)butan-2-yl)hydrazine-1-carboxamide (10t). Yield 73%,
m.p. 104–106 8C. 1H NMR (DMSO-d6):
d
0.70 (t, 3H, JHH = 7.0 Hz,
CH3), 2.15 (q, 2H, JHH = 7.0 Hz, CH2), 6.55 (br. s, 1H, NH), 7.48–7.73
(3H, HAr), 7.95 (d, 1H, JHH = 7.7 Hz, HAr), 8.10 (d, 1H, JHH = 8.1 Hz,
Ar), 8.18 (d, 1H, JHH = 7.4 Hz, HAr), 8.35 (s, 1H, NH), 8.70 (d, 1H,
JHH = 8.1 Hz, HAr), 9.78 (s, 1H, NH). 19F NMR (DMSO-d6):
5.02 s. EI-
(10n). Yield 74%, m.p. 162–164 8C. 1H NMR (DMSO-d6):
d 0.86 (t,
3H, JHH = 7.2 Hz, CH3CH2), 2.32 (q, 2H, JHH = 7.2 Hz, CH2), 4.00 (s,
3H, CH3O), 6.71 (br. s, 1H, NH), 7.10 (d, 1H, JHH = 9.1 Hz, HAr), 7.52
(dd, 1H, JHH = 9.1, 2.6 Hz, HAr), 7.70 (d, 1H, JHH = 2.6 Hz, HAr), 8.42
<
H
d
(s, 1H, NH), 9.12 (br. s, 1H, NH). 19F NMR (DMSO-d6):
d
5.10 (s, 6F,
MS (m/z): 444 [M+1]+. Anal. calcd. for C16H15F6N3O3S: C, 43.34; H,
3.41; F, 25.71; N, 9.48; O, 10.83; S, 7.23; found: C, 43.52; H, 3.52; F,
25.63; N, 9.44.
CF3C). EI-MS (m/z): 458 [M+1]+. Anal. calcd. for C13H14ClF6N3O4S:
C, 34.11; H, 3.08; Cl, 7.74; F, 24.90; N, 9.18; O, 13.98; S, 7.00;
found: C, 34.25; H, 2.96; F, 24.96; N, 9.32.
4.1.3.17. 2-(Naphthalene-2-ylsulfonyl)-N-(1,1,1-trifluoro-2-(trifluor-
4.1.3.11. 2-((5-Bromo-2-methoxyphenyl)sulfonyl)-N-(1,1,1-tri-
fluoro-2-(trifluoromethyl)butan-2-yl)hydrazine-1-carboxamide
omethyl)butan-2-yl)hydrazine-1-carboxamide (10u). Yield 67%,
d 0.71 (t, 3H, JHH = 7.0 Hz,
CH3), 2.20 (q, 2H, JHH = 7.0 Hz, CH2), 5.93 (s, 1H, NH), 6.90 (s, 1H,
m.p. 110–112 8C. 1H NMR (CDCl3):
(10o). Yield 75%, m.p. 178–180 8C. 1H NMR (DMSO-d6):
d
0.87 (t,
3H, JHH = 7.2 Hz, CH3CH2), 2.29 (q, 2H, JHH = 7.2 Hz, CH2), 3.96 (s,
3H, CH3O), 6.70 (br. s, 1H, NH), 7.04 (d, 1H, JHH = 9.1 Hz, HAr), 7.64
(dd, 1H, JHH = 9.1, 2.3 Hz, HAr), 7.66 (d, 1H, JHH = 2.3 Hz, CHAr), 8.38
NH), 7.02 (s, 1H, HAr), 7.55–7.73 (m, 2H, HAr), 7.76–8.03 (m, 4H,
H
Ar), 8.46 (s, 1H, NH). 19F NMR (CDCl3):
d 5.06 s. EI-MS (m/z): 444
[M+1]+. Anal. calcd. for C16H15F6N3O3S: C, 43.34; H, 3.41; F, 25.71;
N, 9.48; O, 10.83; S, 7.23; found: C, 43.42; H, 3,26; F, 25.64; N, 9.55.
(s, 1H, NH), 9.17 (br. s, 1H, NH). 19F NMR (DMSO-d6):
d 5.5 s. EI-MS
(m/z): 503 [M+1]+. Anal. calcd. for C13H14BrF6N3O4S: C, 31.09; H,
2.81; Br, 15.91; F, 22.70; N, 8.37; O, 12.74; S, 6.38; found: C,
31.22; H, 2.91; F, 22.64; N, 8.24.
4.1.3.18. 2-((4-Methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-
yl)sulfonyl)-N-(1,1,1-trifluoro-2-(trifluoromethyl)butan-2-yl)hy-
drazine-1-carboxamide (10v). Yield 55%, m.p. 72–74 8C. 1H NMR
4.1.3.12. 2-((2,5-Dimethoxyphenyl)sulfonyl)-N-(1,1,1-trifluoro-2-
(trifluoromethyl)butan-2-yl)hydrazine-1-carboxamide
(CDCl3): d 0.95 (t, 3H, JHH = 7.4 Hz, CH3), 2.38 (q, 2H, JHH = 7.4 Hz,
CH2), 2.92 (s, 3H, CH3N), 3.31 (m, 2H, CH2N), 4.33 (m, 2H, CH2O),
5.95 (s, 1H, NH), 6.63 (s, 1H, NH), 6.74 (s, 1H, NH), 6.83 (d, 1H,
JHH = 8.4 Hz, HAr,), 7.05 (d, 1H, JHH = 2.1 Hz, HAr,), 6.83 (d, 1H,
(10p). Yield 79%, m.p. 147–149 8C. 1H NMR (DMSO-d6):
d 0.87 (t,
3H, JHH = 7.2 Hz, CH3CH2), 2.26 (q, 2H, JHH = 7.2 Hz, CH2), 3.80 (s,
3H, CH3O), 3.94 (s, 3H, CH3O), 6.71 (br. s, 1H, NH), 7.02 (d, 1H,
JHH = 9.1 Hz, HAr), 7.11 (dd, 1H, JHH = 9.1, 2.8 Hz, HAr), 7.28 (d, 1H,
JHH = 2.8 Hz, HAr), 8.36 (s, 1H, NH), 8.90 (br. s, 1H, NH). 19F NMR
JHH = 8.4, 2.1 Hz, HAr,). 19F NMR (CDCl3):
d 5.04 s. EI-MS (m/z): 465
[M+1]+. Anal. calcd. for C15H18F6N4O4S: C, 38.80; H, 3.91; F, 24.55; N,
12.07; O, 13.78; S, 6.90; found: C, 38.72; H, 3.86; F, 24.72; N, 11.99.
(DMSO-d6):
14H17F6N3O5S: C, 37.09; H, 3.78; F, 25.14; N, 9.27; O, 17.65; S,
d
5.08 s. EI-MS (m/z): 454 [M+1]+. Anal. calcd. for
C
4.1.4. Procedure for the synthesis of compound 10w
7.07; found: C, 36.94; H, 3.87; F, 25.31; N, 9.42.
1 mmol of hydrazide 5w and 1.2 mmol of isocyanate 3 in 10 ml of
benzene were heated in a sealed ampoule during 3 h at 90 8C. The
ampoule was opened and volatiles were evaporated. The residue
was crystallized from benzene. HPLC analysis revealed a single peak.
4.1.3.13. 2-((4-(Difluoromethoxy)phenyl)sulfonyl)-N-(1,1,1-tri-
fluoro-2-(trifluoromethyl)butan-2-yl)hydrazine-1-carboxamide
(10q). Yield 54%, m.p. 44–46 8C. 1H NMR (CDCl3):
d 0.90 (t, 3H,
JHH = 7.2 Hz, CH3), 2.31 (q, 2H, JHH = 7.2 Hz, CH2), 5.91 (s, 1H, NH),
6.61 (t, 1H, JHF = 72.2 Hz, CHF2), 7.17 (s, 1H, NH), 7.26 (d + s, 3H,
JHH = 8.8 Hz, HAr + NH), 7.91 (d, 2H, JHH = 8.8 Hz, HAr). 19F NMR
4.1.4.1. 2-((4-(1,2,3-Thiadiazol-4-yl)phenyl)sulfonyl)-N-(1,1,1-tri-
fluoro-2-(trifluoromethyl)butan-2-yl)hydrazine-1-carboxamide
(10w). Yield 55%, m.p. 170–172 8C. 1H NMR (DMSO-d6):
d 0.88 (t,
(CDCl3):
d
-6.00 (d, 2F, JFH = 72.2 Hz, CF2), 5.07 (s, 6F, CF3C). EI-MS
3H, JHH = 7.4 Hz, CH3), 2.32 (q, 2H, JHH = 7.4 Hz, CH2), 6.65 (s, 1H,
NH), 8.01 (d, 2H, JHH = 7.9 Hz, CHAr), 8.30 (d, 2H, JHH = 7.9 Hz, HAr),
8.39 (s, 1H, NH), 9.30 (s, 1H, NH), 9.40 (s, 1H, HAr). 19F NMR
(m/z): 460 [M+1]+. Anal. calcd. for C13H13F8N3O4S: C, 34.00; H,
2.85; F, 33.09; N, 9.15; O, 13.93; S, 6.98; found: C, 34.12; H, 3.01;
F, 32.98; N, 9.20.
(DMSO-d6):
d
5.02 s. EI-MS (m/z): 478 [M+1]+. Anal. calcd. for

48
E.L. Luzina, A.V. Popov / Journal of Fluorine Chemistry 148 (2013) 41–48
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Acknowledgments
The authors thank Prof. J.G. Gelovani (University of Texas M.D.
Anderson Cancer Center) for permission to use his rules in
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