Exploration of fluoral hydrazones derived from carbohydrazides for the synthesis of trifluoromethylated heterocycles

Article abstract of DOI:10.3987/COM-13-S(S)40

The reaction of fluoral hydrate with carbohydrazides in methanol in the presence of molecular sieves (4 A) gave the desired N-acylated fluoral hydrazones (3a-f) in fair yields. Treatment of the latter with mercaptoacetic acid in benzene led to the corresponding 2-trifluoromethyl-1,3-thiazolidinone derivatives (4a-f), whereas the reaction with acetic anhydride gave 3-acetyl-2,3-dihydro-2-trifluoromethyl-1,3,4-oxadiazoles (5a-f). The structures of each type of product have been established by X-ray crystallography.

Full text of DOI:10.3987/COM-13-S(S)40

HETEROCYCLES, Vol. 88, No. 1, 2014
387
HETEROCYCLES, Vol. 88, No. 1, 2014, pp. 387 - 401. © 2014 The Japan Institute of Heterocyclic Chemistry
Received, 21st June, 2013, Accepted, 12th July, 2013, Published online, 19th July, 2013
DOI: 10.3987/COM-13-S(S)40
EXPLORATION OF FLUORAL HYDRAZONES DERIVED FROM
CARBOHYDRAZIDES FOR THE SYNTHESIS OF
TRIFLUOROMETHYLATED HETEROCYCLES
Grzegorz Mlosto!,a* Katarzyna Urbaniak,a Natalia Jacaszek,1,a Anthony
Linden,b and Heinz Heimgartnerb*
a: University of !ód", Department of Organic and Applied Chemistry, Tamka 12,
PL-91-403 !ód", Poland: e-mail: gmloston@uni.lodz.pl
b: University of Zurich, Institute of Organic Chemistry, Winterthurerstrasse 190,
CH-8057 Zurich, Switzerland; e-mail: heimgart@oci.uzh.ch
Dedicated to Professor Dr. Victor Snieckus on the occasion of his 77th birthday
Abstract – The reaction of fluoral hydrate with carbohydrazides in methanol in
the presence of molecular sieves (4 Å) gave the desired N-acylated fluoral
hydrazones (3a–f) in fair yields. Treatment of the latter with mercaptoacetic acid
in benzene led to the corresponding 2-trifluoromethyl-1,3-thiazolidinone
derivatives (4a–f), whereas the reaction with acetic anhydride gave
3-acetyl-2,3-dihydro-2-trifluoromethyl-1,3,4-oxadiazoles (5a–f). The structures of
each type of product have been established by X-ray crystallography.
INTRODUCTION
In the synthesis of fluorine-containing organic compounds, fluoral hydrate and fluoral ethyl hemiacetal
play an important role. Of special importance are the imines of fluoral, which are available via reactions
of fluoral hemiacetals with primary amines.2 The initially formed fluoral aminals are relatively stable
compounds, and the elimination of water is performed by adding molecular sieves or by azeotropic
removal of water.
Carbohydrazides and their hydrazones are widely applied in the synthesis of diverse heterocycles.3
Recently, we published a series of papers in which heterocyclizations of some hydrazones derived from
imidazole carboxylic acid and proline, respectively, were used as starting materials.4 To the best of our
knowledge, there are only a few publications dealing with preparations of carbohydrazide hydrazones

388
HETEROCYCLES, Vol. 88, No. 1, 2014
derived from fluoral.5 Moreover, there are no known reports on their applications as starting materials for
heterocyclization reactions.
The aim of the present study was the synthesis of fluoral hydrazones derived from carbohydrazides and
subsequent reactions leading to trifluoromethylated heterocycles.
RESULTS AND DISCUSSION
The preparation of the starting hydrazides (1) was performed in a typical manner using the corresponding
carboxylic esters and hydrazine hydrate.4c In preliminary experiments, hydrazide (1a, R = Me) was
reacted with fluoral hemiacetal (2a) or fluoral hydrate (2b) in methanol in the presence of molecular
sieves (4Å). In the case of 2a, only a moderate yield of the required hydrazone (3a) was obtained
(Scheme 1). On the other hand, the reaction with 2b occurred smoothly with complete conversion after 2
h. Based on this observation, all other hydrazides were converted into the hydrazones using 2b. All
fluoral hydrazones (3) were obtained as pure products. The spectroscopic properties proved the structures.
13
For example, in the case of 3d, the C-NMR spectrum in DMSO-d6 showed the signals of the C=O and
C=N groups at 162.8 and 135.1 ppm, respectively. The signal of the CF3 group appeared at 120.6 ppm as
a quartet (1JC,F = 269 Hz), and in the F-NMR spectrum at –66.2 ppm. The data are consistent with the
19
presence of a single isomer in DMSO solution at room temperature. In contrast, the NMR data of 3a in
DMSO-d6 showed that in this case two isomers existed in a ratio of ca. 2:1. For example, in the 19F-NMR
spectrum, two signals appeared at –65.9 ppm for the major and at –66.1 ppm for the minor isomer.6 In all
other cases studied (3b–f), the spectra in DMSO-d6 confirmed that only one isomer was present in the
solution.
Scheme 1

HETEROCYCLES, Vol. 88, No. 1, 2014
389
Finally, the structure of 3c was established by X-Ray crystallography (Figure 1). The space group permits
the compound in the crystal to be enantiomerically pure, but the absolute configuration of the molecule
has not been determined. The enantiomer used in the refinement was based on the known
(S)-configuration of the molecule. The pyrrolidine ring adopts an envelope conformation with N(1) as the
envelope flap and the benzyl group in an exo orientation. The CF3 group is disordered over two equally
occupied orientations. The amide N(2)–H group forms an intermolecular hydrogen bond with the amide
O(1)-atom of a neighboring molecule and thereby links the molecules into extended chains, which run
parallel to the [100] direction. This pattern can be described by a graph set motif 8 of C(4).
Figure 1. ORTEP plot7 of the molecular structure of one conformation of 3c (arbitrary numbering of the
atoms; 50% probability ellipsoids)
Heterocyclizations of hydrazones derived from carbohydrazides using acetic anhydride or mercaptoacetic
acid, to yield 3-acetyl-1,3,4-oxadiazole derivatives and 3-acylamino-1,3-thiadiazolidin-4-ones,
respectively, have been applied for the preparation of biologically active products.9,10 We used both types
of heterocyclization reactions starting with fluoral hydrazones (3) (Scheme 2).
In a typical procedure, a solution of hydrazone (3) in benzene was heated with an equimolar amount of
mercaptoacetic acid in a Dean-Stark apparatus. After evaporation of the solvent, the crude products were
analyzed (1H-NMR). The heterocyclization led to the expected 1,3-thiazolidin-4-ones (4), and in the case
of 4c, a mixture of two diastereoisomers was formed. In this case, chromatographic separation and
subsequent fractional crystallization gave the major isomer as a pure compound. The structures of
products (4) were proposed on the basis of the spectroscopic data. The presence of the CF3 group was
13 19
evidenced by the characteristic signals in the C- and F-NMR spectra (124.0–126.8 and –(75.8–77.8)

390
HETEROCYCLES, Vol. 88, No. 1, 2014
ppm, resp.). In the case of 4b, the structure was unambiguously established by X-Ray crystallography
(Figure 2a).
O
O
R
O
R
(MeCO)2O
N N
HSCH2CO2H
HN N
H
H
CF3
O
N
S
R
N
H
reflux
5-10 h
O
CF3
benzene, reflux
H CF3
4a - 4f (27 - 52%)
3a - 3f
5a,b, 5d - 5f (34 - 82%)
a: R = Me; b: R = Ph; c: R =
; d: R =
; e: R =
; f: R =
N
O
S
N
Bn
Scheme 2
b)
a)
Figure 2. ORTEP plots7 of the molecular structures of a) 4b and b) 5b (arbitrary numbering of the atoms;
50% probability ellipsoids)
Since the space group of 4b is centrosymmetric, the compound in the crystal is racemic. The
five-membered ring adopts an envelope conformation with S(1) as the envelope flap. An unusual feature
of this structure is that the amide H-atom (H–N(2)) is not coplanar with the amide group and the
N(2)-atom shows distinct pyramidalization. The N(2)–C(5) bond is also a little longer (1.3694(14) Å)
than a usual amide N–C bond. This must be a consequence of participation of the ring N(1)-atom in the
delocalization scheme. The amide group (N(2)–H) forms an intermolecular hydrogen bond with the

HETEROCYCLES, Vol. 88, No. 1, 2014
391
amide O(1)-atom of the five-membered ring of a neighboring molecule and thereby links pairs of
molecules into centrosymmetric dimers. The hydrogen bonding can be described with a graph set motif of
R22(10).
The synthesis of 2,3-dihydro-1,3,4-oxadiazoles (5) was performed by refluxing hydrazones (3) in acetic
1
anhydride. The crude products were analyzed by H-NMR spectroscopy. The expected compounds were
obtained as single products, but in the case of the proline derivative (3c), decomposition leading to a
complex mixture of unidentified products was observed. In all other cases, crystalline products were
obtained after chromatographic purification and crystallization. Again, characteristic signals of the CF3
13
19
group were found in the C- and F-NMR spectra in narrow regions (119.7–121.0 and at –82.3 ppm,
resp.). The structure of 5b was also confirmed by X-Ray crystallography (Figure 2b).
The space group of 5b is also centrosymmetric, and therefore the compound in the crystal is racemic. The
five-membered ring is almost planar. The acetyl group at N(1) and the phenyl ring at C(1) are nearly
coplanar with the heterocyclic ring (torsion angle C(2)–N(1)–C(4)–O(2) = –12.7(2)° and
N(2)–C(1)–C(6)–C(7) = 8.7(2)°, respectively).
CONCLUSIONS
The described results show that the little known fluoral hydrazones of aliphatic and aromatic
carbohydrazides can be prepared from commercially available fluoral hydrate and the corresponding
carbohydrazides in the presence of molecular sieves. The isolated hydrazones easily undergo
heterocyclization reactions with mercaptoacetic acid and acetic anhydride leading to trifluoromethylated
1,3-thiazolidin-4-ones (4) and 3-acetyl-2,3-dihydro-1,3,4-oxadiazoles (5), respectively. Keeping in mind
that the presence of fluorinated alkyl groups in an organic molecule significantly changes the
physicochemical and biological properties,11 the application of fluoral-derived hydrazones is of potential
importance not only for the synthesis of 1,3-thiazolidin-4-ones and 3-acetyl-2,3-dihydro-1,3,4-
oxadiazoles but also for other systems available via heterocyclization of carbohydrazide hydrazones.3
Diverse derivatives of type 4 and 5 are known as biologically active systems with a wide spectrum of
activities.
EXPERIMENTAL
General remarks. Melting points were determined in a capillary using a Melt-Temp. II (Aldrich)
apparatus, and they are uncorrected. The IR spectra were recorded on a NEXUS FT-IR spectrophotometer
1
13
19
in KBr; absorptions in cm–1. The H-, C-, and F-NMR spectra were measured on a Bruker Avance III
(600, 150, and 564 MHz, resp.) instrument using solvent signals as reference. Chemical shifts (#) are
given in ppm and coupling constants J in Hz. Assignments of signals in 13C-NMR spectra were made on

392
HETEROCYCLES, Vol. 88, No. 1, 2014
the basis of HMQC experiments. ESI-MS: Varian 500 MS LC Ion Trap spectrometer; HR-ESI-MS:
Bruker maXis spectrometer.
Starting materials. All solvents and reagents are commercially available and were used as received. The
carbohydrazides (1a-f) were prepared from the corresponding esters by treatment with excess hydrazine
hydrate according to published procedures (acetic acid hydrazide (1a, 55%),12a benzoic acid hydrazide (1b,
67%),12b (2S)-1-benzylpyrrolidine-2-carbohydrazide (1c, 82%),4c picolinic acid hydrazide (1d, 37%),12c
furane-2-carbohydrazide (1e, 66%),12d thiophene-2-carbohydrazide (1f, 8%).12e
Synthesis of fluoral hydrazones (3a–3f). – General procedure. A solution of 1 mmol of the
corresponding hydrazide (1) and 1 mmol (116 mg) of fluoral hydrate (2b) in 1 mL of MeOH was placed
in a glass tube. After addition of freshly dried molecular sieves (4 Å), the tube was closed and heated in
an oil bath to 75 ºC for 24 h. Then, the mixture was cooled, filtered, and washed with a portion of MeOH.
The solvent of the combined solutions was evaporated, and the crude products obtained were purified by
column chromatography or on preparative thin layer plates (SiO2). Hydrazones (3) were isolated as
crystalline materials. Analytically pure samples were obtained after recrystallization.
N-[(2,2,2-Trifluoroethyliden)amino]acetamide (3a). Solvent for chromatography: AcOEt. Yield: 79 mg
(51%). Colorless solid, mp 107–114 °C (Et2O/hexane). IR (KBr): 3226s (NH), 1670vs (C=O), 1560m,
1
1374m, 1361m, 1261s, 1195s, 1139s, 1009m, 703m. H-NMR (DMSO-d6): isomer A: 2.13 (s, 3H, CH3);
3
7.50 (q, JH,F = 3.8 Hz, 1H, CH–CF3); 11.72 (br. s, NH); isomer B: 1.99 (s, 3H, CH3); 7.85 (br. q, JH,F
3
$
13
2.6 Hz, 1H, CH–CF3); 11.89 (br. s, NH). C-NMR (DMSO-d6): 19.9 (CH3(A)); 21.8 (CH3(B)); 120.5 (q,
1
2
1JC,F = 269.0 Hz, CF3(A)); 120.8 (q, JC,F = 268.3 Hz, CF3(B)); 129.0 (q, JC,F = 36.5 Hz, CH–CF3(A));
132.8 (q, 2JC,F = 36.8 Hz, CH–CF3(B)); 167.2 (C=O(B)); 172.7 (C=O(A)). 19F-NMR (DMSO-d6): –66.1 (d,
3JH,F = 2.6 Hz, CF3(B)); –65.9 (d, 3JH,F = 3.8 Hz, CF3(A)). The NMR spectra in CDCl3 show only one set of
1
signals: H-NMR (CDCl3): 2.32 (s, 3H, CH3); 7.15 (q, JH,F = 3.4 Hz, 1H, CH–CF3); 9.70 (br. s, NH).
3
3
19F-NMR (CDCl3): –67.5 (d, JH,F = 3.3 Hz, CF3). ESI-MS: 154 (M+, 100); HR-ESI-MS
(MeOH/CH2Cl2+NaI): 177.02469 (calcd. 177.02438 for C4H5F3N2NaO, [M+Na]+).
N-[(2,2,2-Trifluoroethyliden)amino]benzamide (3b). Solvent for chromatography: hexane/AcOEt 7:3.
Yield: 76 mg (35%). Colorless solid, mp 198–200 °C (Et2O/hexane). IR (KBr): 3196s (NH), 3058m,
1
3009w, 1662vs (C=O), 1548m, 1356s, 1261s, 1141s, 1078m, 923w, 694m. H-NMR (DMSO-d6):
7.54–7.57 (m, 2 arom. H); 7.63–7.65 (m, 1 arom. H); 7.89–7.90 (m, 2 arom. H); 8.05 (br. s, CH–CF3);
13 1
12.39 (br. s, NH). C-NMR (DMSO-d6): 120.8 (q, JC,F = 269.0 Hz, CF3); 128.0, 128.8, 132.4 (5 arom.

HETEROCYCLES, Vol. 88, No. 1, 2014
393
19
CH); 132.7 (1 arom. C); 134.3 (br. q, CH–CF3); 164.2 (C=O). F-NMR (DMSO-d6): –66.1 (s, CF3).
ESI-MS: 216 (M+, 77); 215 ([M–1]+, 100); HR-ESI-MS (MeOH/CH2Cl2+NaI): 239.04033 (calcd.
239.04027 for C9H7F3N2NaO, [M+Na]+).
(2S)-1-Benzyl-N-[(2,2,2-trifluoroethyliden)amino]pyrrolidine-2-carboxamide (3c). Solvent for
chromatography: pentane/AcOEt 3:2. Yield: 100 mg (34%). Colorless solid, mp 114–120 °C
(CH2Cl2/hexane). IR (KBr): 3235s (NH), 1693vs (C=O), 1632m, 1525s, 1456m, 1359s, 1320m, 1254m,
1171m, 1141s, 1100s, 1003m, 864m, 761m, 700m. 1H-NMR (CDCl3): 1.73–1.87 (m, 2 H(prol)); 1.96–1.99
(m, 1 H(prol)); 2.25–2.32 (m, 1 H(prol)); 2.46–2.51 (m, 1 H(prol)); 3.12 (t, JH,H = 7.4 Hz, HC(2)(prol));
2
3.34–3.56 (m, 1 H(prol)); 3.68 and 3.80 (AB, JH,H = 12.8 Hz, 2H, CH2–Ph); 7.28–7.35 (m, 5 arom. H);
13
8.42 (br. d, CH–CF3); 10.40 (br. s, NH). C-NMR (CDCl3): 24.2, 30.7, 54.5, 60.1, 67.1 (4 CH2,
1
2
CH(prol)); 120.2 (q, JC,F = 269.9 Hz, CF3); 127.7, 128.7, 128.8 (5 arom. CH); 137.1 (q, JC,F = 38.4 Hz,
CH–CF3); 137.6 (1 arom. C); 172.5 (C=O). 19F-NMR (CDCl3): –68.5 (s, CF3). HR-ESI-MS
(MeOH/CHCl3+NaI): 300.13187 (calcd. 300.13182 for C14H17F3N3O, [M+H]+).
N-[(2,2,2-Trifluoroethyliden)amino]pyridine-3-carboxamide (3d). Solvent for chromatography:
AcOEt. Yield: 64 mg (29%). Colorless solid, mp 160–162 °C (CH2Cl2/pet.ether). IR (KBr): 3201s (NH),
1
3066m, 2961w, 1663vs (C=O), 1591m, 1552m, 1360s, 1270s, 1150s, 1077m, 929w, 707m. H-NMR
(DMSO-d6): 7.59 (br. s, 1 arom. H); 8.06 (br. s, 1 arom. H); 8.24 (br. s, 1 arom. H); 8.79 (br. s, 1 arom.
H); 9.05 (br. s, CH–CF3); 12.55 (br. s, NH). 13C-NMR (DMSO-d6): 120.6 (q, 1JC,F = 269.0 Hz, CF3); 123.8
2
135.8; 148.9; 153.1 (4 arom. CH); 128.3 (1 arom. C); 135.1 (q, JC,F $ 39.0 Hz, CH–CF3); 162.8 (C=O).
3
19F-NMR (DMSO-d6): –66.2 (d, JH,F = 2.4 Hz, CH–CF3). ESI-MS: 217 (M+, 100); HR-ESI-MS
(MeOH/CH2Cl2+NaI): 218.05352 (calcd. 218.05357 for C8H7F3N3O, [M+H]+).
N-[(2,2,2-Trifluoroethyliden)amino]furan-2-carboxamide (3e). Solvent for chromatography:
pentane/AcOEt 1:1. Yield: 70 mg (34%). Colorless solid, mp 184–187 °C (CH2Cl2). IR (KBr): 3261s
(NH), 3115m, 3082m, 1675vs (C=O), 1637m, 1571m, 1551m, 1470s, 1362s, 1288s, 1274s, 1197s, 1176s,
1139s, 1086m, 958w, 767m, 601m. 1H-NMR (DMSO-d6): 6.73–6.74 (m, 1 arom. H); 7.36–7.37 (m, 1 arom.
13
H); 7.99–8.00 (m, 1 arom. H, CH–CF3); 12.32 (br. s, NH). C-NMR (DMSO-d6): 112.5, 146.9 (3 arom.
CH); 120.8 (q, 1JC,F = 270.0 Hz, CF3); 134.0 (1 arom. C); 145.7 (br. s, CH–CF3); 155.3 (C=O). 19F-NMR
3
(DMSO-d6): –66.1 (d, JH,F = 3.4 Hz, CF3). HR-ESI-MS (MeOH+NaI): 229.01941 (calcd. 229.01953 for
C7H5F3N2NaO2, [M+Na]+).
N-[(2,2,2-Trifluoroethyliden)amino]thiophene-2-carboxamide (3f). Solvent for chromatography:

394
HETEROCYCLES, Vol. 88, No. 1, 2014
pentane/AcOEt 1:1. Yield: 179 mg (81%). Colorless solid, mp 126 °C (decomp., CH2Cl2/hexane). IR
(KBr): 3242s (NH), 3044m, 1646vs (C=O), 1567m, 1417m, 1355m, 1263s, 1130vs, 1072m, 899w, 720m.
1H-NMR (DMSO-d6): 7.24–7.25 (m, 1 arom. H); 7.79–7.97 (m, 2 arom. H, CH–CF3); 12.42 (br. s, NH).
1
13C-NMR (DMSO-d6): 120.6 (q, JC,F = 270.0 Hz, CF3); 128.3, 129.5, 131.7 (3 arom. CH); 134.2 (br. s,
19
3
CH–CF3); 138.1 (1 arom. C), 162.3 (C=O). F-NMR (DMSO-d6): –67.2 (d, JH,F = 3.4 Hz, CF3).
HR-ESI-MS: (MeOH + NaI): 244.99650 (calcd. 244.99669 for C7H5F3N2NaOS, [M+Na]+).
Synthesis of trifluoromethylated 1,3-thiazolidin-4-ones (4a–4f). – General procedure. A solution of 1
mmol of the corresponding hydrazone 3 and 1 mmol (94 mg) of mercaptoacetic acid in dry benzene was
heated in a Dean-Stark apparatus until the separation of water ceased (5–18 h). Then, benzene was
evaporated and the residue was treated with a saturated aqueous NaHCO3 solution. The mixture was
extracted with CH2Cl2 (3!), the organic layers were combined and dried over anhydrous MgSO4. After
1
filtration, the solvents were evaporated and the residue analyzed by H-NMR. The crude products were
purified by crystallization. In the case of 4c, the mixture of two diastereoisomeric products was separated
by thin layer chromatography and the main product was obtained as a pure substance by additional
crystallization.
N-(4-Oxo-2-trifluoromethyl-1,3-thiazolidin-3-yl)acetamide (4a). Yield: 113 mg (50%). Colorless solid,
mp 138–140 °C (Et2O/pet. ether). IR (KBr): 3283s (NH), 3006m, 2972m, 1717vs (C=O), 1681vs (C=O),
1
1522m, 1397s, 1270s, 1227s, 1187s, 1175s, 1110vs, 873m, 670m. H-NMR (CDCl3): 2.10 (s, 3H, CH3);
3.53 (A part of AB, 2JH,H = 15.8 Hz, 1H of CH2); 3.73 (B part of AB ! d, 2JH,H = 15.8 Hz, 4JH,H = 1.5 Hz, 1H
3
of CH2); 5.07 (dq, JH,F = 5.6 Hz,, JH,H = 1.5 Hz, CH–CF3); 7.85 (br. s, NH). C-NMR (CDCl3): 20.6
4
13
2
(CH3); 28.3 (CH2); 59.1 (q, JC,F = 34.5 Hz, CH–CF3); 124.1 (q, JC,F = 279.2 Hz, CF3); 168.5, 169.6 (2
1
3
C=O). 19F-NMR (CDCl3): –76.0 (br. d, JH,F = 5.6 Hz, CF3). HR-ESI-MS (MeOH/CH2Cl2+NaI):
251.00748 (calcd. 251.00725 for C6H7F3N2NaO2S, [M+Na]+).
N-(4-Oxo-2-trifluoromethyl-1,3-thiazolidin-3-yl)benzamide (4b). Yield: 124 mg (43%). Colorless
solid, mp 161–163 °C (Et2O/hexane). IR (KBr): 3246s (NH), 2996m, 2974w, 1728vs (C=O), 1683vs
(C=O), 1517m, 1396m, 1284s, 1251s, 1191vs, 1129vs, 753m, 699m, 645m. 1H-NMR (DMSO-d6): 3.69 (A
part of AB, 2JH,H = 15.4 Hz, 1H of CH2); 3.91 (B part of AB ! d, 2JH,H = 15.4 Hz, 4JH,H = 1.5 Hz, 1H of CH2);
5.59 (br. q, 3JH,F = 5.8 Hz, CH–CF3); 7.52–7.55 (m, 2 arom. H); 7.61–7.64 (m, 1 arom. H); 7.88–7.89 (m, 2
arom. H); 11.15 (br. s, NH). C-NMR (CDCl3): 28.5 (CH2); 59.3 (q, 2JC,F = 33.6 Hz, CH–CF3); 124.1 (q,
13
1JC,F = 279.0 Hz, CF3); 127.5, 128.8, 132.9 (5 arom. CH); 130.5 (1 arom. C); 165.6, 170.3 (2 C=O).
3
19F-NMR (CDCl3): –76.0 (br. d, JH,F = 5.7 Hz, CF3). HR-ESI-MS (MeOH/CH2Cl2+NaI): 313.02294

HETEROCYCLES, Vol. 88, No. 1, 2014
395
(calcd. 313.02290 for C11H9F3N2NaO2S, [M+Na]+).
(2S)-1-Benzyl-N-(4-oxo-2-trifluoromethyl-1,3-thiazolidin-3-yl)pyrrolidine-2-carboxamide
(4c).
Yield: 93 mg (49%; pure major isomer). Colorless solid, mp 126–128 °C (CH2Cl2/hexane). IR (KBr):
3264s (NH), 1725vs (C=O), 1687s (C=O), 1485s, 1385m, 1320m, 1254m, 1200s, 1158s, 1124s, 1028m,
986m, 700m, 677m. 1H-NMR (CDCl3): 1.73–1.75 (m, 1 CH(prol)); 1.78–1.86 (m, 1 CH(prol)); 1.88–1.94
3
(m, 2 CH(prol)); 2.23–2.27 (m, 1 CH(prol)); 2.36–2.39 (m, 1 CH(prol)); 3.00 (t, JH,H = 7.4 Hz,
HC(2)(prol)); 3.53 (A part of AB, 2JH,H = 15.7 Hz, 1H of CH2); 3.75 (B part of AB ! d, 2JH,H = 15.7 Hz, 4JH,H
= 1.4 Hz, 1H of CH2); 3.49 and 4.14 (AB, JH,H = 12.6 Hz, CH2–Ph); 5.21 (m, 1H, CH–CF3); 7.28–7.37 (m,
5 arom. H); 9.28 (br. s, NH). 13C-NMR (CDCl3, 150 MHz): 24.0, 28.2, 30.6, 53.2, 59.6 (5 CH2); 58.5 (q,
1
2JC,F = 34.3 Hz, CH–CF3); 66.5 (CH(prol)); 124.0 (q, JC,F = 280.1 Hz, CF3); 127.5, 128.6, 129.2 (5 arom.
19
CH); 137.8 (1 arom. C); 168.7, 173.3 (2 C=O). F-NMR (CDCl3): –75.8 (br. s, CF3). HR-ESI-MS
(MeOH+NaI): 374.11448 (calcd. 374.11446 for C16H19F3N3O2S, [M+H]+).
N-(4-Oxo-2-trifluoromethyl-1,3-thiazolidin-3-yl)pyridine-3-carboxamide (4d). Yield: 80 mg (27%).
Colorless solid, mp 202–204 °C (CH2Cl2/hexane). IR (KBr): 3432m (NH), 2958m, 1740vs (C=O), 1678vs
1
(C=O), 1595m, 1297s, 1268s, 1254m, 1219m, 1197m, 1178s, 1114vs, 652m. H-NMR (CDCl3): 3.60 (A
part of AB, 2JH,H = 15.7 Hz, 1H of CH2); 3.80 (B part of AB ! d, 2JH,H = 15.8 Hz, 4JH,H = 1.5 Hz, 1H of CH2);
3
4
5.21 (dq, JH,F = 5.5 Hz,, JH,H = 1.5 Hz, CH–CF3); 7.42–7.44 (m, 1 arom. H); 8.13–8.15 (m, 1 arom. H);
8.41–8.44 (m, 1 arom. H); 8.80–8.82 (m, 1 arom. H); 9.05 (d, J = 1.5 Hz, NH). 13C-NMR (CD3OD): 30.2
(CH2); 61.3 (q, 2JC,F = 34.5 Hz, CH–CF3); 124.0, 138.5, 150.4, 152.7 (4 arom. CH); 126.8 (q, 1JC,F = 279.0
19
3
Hz, CF3); 130.4 (1 arom. C); 167.3, 172.6 (2 C=O). F-NMR (CD3OD): –77.8 (d, JH,F = 5.4 Hz, CF3).
ESI-MS: 291.1 (M+, 100). HR-ESI-MS (MeOH+NaI): 314.01808 (calcd. 314.01815 for C10H8F3N3NaO2S,
[M+Na]+).
N-(4-Oxo-2-trifluoromethyl-1,3-thiazolidin-3-yl)furan-2-carboxamide (4e). Yield: 146 mg (52%).
Colorless solid, mp 200–206 °C (CH2Cl2/hexane). IR (KBr): 3216m (NH), 1713vs (C=O), 1697vs and
1
1679vs (C=O), 1588m, 1478m, 1299s, 1228m, 1203m, 1181s, 1132vs, 869m, 764m, 660m. H-NMR
2
2
4
(CDCl3): 3.63 (A part of AB, JH,H = 15.9 Hz, 1H of CH2); 3.89 (B part of AB ! d, JH,H = 15.9 Hz, JH,H
=
3
1.5 Hz, 1H of CH2); 5.16 (dq, JH,F = 5.3 Hz, JH,H = 1.5 Hz, CH–CF3); 6.57–6.59 (m, 1 arom. H);
4
13
7.28–7.30 (m, 1 arom. H); 7.53–7.54 (m, 1 arom. H); 8.18 (br. s, NH). C-NMR (CD3OD): 30.1 (CH2);
2
1
61.5 (q, JC,F = 34.1 Hz, CH–CF3); 114.2, 118.6, 148.5 (3 arom. CH); 126.8 (q, JC,F = 279.2 Hz, CF3);
147.8 (1 arom. C); 160.0, 172.5 (2 C=O). 19F-NMR (CD3OD): –77.7 (d, 3JH,F = 5.3 Hz, CF3). HR-ESI-MS
(MeOH+NaI): 303.00238 (caldc. 303.00217 for C9H7F3N2NaO3S, [M+Na]+).

396
HETEROCYCLES, Vol. 88, No. 1, 2014
N-(4-Oxo-2-trifluoromethyl-1,3-thiazolidin-3-yl)thiophene-2-carboxamide (4f). Yield: 142 mg (48%).
Colorless solid, mp 152 °C (decomp., CH2Cl2/hexane). IR (KBr): 3253m (NH), 2981w, 1721vs (C=O),
1664vs (C=O), 1534m, 1416m, 1294s, 1262s, 1191s, 1177s, 1116s, 871w, 722s, 653w. 1H-NMR (CDCl3):
3.58 (A part of AB, 2JH,H = 15.8 Hz, 1H of CH2); 3.78 (B part of AB ! d, 2JH,H = 15.8 Hz, 4JH,H = 1.5 Hz, 1H
3
4
of CH2); 5.20 (dq, JH,F = 5.3 Hz,, JH,H = 1.5 Hz, CH–CF3); 7.10–7.11 (m, 1 arom. H); 7.57–7.59 (m, 1
arom. H); 7.65–7.66 (m, 1 arom. H); 8.27 (br. s, NH). 13C-NMR (CDCl3): 28.5 (CH2); 59.5 (q, 2JC,F = 33.8
1
Hz, CH–CF3); 124.1 (q, JC,F = 280.1 Hz, CF3); 128.1, 130.4, 132.3 (3 arom. CH); 134.1 (1 arom. C);
19
3
160.3, 170.3 (2 C=O). F-NMR (CDCl3): –76.0 (d, JH,F = 5.3 Hz, CF3). HR-ESI-MS (MeOH+NaI):
318.97906 (caldc. 318.97932 for C9H7F3N2NaO2S2, [M+Na]+).
Synthesis of trifluoromethylated 3-acetyl-2,3-dihydro-1,3,4-oxadiazoles (5a,b,d–f). – General
procedure. A solution of 1 mmol of the corresponding hydrazone 3 in excess acetic anhydride (5 mL)
was heated at reflux until complete conversion of the starting material (5–10 h). The progress of the
reaction was monitored by TLC. When the reaction was finished, excess acetic anhydride was distilled off
1
under reduced pressure, and the crude material obtained was analyzed by H-NMR. Isolation of pure
products was achieved either by crystallization or by preparative thin layer chromatography followed by
crystallization.
3-Acetyl-2,3-dihydro-5-methyl-2-trifluoromethyl-1,3,4-oxadiazole (5a). Yield: 161 mg (82%).
Colorless solid, mp 40–42 °C (pentane/pet. ether). IR (KBr): 2931w, 2860w, 1692vs (C=O), 1646s (C=N),
1
1425s, 1373s, 1242m, 1150s, 1044m, 856m, 623m, 594m. H-NMR (CDCl3): 2.12 (s, 3H, CH3); 2.26 (s,
3
3H, CH3); 6.34 (q, JH,F = 4.1 Hz, CH–CF3). C-NMR (CDCl3): 10.8 (CH3); 21.2 (CH3); 84.4 (q, JC,F
13
2
=
37.5 Hz, CH-CF3); 120.8 (q, 1JC,F = 285.0 Hz, CF3); 156.5 (C=N); 169.9 (C=O). 19F-NMR (CDCl3): –82.3
3
(d, JH,F = 3.3 Hz, CF3). HR-ESI-MS (MeOH+NaI): 219.03463 (calcd. 219.03518 for C6H7F3N2NaO2,
[M+Na]+).
3-Acetyl-2,3-dihydro-5-phenyl-2-trifluoromethyl-1,3,4-oxadiazole (5b). Solvent for chromatography:
hexane/AcOEt 4:1. Yield: 186 mg (72%). Colorless solid, mp 74–76 °C (pet. ether). IR (KBr): 2966w,
1683v (C=O), 1642m (C=N), 1418s, 1398s, 1288s, 1272s, 1187s, 1168vs, 1155vs, 1058m, 1029m, 864m,
856m, 771m, 717m, 688m, 644m. 1H-NMR (CDCl3): 2.39 (s, 3H, CH3); 6.54 (q, 3JH,F = 4.1 Hz, CH–CF3);
13
2
7.46–7.88 (m, 5 arom. H). C-NMR (CDCl3): 21.4 (CH3); 84.8 (q, JC,F = 38.1 Hz, CH-CF3); 120.9 (q,
1JC,F = 284.3 Hz, CF3); 123.1 (1 arom. C); 127.2, 128.9, 132.3 (5 arom. CH); 156.2 (C=N); 169.9 (C=O).
3
19F-NMR (CDCl3): –82.3 (d, JH,F = 3.3 Hz, CF3). HR-ESI-MS (MeOH/CH2Cl2+NaI): 281.05093 (calcd.
281.05083 for C11H9F3N2NaO, [M+Na]+).

HETEROCYCLES, Vol. 88, No. 1, 2014
397
3-Acetyl-2,3-dihydro-5-(pyridin-3-yl)-2-trifluoromethyl-1,3,4-oxadiazole (5d). Yield: 143 mg (55%).
Colorless solid, mp 80–82 °C (CH2Cl2/hexane). IR (KBr): 1691vs (C=O), 1644m (C=N), 1412s, 1262s,
1194s, 1158s, 1106m, 894m, 852m, 698m, 642m. 1H-NMR (CDCl3): 2.40 (s, 3H, CH3); 6.57 (q, 3JH,F = 4.1
Hz, CH-CF3); 7.41–7.43 (m, 1 arom. H); 8.13–8.15 (m, 1 arom. H); 8.77–8.78 (m, 1 arom. H); 9.10–9.11
(m, 1 arom. H). 13C-NMR (CDCl3): 21.3 (CH3); 85.0 (q, 2JC,F = 38.3 Hz, CH-CF3); 119.7 (q, 1JC,F = 283.7
Hz, CF3); 123.5 (1 arom. C); 123.5, 134.3, 148.3, 152.9 (4 arom. CH); 154.2 (C=N); 169.8 (C=O).
3
19F-NMR (CDCl3): –82.3 (d, JH,F = 3.4 Hz, CF3). ESI-MS: 258 ([M–1]+, 100); HR-ESI-MS
(MeOH/CH2Cl2+NaI): 282.04581 (calcd. 282.04608 for C10H8F3N3NaO2, [M+Na]+); 260.06363 (calcd.
260.06414 for C10H9F3N3O2, [M+H]+).
3-Acetyl-5-(furan-2-yl)-2,3-dihydro-2-trifluoromethyl-1,3,4-oxadiazole (5e). Yield: 161 mg (65%).
Colorless solid, mp 75–77 °C (pentane). IR (KBr): 2979m, 1682vs (C=O), 1646m (C=N), 1482s, 1391s,
1
1275s, 1165vs, 1011m, 854m, 766m, 708m, 646m, 593w. H-NMR (CDCl3): 2.38 (s, 3H, CH3); 6.51 (q,
3JH,F = 4.1 Hz, CH-CF3); 6.57–6.58 (m, 1 arom. H); 7.06–7.07 (m, 1 arom. H); 7.62-7.63 (m, 1 arom. H).
2
13C-NMR (CDCl3): 21.3 (CH3); 84.7 (q, JC,F = 39.0 Hz, CH-CF3); 112.1, 116.0, 146.6 (3 arom. CH);
121.0 (q, 1JC,F = 285.0 Hz, CF3); 138.4 (1 arom. C); 149.1 (C=N); 169.9 (C=O). 19F-NMR (CDCl3): –82.3
3
(d, JH,F = 3.4 Hz, CF3). HR-ESI-MS (MeOH+NaI): 271.02978 (calcd. 271.03010 for C9H7F3N2NaO3,
[M+Na]+).
3-Acetyl-2,3-dihydro-5-(thiophen-2-yl)-2-trifluoromethyl-1,3,4-oxadiazole (5f). Yield: 89 mg (34%).
Colorless solid, mp 90 °C (decomp., hexane). IR (KBr): 2967m, 1679vs (C=O), 1642m (C=N), 1445s,
1
1411s, 1265s, 1164vs, 1035m, 853m, 722m, 708m, 643m, 597w. H-NMR (CDCl3): 2.40 (s, 3H, CH3);
3
6.55 (q, JH,F = 4.1 Hz, CH-CF3); 7.16–7.18 (m, 1 arom. H); 7.58–7.59 (m, 1 arom. H); 7.68–7.69 (m, 1
13
2
1
arom. H). C-NMR (CDCl3): 21.3 (CH3); 84.8 (q, JC,F = 38.5 Hz, CH–CF3); 120.8 (q, JC,F = 283.5 Hz,
19
CF3); 123.6 (1 arom. C); 128.0, 131.0, 131.2 (3 arom. CH); 153.4 (C=N); 169.9 (C=O). F-NMR
3
(CDCl3): –82.3 (d, JH,F = 3.4 Hz, CF3). HR-ESI-MS (MeOH+NaI): 287.00700 (calcd. 287.00725 for
C9H7F3N2NaO2S, [M+Na]+).
X-Ray Crystal-Structure Determination of 3c, 4b, and 5b (Figures 1 and 2).13 All measurements for 3c
were made on a Nonius KappaCCD area detector diffractometer14 using graphite-monochromated MoK!
radiation (" = 0.71073 Å) and an Oxford Cryosystems Cryostream 700 cooler, and those for 4b and 5b on
an Agilent Technologies SuperNova area-detector diffractometer15 using MoK! (4b) or CuK" (5b; " =
1.54184 Å) radiation from a micro-focus X-ray source and an Oxford Instruments Cryojet XL cooler.
Data reduction was performed with HKL Denzo and Scalepack16 (3c) and CrysAlisPro15 (4b and 5b),

398
HETEROCYCLES, Vol. 88, No. 1, 2014
respectively. The intensities were corrected for Lorentz and polarization effects, and in the cases of 4b
and 5b, an empirical absorption correction using spherical harmonics15 was applied. Equivalent
reflections, other than the Friedel pairs for 3c, were merged. The data collection and refinement
parameters are given below. Views of the molecules are shown in Figures 1 and 2. The structures were
solved by direct methods using SHELXS97,17 which revealed the positions of all non-H-atoms. The CF3
group of 3c is disordered over two nearly equally occupied orientations. Two sets of positions were
defined for the F-atoms and the site occupation factor of the major conformation of the group refined to
0.502(6). Similarity restraints were applied to the chemically equivalent C–F and F…F distances, while
neighboring F-atoms from each conformation were restrained to have similar atomic displacement
parameters. The non-H-atoms were refined anisotropically. The amide H-atoms of 3c and 4b were placed
in the positions indicated by a difference electron density map and their positions were allowed to refine
together with individual isotropic displacement parameters. All remaining H-atoms in each structure were
placed in geometrically calculated positions and refined by using a riding model where each H-atom was
assigned a fixed isotropic displacement parameter with a value equal to 1.2U of its parent C-atom
eq
2
(1.5U for the methyl group of 5b). The refinement of each structure was carried out on F by using
eq
full-matrix least-squares procedures, which minimized the function #w(Fo2–Fc2)2. Corrections for
secondary extinction were applied. Neutral atom scattering factors for non-H-atoms were taken from ref.18,
and the scattering factors for H-atoms were taken from ref.19 Anomalous dispersion effects were included
in F ;20 the values for ƒ’ and ƒ” were those of ref.21 The values of the mass attenuation coefficients are
c
those of ref.22 All calculations were performed using the SHELXL97 program.17
Crystal data for 3c: Crystallized from hexane/CH2Cl2, C14H16F3N3O, M = 299.30, colorless, needle, crystal
dimensions 0.10 ! 0.13 ! 0.23 mm, orthorhombic, space group P212121, Z = 4, reflections for cell
determination 1957, 2$ range for cell determination 4–55°, a = 5.1299(1) Å, b = 15.0924(3) Å, c =
18.6500(4) Å, V = 1443.93(5) Å3, DX = 1.377 g#cm–3, µ(MoK!) = 0.115 mm–1, T = 160(1) K, % and & scans,
2$max = 55°, total reflections measured 22075, symmetry independent reflections 3296, reflections with I
> 2'(I) 2421, reflections used in refinement 3293, parameters refined 223, restraints 66, final R(F) (I >
2'(I) reflections) = 0.0509, wR(F2) (all data) = 0.1285 (w = ['2(Fo2) + (0.0568P)2 + 0.4765P]–1 where P =
(Fo2 + 2Fc2)/3, goodness of fit 1.018, secondary extinction coefficient 0.015(3), final (max/' = 0.001, ()
(max; min) = 0.47; –0.26 e Å–3.
Crystal data for 4b: Crystallized from Et2O/hexane, C11H9F3N2O2S, M = 290.26, colorless, prism, crystal
_
dimensions 0.10 ! 0.15 ! 0.22 mm, triclinic, space group P1, Z = 2, reflections for cell determination
8405, 2$ range for cell determination 4–61°, a = 8.7000(3) Å, b = 8.8660(3) Å, c = 8.8889(3) Å, ! =
63.283(4)°, * = 81.807(3)°, $ = 89.503(3)°, V = 605.00(4) Å3, DX = 1.593 g#cm–3, µ(MoK!) = 0.305 mm–1,

HETEROCYCLES, Vol. 88, No. 1, 2014
399
T = 160(1) K, & scans, 2$max = 60.9°, transmission factors (min; max) 0.934; 1.000, total reflections
measured 15137, symmetry independent reflections 3379, reflections with I > 2'(I) 2917, reflections used
in refinement 3379, parameters refined 177, restraints 0, final R(F) (I > 2'(I) reflections) = 0.0306,
wR(F2) (all data) = 0.0796 (w = ['2(Fo2) + (0.0346P)2 + 0.1802P]–1 where P = (Fo2 + 2Fc2)/3, goodness of
fit 1.052, secondary extinction coefficient 0.012(2), final (max/' = 0.001, () (max; min) = 0.36; –0.28 e
Å–3.
Crystal data for 5b: Crystallized from petroleum ether, C11H9F3N2O2, M = 258.20, colorless, prism, crystal
dimensions 0.12 ! 0.20 ! 0.25 mm, monoclinic, space group P21/n, Z = 4, reflections for cell
determination 6567, 2$ range for cell determination 10–149°, a = 8.88944(13) Å, b = 7.43167(12) Å, c =
17.7441(3) Å, * = 94.8117(16)°, V = 1168.11(3) Å3, DX = 1.468 g#cm–3, µ(CuK!) = 1.181 mm–1, T =
160(1) K, & scans, 2$max = 148.8°, transmission factors (min; max) 0.255; 1.000, total reflections
measured 11304, symmetry independent reflections 2338, reflections with I > 2'(I) 2163, reflections used
in refinement 2338, parameters refined 165, restraints 0, final R(F) (I > 2'(I) reflections) = 0.0309,
wR(F2) (all data) = 0.0843 (w = ['2(Fo2) + (0.0428P)2 + 0.3239P]–1 where P = (Fo2 + 2Fc2)/3, goodness of
fit 1.050, secondary extinction coefficient 0.0021(4), final (max/' = 0.001, () (max; min) = 0.23; –0.18 e
Å–3.
ACKNOWLEDGEMENTS
We thank the analytical services of our institute for NMR spectra and PD Dr. L. Bigler, University of
Zurich, for HR-ESI-MS. Skilful help by Mrs. Ma%gorzata Celeda in performing of some experiments is
acknowledged.
REFERENCES AND NOTES
1. Part of the planned Master Thesis of N.J., University of !ód".
2. a) H. Mimura, K. Kawada, T. Yamashita, T. Sakamoto, and Y. Kikugawa, J. Fluorine Chem., 2010,
131, 477; b) L. Caroccia, S. Fioravanti, L. Pellacani, C. Sadun, and P. A. Tardella, Tetrahedron,
2011, 67, 5375; c) A. Abouabdellah, J.-P. Begue, D. Bonnet-Delpon, and T. T. T. Nga, J. Org.
Chem., 1997, 62, 8826; d) Y. Gong and K. Kato, Tetrahedron: Asymmetry, 2001, 12, 2121; e) P.
Bravo, M. Giudetti, F. Viani, M. Zanda, A. Markowski, A. E. Sorochinski, I. V. Soloshonok, and V.
A. Soloshonok, Tetrahedron, 1998, 54, 12789; f) L. Caroccia, S. Fioravanti, L. Pellacania, and P. A.
Tardella, Synthesis, 2010, 4096.
3. A. A. Hassan and A. M. Shawky, J. Heterocycl. Chem., 2010, 47, 745.
4. a) G. Mlosto&, A. M. Pieczonka, A. Wróblewska, A. Linden, and H. Heimgartner, Heterocycles,
2012, 86, 343; b) A. M. Pieczonka, G. Mlosto&, and H. Heimgartner, Helv. Chim. Acta, 2012, 95,

400
HETEROCYCLES, Vol. 88, No. 1, 2014
404; c) G. Mlosto&, A. M. Pieczonka, A. Wróblewska, A. Linden, and H. Heimgartner, Tetrahedron:
Asymmetry, 2012, 23, 795; d) A. M. Pieczonka, K. Ciepielowski, Z. Cebulska, G. Mlosto&, A.
Linden, and H. Heimgartner, Helv. Chim. Acta, 2013, 96, 397.
5. a) K. H. Pilgram and R. D. Skiles, J. Org. Chem., 1976, 41, 3392; b) K. H. Pilgram and R. D. Skiles,
J. Org. Chem., 1982, 47, 3865; c) K. H. Pilgram and R. D. Skiles, J. Heterocycl. Chem., 1987, 24,
1265; d) Z.-L. Yuan, M. Shi, and Y. Wei, Eur. J. Org. Chem., 2010, 4088.
1
19
6. The H- and F-NMR spectra in CDCl3 showed only one set of signals. For this reason we believe
that the two forms observed in DMSO solution are rotamers.
7. C. K. Johnson, ORTEP II, Report ORNL-5138, Oak Ridge National Laboratory, Oak Ridge,
Tennessee, 1976.
8. J. Bernstein, R. E. Davis, L. Shimoni, and N.-L. Chang, Angew. Chem., 1995, 107, 1689; Angew.
Chem. Int. Ed. Engl., 1995, 34, 1555.
9. a) S. G. Küçükgüzel, E. E. Oruç, S. Rollas, F. Sahin, and A. Özbek, Eur. J. Med. Chem., 2002, 37,
197; b) M. Ishii, S. D. Jorge, A. A. De Oliveira, F. Palace-Berl, I. Y. Sonehara, K. F. Mesquita
Pasqualoto, and L. Costa Tavares, Bioorg. Med. Chem., 2011, 19, 6292; c) R. Yan, Z.-M. Zhang,
X.-Y. Fang, Y. Hu, and H.-L. Zhu, Bioorg. Med. Chem., 2012, 20, 1373.
10. a) S. Jaju, M. Palkar, V. Maddi, P. Ronad, S. Mamledesai, D. Satyanarayana, and M. Ghatole, Arch.
Pharm. Chem. Life Sci., 2009, 342, 723; b) A. S. El-Azab, and K. E. H. Eltahir, Bioorg. Med. Chem.
Lett., 2012, 22, 327; c) C. Nandagokula, B. Poojari, S. Vittal, S. Shenoy, P. Shetty, and A. Tangavela,
Med. Chem. Res., 2013, 22, 253.
11. a) J.-P. Bégué and D. Bonnet-Delpon, Bioorganic and Medicinal Chemistry of Fluorine, J. Wiley &
Sons, Inc. Hoboken, New Jersey, 2008; b) Fluorinated Heterocyclic Compounds: Synthesis,
Chemistry, and Applications, ed. by V. A. Petrov, J. Wiley & Sons, Inc. Hoboken, New Jersey,
2009; c) Fluorine in Heterocyclic Chemistry, ed. by V. G. Nenajdenko, Springer Verlag, Berlin,
2013.
12. a) B. Wang, S. Ke, B. Kishore, X. Xu, Z. Zou, and Z. Li, Synth. Commun., 2012, 42, 232; b) M. M.
Fahmy, R. R. Mohamed, and N. A. Mohamed, Molecules, 2012, 17, 7927; c) K. M. Khan, M. Z.-U.
Rasheed, S. Hayat, F. Kaukab, M. I. A.-R. Choudhary, Atta-ur-Rahman, and S. Perveen, Bioorg.
Med. Chem., 2003, 11, 1381; d) X. Chen, C. Liu, J. Wang, and Y. Li, J. Heterocycl. Chem., 2010, 47,
1225; e) G. Rai, A. Jadhav, L. Schultz, W. Leister, A. Simeonov, M. Anton, D. J. Maloney, V.
Kenyon, M. Armstrong, J. B. Jameson, E. Hoobler, and T. R. Holman, J. Med. Chem., 2010, 53,
7392.
13. CCDC-943622–943624 contain the supplementary crystallographic data for this paper. These data
can be obtained free of charge from the Cambridge Crystallographic Data Centre via

HETEROCYCLES, Vol. 88, No. 1, 2014
401
www.ccdc.cam.ac.uk/data_request/cif.
14. R. Hooft, KappaCCD Collect Software, Nonius BV, Delft, The Netherlands, 1999.
15. CrysAlisPro, Version 1.171.35.19, Agilent Technologies, Yarnton, Oxfordshire, England, 2011.
16. Z. Otwinowski and W. Minor, in ‘Methods in Enzymology’, Vol. 276, ‘Macromolecular
Crystallography’, Part A, ed. by C. W. Carter Jr. and R. M. Sweet, Academic Press, New York, 1997,
p. 307.
17. G. M. Sheldrick, Acta Crystallogr. Sect. A, 2008, 64, 112.
18. E. N. Maslen, A. G. Fox, and M. A. O'Keefe, in 'International Tables for Crystallography', ed. by A.
J. C. Wilson, Kluwer Academic Publishers, Dordrecht, 1992, Vol. C, Table 6.1.1.1, p. 477.
19. R. F. Stewart, E. R. Davidson, and W. T. Simpson, J. Chem. Phys., 1965, 42, 3175.
20. J. A. Ibers and W. C. Hamilton, Acta Crystallogr., 1964, 17, 781.
21. D. C. Creagh and W. J. McAuley, in 'International Tables for Crystallography', ed. by A. J. C.
Wilson, Kluwer Academic Publishers, Dordrecht, 1992, Vol. C, Table 4.2.6.8, p. 219.
22. D. C. Creagh and J. H. Hubbell, in 'International Tables for Crystallography', ed. by A. J. C. Wilson,
Kluwer Academic Publishers, Dordrecht, 1992, Vol. C, Table 4.2.4.3, p. 200.