1,2-Diaryl(3-pyridyl)ethanone oximes. Intermolecular hydrogen bonding networks revealed by X-ray diffraction

Article abstract of DOI:10.3390/molecules13020301

The synthesis of a set of 1-aryl-2-aryl(3-pyridyl)ethanones 1-5 and the corresponding ketoximes 6-9 is reported. Structural studies of oximes 6, 7 and 9 were performed in solution using ¹H-NMR and in the solid state by X-ray crystallography, providing evidence of H-bonding networks. The crystal packing was controlled by homomeric intermolecular oxime...oxime H-bond interactions for 6 and cooperative oxime...N(pyridyl) and CH/π interactions for 7 and 9.

Full text of DOI:10.3390/molecules13020301

Molecules 2008, 13, 301-318
molecules
ISSN 1420-3049
© 2008 by MDPI
www.mdpi.org/molecules
Full Paper
1,2-Diaryl(3-pyridyl)ethanone Oximes. Intermolecular
Hydrogen Bonding Networks Revealed by X-ray Diffraction
Ermitas Alcalde 1,*, Neus Mesquida 1,*, Carmen Alvarez-Rúa 2, Rosa Cuberes 3, Jordi Frigola 3
and Santiago García-Granda 2
1
Laboratori de Química Orgànica, Facultat de Farmàcia, Universitat de Barcelona, Avda. Joan XXIII
s/n, 08028 Barcelona, Spain
2
Departamento de Química Física y Analítica, Facultat de Química, Universidad de Oviedo, 33006
Oviedo, Spain
3
Laboratorios del Dr. Esteve, S.A., Avda. Mare de Déu de Montserrat, 221, 08041 Barcelona, Spain
* Authors to whom correspondence should be addressed; E-mail: ealcalde@ub.edu
Received: 30 December 2007; in revised form: 1 February 2008 / Accepted: 4 February 2008 /
Published: 7 February 2008
Abstract: The synthesis of a set of 1-aryl-2-aryl(3-pyridyl)ethanones 1-5 and the
corresponding ketoximes 6-9 is reported. Structural studies of oximes 6, 7 and 9 were
1
performed in solution using H-NMR and in the solid state by X-ray crystallography,
providing evidence of H-bonding networks. The crystal packing was controlled by
homomeric intermolecular oxime···oxime H-bond interactions for 6 and cooperative
oxime···N(pyridyl) and CH/π interactions for 7 and 9.
Keywords: Oximes, ethanones, hydrogen bonds, self-assembly, X-ray diffraction
crystallography
Introduction
1,2-Disubstituted ethanones are valuable synthetic intermediates for a broad array of bioactive
molecules, both natural and synthetic [1–3]. One relevant use of oximes I and ethanones II is in the
preparation of pharmaceutically useful vicinal diaryl(heteroaryl)-substituted heterocycles III (Scheme
1). For example, highly selective COX-2 inhibitors have been developed in which the heterocyclic

Molecules 2008, 13
302
core is an oxazole, isoxazole and pyridine, among others, i.e. Tilmacoxib [4a], Valdecoxib [4b] and
Etoricoxib [3,5].
In parallel, hydrogen bonds [6,7] are the main driving forces for oxime non-covalent interactions
and oxime functionality can be stereoelectronically adjusted for precise directed assembly of
homomeric intermolecular oxime···oxime and oxime···N-heterocycle molecular motifs [8–10].
Moreover, the CH/π hydrogen bonds [11] are weaker intermolecular hydrogen bond interactions that
modulate the crystal packing of molecules and their self-assembly.
Scheme 1.
Ar(Het)2
Ar(Het)2
HO
N
Ar(Het)1
O
Ar(Het)1
I
II
Ar(Het)2
Ar(Het)1
X
III
The present study examines several examples of 1-aryl-2-aryl(3-pyridyl)ethanones 1-5 and the
corresponding ketoximes 6-9 (Figure 1).
Figure 1.
X
X
SMe
F
1 X = O
2 X = O
6 X = N-OH
N
N
R6
X
X
SMe
SO2Me
5 X = O
9 X = N-OH
3 X = O
4 X = O
R6 = H
R6 = Me
7 X = N-OH R6 = H
8 X = N-OH R6 = Me

Molecules 2008, 13
303
Distinct methodologies for the preparation of diarylethanones II could lead to compounds 1 and 2,
whereas for 1-aryl-2-(3-pyridyl)ethanones 3-5, the synthetic protocols were limited by the presence of
a 3-pyridyl moiety. By coupling of acid chlorides with organozinc bromides in the presence of
CuCN/LiBr, compounds 1 and 2 were directly obtained, whereas ethanones 3-5 were prepared
following a modified two-step Horner-Wittig reaction protocol.
1
The structural properties of oximes 6-9 are discussed with the data obtained in solution by H-
NMR and in the solid state by X-ray crystallography of compounds 6, 7 and 9. Crystal packing was
mainly governed by hydrogen bond networks based on homomeric intermolecular oxime···oxime
interactions for 6. The oxime and pyridyl structural motifs present in oximes 7 and 9 driven their self-
assembly through intermolecular oxime···N-heterocycle and CH/π interactions.
Results and Discussion
Synthesis
Different synthetic protocols have been developed for syntheses of 1,2-diarylethanones [1,4,12]
and for 1-substituted-2-azinylethanones [1b] each of which has its own area of application. Moreover,
both the 2-aryl-1-(3-pyridyl)ethanones [Ar-CH2-CO-(3-Py)] [3,5] and their isomers [Ar-CO-CH2-(3-
Py)] [13] have received far less attention, probably due to the presence of the 3-pyridyl group which
may limit their synthetic accessibility. A widely used pathway for the preparation of ketones is the
coupling of acid halides with organometallic reagents and two alternative procedures were then
examined for the synthesis of ethanones 1 and 2, the best results were obtained with Cu(I)-mediated
coupling of organozinc reagents [14] and acid halides. As shown in Scheme 2, reaction of either acid
chloride 11 or 13 with the organozinc bromide 10 or 14 in the presence of CuCN/LiBr gave ethanones
1 and 2 in 59% and 68% yield, respectively. At the same time, diarylethanone 2 has been prepared by a
conventional Friedel-Crafts acylation reaction of thioanisole using phenylacetyl chloride in 75% yield
[12a].
Among several alternative protocols for 1,2-diaryl/heteroaryl ethanone synthesis, two reasonable
approaches to new ethanones 3-5 were examined, given that other methods appeared to be inefficient
or might be useless, due to the presence of the 3-pyridyl moiety (Scheme 3). Method A refers to the
reaction of Weinreb amides [15] with Grignard reagents and method B involves the Horner-Wittig
reaction [16], a general procedure for the synthesis of arylacetylpyridines [3,16b]. Since under
standard conditions [15], the preparation of the N-methoxy-N-methylamide 15 either from ester 16 or
acid 17 gave in low yield (33%), this alternative was then abandoned. In consequence, the Horner-
Wittig process appeared to be the method of choice to prepare the pyridylacetylarenes 3-5, and the
reaction was first tested for preparation of ethanone 3 because pyridylcarbaldehyde 20 was
commercially available. Reaction of arylcarbaldehyde 18 with aniline and diphenylphosphite gave the
corresponding N,P-acetal 19 in 98% yield and the coupling of 19 and pyridylcarbaldehyde 20 in the
presence of Cs2CO3 in THF/i-PrOH produced enamine followed by HCl 3N hydrolysis to give
ethanone 3 in 82% yield (Scheme 3). The best reaction conditions for method B were then applied to
the preparation of targeted pyridylacetylarenes 4 and 5, giving overall yields of 46% and 69%,
respectively.

Molecules 2008, 13
304
Scheme 2.
(1) (Ph3P)4Pd
(2) 10
F
COCl
42%
11
O
F
1
(1) CuCN/LiBr
(2) 11
ZnBr
59%
10
12
MeS
MeS
(1) SOCl2
CO2H
COCl
13
(2) Zn
(3) (Ph3P)4Pd
(4) PhCH2Br
29%
(1) CuCN/LiBr
(2) 13
O
ZnBr
68%
MeS
14
2
Scheme 3.
Method A
(1) Me(MeO)NH·HCl
(2) i-PrMgCl
CO2Et
33%
Me
N
N
16
OMe
O
(1) I-E.R. (OH¯ form)
(2) CDI
(3) Me(MeO)NH·HCl
N
15
CO2H
·HCl
17
33%
N

Molecules 2008, 13
305
Scheme 3. Cont.
Method B
(1)
CHO
R6
N
O
20 R6 = H
21 R6 = Me
N
R6
PhHN
P(OPh)2
CHO
PhNH2
(PhO)2P(O)H
(2) Cs2CO3
(3) 3N HCl
98%
O
SO2Me
SO2Me
19
SO2Me
18
3 R6 = H (82%)
4 R6 = Me(46%)
O
N
PhHN
P(OPh)2
(1) 20
(2) Cs2CO3
(3) 3N HCl
CHO
PhNH2
(PhO)2P(O)H
97%
71%
O
SMe
22
SMe
23
SMe
5
In accordance with standard protocol, oximes 6–9 were prepared from ethanones 2-5 in ≥ 81% yield
and standard crystallization in 96% EtOH produced crystals of 6, 7 and 9 suitable for X-ray diffraction
analysis (see below).
Scheme 4.
X
R6
X
R6
NH2OH·HCl
NaOAc·3H2O
HO
N
(81-87%)
O
R4
R4
2-5
6-9
2, 6 X = CH R6 = H R4 = SMe
3, 7 X = N R6 = H R4 = SO2Me
4, 8 X = N R6 = Me R4 = SO2Me
5, 9 X = N R6 = H R4 = SMe

Molecules 2008, 13
306
Structural Studies
The molecular structures of the new compounds were identified from their spectroscopic data and
the structural properties of ketoximes 6-9 were examined in solution by 1H-NMR and in the solid state
by X-ray crystallography (only ketoximes 6, 7 and 9).
The IR spectra (KBr) of ethanones 1-5 showed the characteristic carbonyl band in the range of
1694-1681 cm-1 and the νC=N absorption of ketoximes 6-9 in the 1597-1588 cm-1 range. Broad
absorption at 2703 cm-1 (νOH) was shown by ketoxime 6, while the ketoximes 7-9 showed broad
1
13
absorption bands in the range of 2805-2700 cm-1 (νOH). Both the H- and C-NMR data permitted
1
unambiguous assignments with the aid of HMQC. In the H-NMR spectra of oximes 6, 7 and 9, the
characteristic δH chemical shift of the oxime proton was similar to those observed for several oxime-
substituted pyridines in DMSO-d6 [9,17] and the δNOH values appeared in the range of 12.02 to 11.38
ppm in DMSO-d6 and 9.65 to 9.07 ppm in CD3CN (Table 1).
1
Table 1. Significant H-NMR chemical shifts of ketoximes 6, 7 and 9 in CD3CN and
DMSO-d6 (200 MHz) at 298 K.
Compd. Solvent
Conc. (mM) C=NO-H 2H-Py 6H-Py –CH2– –CH3
6
7
9
CD3CN
9.33-103.62
9.07
–
–
4.15
4.10a
4.22
4.22a
4.15
4.12a
2.46
2.43
3.04
3.20
2.46
DMSO-d6
CD3CN
10.88-103.62 11.38a
–
–
10.36b
45.92
11.87b
9.65
12.02a
8.47
8.47
8.46
8.44
8.39
8.37
8.36
8.33
c
DMSO-d6
CD3CN
9.20
DMSO-d6
10.84-103.74 11.51a
2.44
a NOESY experiment at 400 MHz. At higher concentrations the compound was insoluble. At
b
c
400 MHz.
Figure 2 shows the molecular structures of ketoximes 6, 7 and 9 and the molecular shape was
similar for oximes 6 and 9. In all cases, the oxime functionality [8-10] bears the common
antiperiplanar conformation of the thermodynamically preferred E-isomer. Particularly relevant is
their crystal packing, which is governed by a robust hydrogen bonding network. The nature of the ring
fragments modulated the intermolecular H-bond interactions. Each of oximes 6, 7 and 9 adopted a
crystal structure [18] in which the molecular units were linked by either H-bond intermolecular
oxime···oxime for 6 or oxime···N(py) molecular motifs for 7 and 9.
2
Compound 6 formed a head-to-head R2 (6) motif, which is the characteristic six-member ring
arrangement in oximes, resulting in classical oxime dimers, whereas 9 formed a head-to-tail
oxime···N(py) motif leading to non-classical oxime dimers. Similar to 9, the crystal structure of oxime
7 formed an oxime···N(py) motif that generated an infinite chain.
The crystal packing arrangements varied for 6, 7 and 9, depending on the rings attached to the
ethanone oxime either 1,2-diaryl for 6 or 1-aryl-2-(3-pyridyl) for 7 and 9 (Figure 3). Oxime 6 forms
2
zig-zag hydrogen-bonded layers propagated via R2 (6) O-H···N(oxime) arrangement. The crystal
structure of 9 contains dimers assembled through a head-to-tail O-H···N(py) hydrogen bond. In 7, the
molecules formed infinite layers through O-H···N(py) hydrogen bond.

Molecules 2008, 13
Figure 2. Oximes 6, 7 and 9. Molecular structures and thermal ellipsoids (50%
307
probability level). Intermolecular hydrogen bond oxime···oxime for 6 and oxime···N(py)
for 7 and 9.
6
9
7
Figure 3. Crystal structure arrangements. Oxime 6: Zig-zag layers formed by isolated
dimers (viewed down the crystallographic b axis). Oxime 9: Packing of dimers, viewed
down the crystallographic b axis. Oxime 7: Infinite chains, viewed down the
crystallographic a axis (left) and b axis (right).
6
9

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308
Figure 3. Cont.
7
Significant intermolecular non-covalent interaction data are listed in Table 2. The atom-numbering
system used for the X-ray data is not the same as the IUPAC numbering system. The selected weak
intermolecular interactions show that the main network is formed via O-H···N hydrogen bond and the
acceptor centre is either the oxime for 6 or the pyridyl moiety for 7 and 9, with a distance range of
1.828-1.979 Å (H···A), 2.704-2.796 Å (O···A) and with the O-H···A angle varied from 172.90° to
158.22°. The evidence for CH/π hydrogen bonds in 7 and 9 is considerable (Figure 4).
Table 2. Significant H-bonding interactions for ketoximes 6, 7 and 9, and CH···π
interactions for 7 and 9, distances (Å) and angles (°).a-c
Compd. D–H
d(D–H) d(H···A)
<DHA
d(D···A)
A
6
6
9
9
7
7
9
9
O8–H8
0.860
1.979
2.306
1.828
2.567
1.818
[1]
[2]
[3]
[4]
[5]
158.22 [1] 2.796
102.83 [2] 2.679
160.32 [3] 2.704
158.38 [4] 3.497
172.90 [5] 2.741
164.86 [6] 3.577
176.20 [7] 3.534
[1] N8
[2] O8
[3] N12
[4] N8
[5] N12
[6] Fa
[7] Fb
[8] Fb
C9–H9B 0.944
O8–H8
C1–H1B 0.980
O8–H8 0.927
0.911
C1–H1C 0.980
C13–H13 0.943
C1–H1C 0.980
2.66(2) [6]
2.62(2) [7]
2.63(2) [8]
144.14 [8] 3.463
aCCDC deposition numbers 6: 635926; 7: 635927; 9: 635928. Equivalent positions: [1] –x, –y,
z+2; [2] x, y, z; [3] –x, –y, –z+1; [4] x, –y–½, +z–½; [5] x, –y–½, +z+½; [6] –x +1, y+½, -z+½ ;
[7] –x , y+½, -z+½ ; [8] –x +1, y-½, -z+½ cFa and Fb labels –centroid and ring in parenthesis: Fa
(Pyridine) and Fb (Arene). Fa: C10-C11-N12-C13-C14-C15 and Fb: C2-C3-C4-C5-C6-C7.
b
Oximes 7 and 9 showed a different pattern of C-H/π hydrogen bond, consistent with the acidity of
the hydrogen bond donor, the soft acid CH group. Thus, the p-(methylsulfonyl)aryl CH of oxime 7
interacted with the face of the π-deficient heteroaromatic moiety (3-pyridyl) of the adjacent molecule
and conversely, the α-CH of pyridyl moiety of oxime 9 pointed towards the p-(methylthio)aryl π-
excessive aromatic ring (Figure 4). For oxime 7, the C-H···centroid(py) distance is 2.66 Å with an
angle of 164.86° and oxime 9 has the C-H/π contact the C-H···centroid(aryl) distance of 2.62 Å and an
angle of 176.20°.

Molecules 2008, 13
Figure 4. C-H/π Hydrogen bonds. Oxime 7: (methyl)C-H···centroid(py) [2.66 Å,
309
164.86°]. Oxime 9: (py)C-Hα···centroid(aryl) [2.62 Å, 176.20°].
N
N
HO
HO
N
N
SO2Me
S-Me
7
9
7
9
The present crystallographic results show that the homomeric O-H···N(pyridyl) hydrogen bond
[8a,b,f] is the driving force that modulates and controls the assembly of compounds containing both
oxime and pyridyl structural motifs [8,9]. In crystal structures of oximes 7 and 9, O-H···N(py) and
CH/π hydrogen bonds cooperated in bringing the whole molecule into infinite layers for 7 and non-
classical packing of dimers for 9.
Conclusions
Depending on the aryl/3-pyridyl moieties present in 1,2-diaryl/heteroarylethanones 1-5, two
synthetic approaches were used for their preparation. For cyclohexy/arylethanone 1 and diarylethanone
2, the Cu(I)-mediated coupling reaction between the corresponding organozinc reagent and acid
chloride was performed in ≥ 59% yield. The selected route for pyridylacetylarenes 3-5 was the Horner-
Wittig reaction. We identified the optimal conditions for the preparation of ethanone 3 and the best
experiment gave 80% overall yield, whereas the yield was reduced to 45% for 4 and 69% for 5.
Moreover, ethanones 2-5 were transformed to their ketoximes 6–9 in ≥ 81% yield. The structural
1
properties of oximes 6–9 were examined in solution by H-NMR and in the solid-state by X-ray
crystallography. The crystal structures of oximes 6, 7 and 9 showed that the dominating hydrogen
bond network was head-to-head OH···N(oxime) for 6 and, that both intermolecular head-to-tail O-
H···N(py) and CH/π interactions modulated and controlled the self-assembly of molecules of oximes 7
and 9.

Molecules 2008, 13
Experimental
General
310
(Cyclohexylmethyl)zinc bromide (10) [19] and benzyl zinc bromide (14) were prepared as
described by Rieke et al. [20]. Both are also currently commercially available. 3-Fluorobenzoyl
chloride (11), 4-(methylthio)benzoic acid (12), ethyl pyridin-3-ylacetate (16), pyridin-3-ylacetic acid
hydrochloride (17), 4-(methylsulfonyl)benzaldehyde (18), 3-pyridinecarboxaldehyde (20) and 4-
(methylthio)benzaldehyde (22) are commercially available. 6-Methyl-3-pyridinecarboxaldehyde (21)
was prepared, as described elsewere [3]. Melting point: Gallenkamp Melting Point Apparatus
MPD350.BM2.5 equipped with a digital thermometer. IR (KBr disks or thin film): Nicolet 205 FT or
Perkin Elmer 1430 spectrophotometers. 1H-NMR: Varian Gemini 200 (200 MHz), Varian Gemini 300
(300 MHz) and Mercury 400 (400 MHz) spectrometers at 298 °K. Chemical shifts were referenced and
expressed in ppm (δ) relative to the central peak of DMSO-d6 (2.49 ppm) and TMS for chloroform-d.
13C-NMR: Varian Gemini 200 (50.3 MHz) and Varian Gemini 300 (75.4 MHz) spectrometers at 298
°K. Chemical shifts were referenced and expressed in ppm (δ) relative to the central peak of DMSO-d6
(39.7 ppm) and chloroform-d (77.0 ppm). HMQC experiments: Unity-300 spectrometer. NOESY
experiments: Mercury 400 spectrometer (400 MHz). ESI-HRMS: Mass spectra were obtained using an
Agilent LC/MSD-TOF spectrometer. TLC: Merck precoated silica gel 60 F254 plates using UV light
(254 nm) as a viewing agent and/or H2PtCl2 3% aq. / KI 10% aq. (1:1) or KMnO4 ethanolic solution.
Column chromatography was performed on silica gel 60 ACC 35-70 μm Chromagel (SDS).
Synthesis of 1-aryl-2-(aryl/alkyl)ethanones 1 and 2: 2-Cyclohexyl-1-(3-fluorophenyl)ethanone (1)
Method A: To a solution of 3-fluorobenzoyl chloride (11, 1.99 g, 12.6 mmol) in dry 1,2-
dimethoxyethane (DME, 25 mL) was added Pd(Ph3P)4 (728 mg, 0.63 mmol) under argon atmosphere
and was cooled to –50 °C. To this mixture was added a solution of (cyclohexylmethyl)zinc bromide 10
(3.05 g, 12.6 mmol) in dry THF (25 mL). The reaction mixture was stirred for 4 h with cooling and
then for 12 h at room temperature. The mixture was then worked up by pouring into a saturated NH4Cl
aqueous solution (100 mL) and extracting with diethyl ether (3 × 100 mL). The combined organic
layers were dried over anhydrous Na2SO4, filtered and evaporated. The resultant crude product was
purified by column chromatography on silica gel (hexane/ethyl acetate, 95:5) to give ethanone 1 (1.16
g, 42%) as a yellow oil. IR (thin film): ν(C=O) 1694, ν(C–F) 1440 cm–1; 1H-NMR (200 MHz, DMSO-
d6): δ 0.90-1.30 (m, 5H), 1.60-1.66 (m, 5H), 1.70-1.85 (m, 1H), 2.86 (d, J=7.0 Hz, 2H), 7.41-7.61 (m,
13
2H), 7.65-7.72 (m, 1H), 7.77-7.81 (m 1H) ppm; C-NMR (50.3 MHz, DMSO-d6): δ 25.7-25.9 (3 ×
CH2), 32.6 (CH2), 33.9 (CH), 45.5 (CH2), 114.3 (d, JC-F=21.9 Hz, CH), 119.9 (d, JC-F=21.5 Hz, CH),
124.2 (d, JC-F=2.8 Hz, CH), 130.9 (d, JC-F=7.8 Hz, CH), 139.2 (d, JC-F=6.0 Hz, C), 162.2 (d, JC-F=245.0
Hz, CH), 198.6 (C=O) ppm; ESI-HRMS calcd for C14H18OF [M+H]+ 221.1336; found 221.1343.
Method B: To a suspension of CuCN (448 mg, 5 mmol) and LiBr (435 mg, 5.0 mmol) in dry DME
(50 mL) at –45 °C was added a solution of (cyclohexylmethyl)zinc bromide (10, 6.06 g, 25.0 mmol) in
dry THF (50 mL) under argon atmosphere. 3-Fluorobenzoyl chloride (11, 3.96 g, 25 mmol) was added
neat, and the mixture was warmed slowly to room temperature over 4 h. The reaction mixture was

Molecules 2008, 13
311
quenched with 3 M HCl (200 mL) and extracted with diethyl ether (3 × 100 mL). The combined
organic layers were washed with water (100 mL), dried over Na2SO4, and concentrated. Ethanone 1
(3.24 g, 59%) was isolated from the crude reaction mixture by column chromatography (hexane/ethyl
acetate, 95:5) as a yellow oil.
1-[4-(Methylthio)phenyl]-2-phenylethanone (2)
Method A: A mixture of SOCl2 (10 mL, 137.43 mmol) and 4-(methylthio)benzoic acid (12, 4 g,
23.78 mmol) was stirred at reflux temperature for 1 h. The reaction mixture was concentrated under
reduced pressure to afford 4-(methylthio)benzoyl chloride (13). The resulting brown solid, zinc (2.13
g, 32.58 mmol) and Pd(Ph3P)4 (1.37 g, 1.19 mmol) were taken into dry DME (75 mL) under argon
atmosphere. To this mixture was added a solution of benzyl bromide (2.97 mL, 24.97 mmol) in dry
DME (25 mL) at room temperature. After 2.5 h, the mixture was filtered through Celite, the liquid
filtrates were evaporated, dissolved with CH2Cl2 (200 mL), washed with water (100 mL) and brine
(100 mL), dried over anhydrous Na2SO4 and evaporated to dryness. The resultant crude product was
chromatographed on silica gel (hexane/ethyl acetate, 75:25) to give ethanone 2 (1.65 g, 29%) as a
1
yellow solid. Mp 105-6 °C; IR (KBr): ν(C=O) 1681, ν(C–S) 704 cm–1; H-NMR (300 MHz, DMSO-
d6): δ 2.51 (s, 3H), 4.32 (s, 2H), 7.20-7.32 (m, 5H), 7.34 (d, J=8.4 Hz, 2H), 7.95 (d, J=8.4 Hz, 2H)
13
ppm; C-NMR (75.4 MHz, DMSO-d6): δ 14.6 (CH3), 45.2 (CH2), 125.6 (CH), 127.1 (CH), 129.0
(CH), 129.6 (CH), 130.3 (CH), 133.1, 136.0, 146.3, 197.3 (C=O) ppm; EI-MS m/z (%): 242 [M+·] (5),
151 [M+·–91] (100).
Method B: A mixture of SOCl2 (20 mL, 274.86 mmol) and 4-(methylthio)benzoic acid (12, 4.2 g,
25.00 mmol) was stirred at reflux temperature for 1.5 h. The reaction mixture was concentrated under
reduced pressure to afford 4-(methylthio)benzoyl chloride (13). To a suspension of CuCN (448 mg, 5
mmol) and LiBr (435 mg, 5 mmol) in dry DME (50 mL) at –60 °C was added a solution of benzylzinc
bromide 14 (5.91 g, 25 mmol) in dry THF (50 mL) under argon atmosphere. A solution of the 4-
(methylthio)benzoyl chloride (13) in dry DME (20 mL) was added and the mixture was warmed
slowly to room temperature over 4 h. The reaction mixture was quenched with 3 M HCl (200 mL) and
extracted with diethyl ether (3 × 100 mL), and the combined organic layers were washed with water
(100 mL), dried over Na2SO4, and concentrated. Ethanone 2 (4.12 g, 68%) was isolated from the crude
reaction mixture by column chromatography (hexane/ethyl acetate, 85:15) as a yellow solid.
N-Methoxy-N-methyl-2-pyridin-3-ylacetamide (15)
Method A: Ethyl pyridin-3-ylacetate (16, 1 mL, 6.57 mmol) and Me(MeO)NH·HCl (1.29g, 13.14
mmol) were stirred in dry THF (25 mL) cooled to –10 °C under argon. A solution of i-PrMgCl in THF
(13.2 mL, 2.0 M) was added and the mixture was warmed slowly to room temperature over 12 h. The
reaction mixture was quenched with 20% aqueous NH4Cl. The product was extracted with EtOAc (2 ×
50 mL) and the organic solution was dried over anhydrous Na2SO4 and concentrated. Chromatographic
purification using CH2Cl2:MeOH (95:5) as the eluent afford amide 15 as a brown residue (yield
33%).1H-NMR (200 MHz, CDCl3): δ 3.21 (s, 3H), 3.69 (s, 3H), 3.78 (s, 2H), 7.25-7.29 (m, 1H), 7.60-
7.70 (m, 1H), 8.50-8.53 (m, 2H) ppm.

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Method B: A solution of pyridin-3-ylacetic acid hydrochloride (17, 1 g, 5.76 mmol) in 96% ethanol
(50 mL) was passed through a column packed with a strongly basic anion-exchange (Amberlite IRA
401, hydroxide form). The eluates were concentrated to dryness to afford pyridin-3-ylacetic acid as a
white solid. To a solution of the former solid in dry DMF/CH3CN (1:19, 50 mL) was added CDI (1.12
g, 6.91 mmol) and the solution was stirred 1.5 h, and Me(MeO)NH·HCl (0.68 g, 6.91 mmol) was
added. After 12 h at room temperature, the reaction mixture was concentrated. The resulting residue
was dissolved with EtOAc (200 mL), washed with brine (100 mL) and water (2 × 100 mL), dried over
anhydrous Na2SO4 and evaporated to dryness to give the amide 15 as a brown residue (yield 33%).
Diphenyl {anilino[4-(methylsulfonyl)phenyl]methyl}phosphonate (19)
4-(Methylsulfonyl)benzaldehyde (18, 4 g, 21.71 mmol) was dissolved in isopropyl acetate (100
mL) and stirred at room temperature. Aniline (2.38 mL, 26.05 mmol) was added in one portion
followed by the addition of diphenylphosphite (6.68 mL, 34.74 mmol) in one portion. The resulting
slurry was stirred 12 h at room temperature, filtered and washed with i-PrOH to give N,P-acetal 19 as a
off-white solid (yield 98%). Mp 160-1 °C; IR (KBr): ν(NH) 3286; ν(SO2) 1307, 1150; ν(P=O) 1262
1
cm–1; H-NMR (200 MHz, CDCl3): δ 3.03 (s, 3H), 5.22 (d, J=26 Hz, 1H), 6.58-7.33 (m, 10H), 7.76-
7.91 (m, 4H) ppm; 13C-NMR (50.3 MHz, CDCl3): δ 44.7 (CH3), 56.0 (d, J=151 Hz, CH), 114.0 (CH),
119.6 (CH), 120.4 (dd, J=4, 17 Hz, CH), 125.8 (d, J=5.5 Hz, CH), 128.0 (CH), 129.1 (d, J=5.5 Hz,
CH), 129.6 (CH), 130.0 (CH), 142.0 ppm.
Diphenyl {anilino[4-(methylthio)phenyl]methyl}phosphonate (23)
4-(Methylthio)benzaldehyde (22, 5 g, 32.85 mmol) was dissolved in i-PrOH (150 mL) and stirred at
room temperature. Aniline (3.60 mL, 39.42 mmol) was added in one portion followed by the addition
of diphenylphosphite (10.10 mL, 52.56 mmol) in one portion. The resulting slurry was stirred 4 h at
room temperature, filtered and washed with i-PrOH to give N,P-acetal 23 as a off-white solid (yield
1
97%). Mp 134-5 °C; IR (KBr): ν(NH) 3329; ν(P=O) 1248 cm–1; H-NMR (200 MHz, CDCl3): δ 2.45
13
(s, 3H), 5.10 (d, J=24 Hz, 1H), 6.61-6.92 (m, 3H), 7.06-7.26 (m, 7H), 7.43-7.49 (m, 1H) ppm; C-
NMR (50.3 MHz, CDCl3): δ 15.7 (CH3), 55.6 (d, J=156 Hz, CH), 114.0 (CH), 118.9 (CH), 120.4 (dd,
J=4, 16 Hz, CH), 125.3 (d, J=7.8 Hz, CH), 12.6 (d, J=2.8 Hz, CH), 128.5 (d, J=5.9 Hz, CH), 129.2
(CH), 1º29,7 (d, J=3.2 Hz, CH), 131.3, 138.7, 145.7 (d, J=15 Hz) ppm.
Synthesis of 1-aryl-2-(3-pyridyl)ethanones 3–5. General procedure
N,P-acetal 19 or 23 (1 equiv) and 3-pyridinecarboxaldehyde 20 or 21 (1.1 equiv) were dissolved in
a 4/1 mixture of THF/i-PrOH. Anhydrous Cs2CO3 (1.3 equiv) was added in one portion and the
reaction was stirred for 16 h at room temperature under argon atmosphere. Enamine intermediates
were hydrolyzed by the addition of 3N aqueous HCl (3 equiv). After 3 h at room temperature, the
reaction mixture was diluted with 5% aqueous NaOH (to pH 7-8) and extracted with EtOAc. The
combined organic layers were washed with brine and concentrated. The ketopyridines 3-5 were

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isolated from the crude reaction mixture by column chromatography using EtOAc/MeOH as the
eluent.
1-[4-(Methylsulfonyl)phenyl]-2-pyridin-3-ylethanone (3). The above procedure was followed using
N,P-acetal 19 (1g, 2.09 mmol), 3-pyridinecarboxaldehyde 20 (0.22 mL, 2.30 mmol) and Cs2CO3 (0.89
g, 2.72 mmol) in a mixture of dry THF/i-PrOH (8/2 mL). The product was obtained as a white solid;
1
yield 82%. Mp 164-5 °C; IR (KBr): ν(C=O) 1687, ν(SO2) 1292, 1146 cm–1; H-NMR (300 MHz,
CDCl3): δ 3.10 (s, 3H), 4.36 (s, 2H), 7.30-7.38 (m, 1H), 7.60-7.65 (m, 1H), 8.08 (d, J=8.7 Hz, 2H),
13
8.20 (d, J=8.4 Hz, 2H), 8.53-8.60 (m, 2H) ppm; C-NMR (75.4 MHz, CDCl3): δ 42.8 (CH2), 44.3
(CH3), 123.6 (CH), 127.9 (CH), 129.2 (CH), 137.2 (CH), 140.0, 144.5, 148.5 (CH), 150.3 (CH), 195.1
(C=O) ppm; ESI-HRMS: calcd for C14H14NO3S [M+H]+ 276.0688; found 276.0684.
2-(6-Methylpyridin-3-yl)-1-[4-(methylsulfonyl)phenyl]ethanone (4). The above procedure was
followed using N,P-acetal 19 (0.75 g, 1.56 mmol), 6-methyl-3-pyridinecarboxaldehyde 21 (0.21 g,
1.73 mmol) and Cs2CO3 (0.66 g, 2.02 mmol) in a mixture of dry THF/i-PrOH (8/2 mL). The product
was obtained as a white solid; yield 46%. Mp 150-1 °C; IR (KBr): ν(C=O) 1689, ν(SO2) 1292, 1144
1
cm–1; H-NMR (200 MHz, CDCl3): δ 2.56 (s, 3H), 3.09 (s, 3H), 4.31 (s, 2H), 7.16 (d, J=7.6 Hz, 1H),
7.45-7.55 (m, 1H), 8.07 (d, J=8.8 Hz, 2H), 8.19 (d, J=8.8 Hz, 2H), 8.39 (s, 1H) ppm; 13C-NMR (50.3
MHz, CDCl3): δ 24.1 (CH3), 42.5 (CH2), 44.3 (CH3), 123.2 (CH), 126.0, 127.9 (CH), 129.2 (CH),
137.5 (CH), 140.1, 144.3, 149.5 (CH), 157.3, 195.5 (C=O) ppm. ESI-HRMS: calcd for C15H16NO3S
[M+H]+ 290.0845; found 290.0841.
1-[4-(Methylthio)phenyl]-2-pyridin-3-ylethanone (5). The above procedure was followed using N,P-
acetal 23 (3 g, 6.7 mmol), 3-pyridinecarboxaldehyde 20 (0.7 mL, 7.37 mmol) and Cs2CO3 (2.8 g, 8.71
mmol) in a mixture of dry THF/i-PrOH (20/5 mL). The product was obtained as a white solid; yield
71%. Mp 89-90 °C; IR (KBr): ν(C=O) 1678, ν(C–S) 717 cm–1; 1H-NMR (200 MHz, CDCl3): δ 2.53 (s,
3H), 4.26 (s, 2H), 7.26-7.30 (m, 3H), 7.55-7.65 (m, 1H), 7.91-7.95 (m, 2H), 8.52-8.53 (m, 2H) ppm;
13C-NMR (50.3 MHz, CDCl3): δ 14.8 (CH3), 42.1 (CH2), 123.4 (CH), 125.0 (CH), 128.8 (CH), 132.3,
137.2 (CH), 146.6, 148.1 (CH), 150.4 (CH), 195.3 (C=O) ppm; ESI-HRMS: calcd for C14H14NOS
[M+H]+ 244.0790; found 244.0785.
Syntheis of ketoximes 6–9. General procedure
A solution of ethanones 2, 3, 4 or 5 (1 equiv) in 30% aqueous ethanol was treated with
hydroxylamine hydrochloride (2 equiv) and NaOAc·3H2O (2 equiv). The resultanting solution was
heated to reflux for 2-4 h. The reaction mixture was diluted with 30% aqueous EtOH and allowed to
cool to room temperature. The solid obtained was isolated by filtration.
1-[4-(Methylthio)phenyl]-2-phenylethanone oxime (6). The above procedure was followed using
ethanone 2 (1.00 g, 4.13 mmol), NH2OH·HCl (0.57 g, 8.26 mmol) and NaOAc·3H2O (1.12 g, 8.26
mmol) in 30% aqueous EtOH (26 mL and 10 mL). The product was obtained as a white solid; yield
1
87%. Mp 132-3 °C; IR (KBr): ν(OH) 3239, ν(C=N) 1592 cm-1; H-NMR (200 MHz, DMSO-d6): δ

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13
2.43 (s, 3H), 4.10 (s, 2H), 7.16-7.21 (m, 7H), 7.58 (d, J=8.4 Hz, 2H), 11.38 (s, 1H) ppm; C-NMR
(75.4 MHz, CDCl3): δ 15.3 (CH3), 32.0 (CH2), 125.9 (CH), 126.3 (CH), 126.7 (CH), 128.4 (CH),
128.5 (CH), 131.9, 136.3, 140.2, 156.8 (C=N) ppm; ESI-HRMS: calcd for C15H16NOS [M+H]+
258.0947; found 258.0940.
1-[4-(Methylsulfonyl)phenyl]-2-pyridin-3-ylethanone oxime (7). The above procedure was followed
using ethanone 3 (0.55 g, 2.00 mmol), NH2OH·HCl (0.28 g, 4.00 mmol) and NaOAc·3H2O (0.54 g,
4.00 mmol) in 30% aqueous EtOH (16 mL and 14.5 mL). The product was obtained as a white solid;
1
yield 86%. Mp 187-8 °C. IR (KBr): ν(OH) 2703, ν(C=N) 1597, ν(SO2) 1300, 1146 cm-1. H NMR
(400 MHz, DMSO-d6): δ 3.20 (s, 3H), 4.22 (s, 2H), 7.27-7.30 (m, 1H), 7.56-7.58 (m, 1H), 7.88-7.96
(m, 4H), 8.37-8.38 (m, 1H), 8.47 (s, 1H), 12.03 (s, 1H) ppm. 13C (50.3 MHz, DMSO-d6): δ 27.7 (CH2),
43.4 (CH3), 123.7 (CH), 126.6 (CH), 127.2 (CH), 132.5, 135.7 (CH), 140.0, 136.3, 140.7, 147.4 (CH),
149.5 (CH), 153.3 (C=N) ppm. ESI-HRMS: calcd for C14H15N2O3S [M+H]+ 291.0798; found
291.0804.
2-(6-Methylpyridin-3-yl)-1-[4-(methylsulfonyl)phenyl]ethanone oxime (8). The above procedure was
followed using ethanone 4 (0.20 g, 0.69 mmol), NH2OH·HCl (0.10 g, 1.38 mmol) and NaOAc·3H2O
(0.19 g, 1.38 mmol) in 30% aqueous EtOH (8 mL and 10 mL). The product was obtained as a white
solid; yield 81%. Mp 223-4 °C; IR (KBr): ν(OH) 2805-2730, ν(C=N) 1590, ν(SO2) 1312, 1151 cm-1;
1H-NMR (200 MHz, DMSO-d6): δ 2.35 (s, 3H), 3.19 (s, 3H), 4.15 (s, 2H), 7.09-7.13 (m, 1H), 7.38-
7.45 (m, 1H), 7.86 -7.91 (m, 4H), 8.32 (s, 1H), 12.05 (s, 1H) ppm; 13C-NMR (75.4 MHz, DMSO-d6): δ
23.5 (CH3), 27.3 (CH2), 43.4 (CH3), 122.9 (CH), 126.7 (CH), 127.2 (CH), 129.3, 136.1 (CH), 140.1,
140.7, 148.8 (CH), 153.5 (C=N), 155.7 ppm; ESI-HRMS: calcd for C15H17N2O3S [M+H]+ 305.0954;
found 305.0950.
1-[4-(Methylthio)phenyl]-2-pyridin-3-ylethanone oxime (9). The above procedure was followed using
ethanone 5 (0.90 g, 3.72 mmol), NH2OH·HCl (0.52 g, 7.44 mmol) and NaOAc·3H2O (1.00 g, 7.44
mmol) in 30% aqueous EtOH (33 mL and 30 mL). The product was obtained as a white solid; yield
1
85%. Mp 144-5 °C; IR (KBr): ν(OH) 3805-2730, ν(C=N) 1588, ν(C–S) 706 cm-1; H-NMR (200
MHz, DMSO-d6): δ 2.44 (s, 3H), 4.12 (s, 2H), 7.18-7.28 (m, 3H), 7.51-7.63 (m, 3H), 8.34 (d, J=4.8
Hz, 1H), 8.44 (s, 1H), 11.51 (s, 1H) ppm; 13C-NMR (75.4 MHz, DMSO-d6): δ 14.3 (CH3), 27.7 (CH2),
123.6 (CH), 125.5 (CH), 126.4 (CH), 131.7, 133.0, 135.8 (CH), 139.3, 147.3 (CH), 149.6 (CH), 153.7
(C=N) ppm; ESI-HRMS: calcd for C14H15N2OS [M+H]+ 259.0900; found 259.0896.
Single-crystal X-ray determination of ketoximes 6, 7 and 9
CCDC 635926 (compound 6), 635927 (compound 7) and 635928 (compound 9) contain the
supplementary crystallographic data for this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/conts/retrieving.html (or from the CCDC, 12 Union Road, Cambridge CB2 1EZ,
UK; fax: +44 1223 336033; e-mail: deposit@ccdc.cam.ac.uk).
Data collections for compounds 6, 7 and 9 were performed at 120(2) K on a Nonius KappaCCD
single crystal diffractometer, using Cu-Kα radiation (λ= 1.5418 Å). Images were collected at a 29 mm

Molecules 2008, 13
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fixed crystal-detector distance, using the oscillation method, with 2º oscillation and 40 s exposure time
per image. Data collection strategy was calculated with the program Collect [21]. Data reduction and
cell refinement were performed with the programs HKL Denzo and Scalepack [22]. A semi-empirical
absorption correction was applied on each data set using the program SORTAV [23]. The structures
were solved using direct methods, with the program SIR-92 [24]. Anisotropic least-squares refinement
was carried out with SHELXL-97 [25]. All non-hydrogen atoms were anisotropically refined. All
hydrogen atoms, except those of the methyl group, were located on a difference Fourier map and their
isotropic displacement parameters were freely refined. Hydrogen atoms at the methyl groups were
geometrically placed and refined as riding on their parent atoms with isotropic displacement
parameters set to 1.5 times the Ueq of the atoms to which they are attached.
Crystal data for ketoxime 6. C15H15NOS, M = 257.34, colorless crystal, dimensions 0.30 x 0.15 x 0.10
mm, monoclinic, space group P21/c, a = 7.7870(2), b = 8.7750(2), c = 19.1060(2), β = 93.002(13), V =
1303.74(5) Å3, Z = 4, ρcalcd = 1.311 g cm-3, 39259 reflections collected, θmax = 69.70°, 2464
independent reflections (Rint = 0.044), 2052 observed (F2>2σ(F2)), 211 parameters, R1(F2>2σ(F2)) =
0.0360, wR2 (F2>2σ(F2)) = 0.1095, R1 (all data) = 0.0499, wR2 (all data) = 0.1237, residual electron
density 0.435, -0.511 eÅ-3, μ = 2.088 mm-1, max./ min transmission factors 0.829 /0.706.
Crystal data for ketoxime 7. C14H14N2O3S, M = 290.33, colorless crystal, dimensions 0.27 x 0.25 x
0.22 mm, monoclinic, space group P21/c, a = 8.2170(1), b = 15.6630(2), c = 10.5240(2), β =
104.027(1), V = 1314.08(3) Å3, Z = 4, ρcalcd = 1.468 g cm-3, 37917 reflections collected, θmax = 69.70°,
2455 independent reflections (Rint = 0.037), 2247 observed (F2>2σ(F2)), 225 parameters,
R1(F2>2σ(F2)) = 0.0334, wR2 (F2>2σ(F2)) = 0.0890, R1 (all data) = 0.0355, wR2 (all data) = 0.0903,
residual electron density 0.283, -0.428 eÅ-3, μ = 2.282 mm-1, max./ min transmission factors 0.661
/0.555.
Crystal data for ketoxime 9. C14H14N2OS, M = 258.33, colorless crystal, dimensions 0.27 x 0.22 x 0.03
mm, monoclinic, space group P21/c, a = 13.6300(2), b = 6.3300(1), c = 14.4600(2), β = 96.4800(11), V
= 1240.20(4) Å3, Z = 4, ρcalcd = 1.384 g cm-3, 29295 reflections collected, θmax = 69.67°, 2330
independent reflections (Rint = 0.042), 2031 observed (F2>2σ(F2)), 207 parameters, R1(F2>2σ(F2)) =
0.0348, wR2 (F2>2σ(F2)) = 0.0990, R1 (all data) = 0.0380, wR2 (all data) = 0.1006, residual electron
density 0.279, -0.310 eÅ-3, μ = 2.222 mm-1, max./ min transmission factors 0.867 /0.741.
Supplementary Material
The Supplementary Material for this paper is available via the Internet at
http://www.mdpi.org/molecules/papers/13020301sm.pdf, 12 pages.
Acknowledgements
This research was supported by Laboratorios del Dr. Esteve S.A., Barcelona, Spain, through
project FBG2001/2002-301362, Fundació Bosch i Gimpera-Universitat de Barcelona, Spain. N.M. is
grateful to Laboratorios del Dr. Esteve S.A. for a post-doctoral fellowship. The authors wish to thank

Molecules 2008, 13
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to Dr. Irene Fernández, Universitat de Barcelona, Spain, for running the HRMS. Thanks are also due
to the DGI-MEC (CTQ2006-1182/BQU) and the AGAUR, Grup de Recerca Consolidat
2005SGR00158.
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Sample Availability: Contact the authors.
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