4-Hydroxy-2-quinolones 145. p-toluenesulfonylhydrazide as a tosylating agent

Article abstract of DOI:10.1007/s10593-008-0109-2

The reaction of ethyl 4-chloro-1-methyl-2-oxo-1,2-dihydroquinoline-3- carboxylate with p-toluene-sulfonylhydrazide in anhydrous solvents in the presence of triethylamine results in the tosylation of position 4 of the quinolone. Features of the steric structure of the tosyl-substituted compound are discussed.

Full text of DOI:10.1007/s10593-008-0109-2

Chemistry of Heterocyclic Compounds, Vol. 44, No. 6, 2008
4-HYDROXY-2-QUINOLONES
145*. p-TOLUENESULFONYLHYDRAZIDE
AS A TOSYLATING AGENT
I. V. Ukrainets1, A. A. Tkach1, V. V. Kravtsova1, and S. V. Shishkina2
The reaction of ethyl 4-chloro-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylate with p-toluene-
sulfonylhydrazide in anhydrous solvents in the presence of triethylamine results in the tosylation of
position 4 of the quinolone. Features of the steric structure of the tosyl-substituted compound are
discussed.
Keywords: 4-chloro-2-oxo-1,2-dihydroquinoline-3-carboxylate, p-toluenesulfonylhydrazide, X-ray
structural analysis, tosylation.
p-Toluenesulfonylhydrazide is well known as a chemical reagent in organic chemistry. It is quite often
used in laboratory practice for converting aliphatic, aromatic, and heteroaromatic carboxylic acids to the
corresponding aldehydes via the McFayden-Stevens reaction [2]. Aldehydes or ketones can be transformed to
diazo compounds which, in turn, decompose to olefins upon treatment with bases [3]. As examples of
preparatively important reactions occurring with the participation of p-toluenesulfonylhydrazide mention should
be made of interesting rearrangements of the carbon skeleton in pinacol, camphor, and a series of other
compounds, the synthesis of cyclopropenes from α,β-unsaturated aldehydes, identification of sugars, and the
dehalogenation of activated hetaryl halides [3, 4].
A characteristic of all of the reactions listed above is that the p-toluenesulfonylhydrazide itself is used in
them only at the intermediate stages of formation of β-N-acyl(hetaryl)tosylhydrazides or tosylhydrazones. In the
final step this residue is generally completely removed. An exception is diazo compounds, the diazide group of
which consists of nitrogen atoms initially occurring in the p-toluenesulfonylhydrazide. On the other hand we
were unable to find examples where the p-toluenesulfonylhydrazide would, in fact, serve as a source of a
p-toluenesulfonyl group, i.e. behave in the role of a tosylating agent.
A further example of the "utilization" of the nitrogen atoms of the starting reagent in the final product
are the 5-alkyl substituted 3-hydroxy-1,5-dihydropyrazolo[4,3-c]quinolin-4-ones prepared by reaction of ethyl
4-chloro-1-R-2-oxo-1,2-dihydroquinoline-3-carboxylates with p-toluenesulfonylhydrazide in refluxing ethanol
[5]. It was suggested that one of the basic factors influencing the direction of this reaction is the presence of
water in the alcohol. Hence it was certainly of interest to carry out the synthesis in an anhydrous solvent.
_______
* For Communication 144 see [1].
__________________________________________________________________________________________
2
1National Pharmaceutial University, Kharkiv 61002, Ukraine; e-mail: uiv@kharkov.ua. STC Institute
for Single Crystal, Ukraine National Academy of Sciences, Kharkiv 61001; e-mail:
sveta@xray.isc.kharkov.com. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 847-852,
June, 2008. Original article submitted June 8, 2007.
0009-3122/08/4406-0677©2008 Springer Science+Business Media, Inc.
677

As a result of the experiments carried out by us it was shown that the this modification to the reaction
conditions basically changes the direction of the reaction of ethyl 4-chloro-1-methyl-2-oxo-1,2-dihydro-
quinoline-3-carboxylate (1) with p-toluenesulfonylhydrazide in anhydrous acetonitrile or THF such that it
1
occurs quite differently. Firstly the H NMR spectrum clearly shows the presence of a p-toluenesulfonyl
fragment in the formed product. In the second no signal at all is found which might be identified as belonging to
an NH group proton of a hydrazide fragment. The recorded mass spectroscopic fragment ions with m/z 340 and
312 correspond to successive loss of ethoxy and carbonyl groups from the molecular ion confirming the NMR
data regarding the presence of a ethoxycarbonyl group in the sample studied. However, more important for
proving the structure of the product, was the peak with m/z 385 which can evidently be assigned as due to the
molecular ion. This being so the overall spectroscopic parameters for the product of the reaction of the 4-chloro-
substituted ester 1 with p-toluenesulfonylhydrazide in anhydrous acetonitrile or THF point to it being the ethyl
1-methyl-2-oxo-4-tosyl-1,2-dihydroquinoline-3-carboxylate (2).
Me
O
Cl
S
O
COOEt
O
COOEt
O
H2NNH-Ts
N
Me
1
N
Me
2
In the mass spectrum, fragment ion peaks which might be regarded as due to the loss of a
toluenesulfonyl substituent from the molecular ion or its derivative are absent. None the less, the X-ray
structural analysis carried out by us fully confirms the initial conclusion regarding the structure of the material
Fig. 1. Structure of the tosylquinoline 2 molecule with atomic numbering.
678

prepared (see Figure 1 and Tables 1 and 2). It was found that the bicyclic fragment and atoms O(1), S(1), and C(10)
of the tosylquinoline 2 lie in a single plane to within 0.03 Å. The toluenesulfonyl substituent is located such that
the S(1)–O(5) bond is virtually coplanar with the endocyclic C(7)–C(8) bond and the S(1)–O(4) has an -ac-orientation
relative to it (torsional angles O(5)–S(1)–C(7)–C(8) -7.8(2)º and O(4)–S(1)–C(7)–C(8) -137.5(2)ºC). The tolyl group has
an -ac orientation relative to the C(7)–C(8) bond (torsional angle C(14)–S(1)–C(7)–C(8) 107.0(2)º) and is strongly
twisted relative to the C(7)–S(1) bond (torsional angle C(7)–S(1)–C(14)–C(15) 110.1(2)º). Such a position for the
TABLE 1. Bond Lengths (l) in the Tosylquinoline Structure 2
Bond
l, Å
Bond
l, Å
1.421(3)
1.744(5)
1.348(4)
1.466(3)
1.196(4)
1.446(4)
1.403(3)
1.363(4)
1.406(5)
1.358(5)
1.491(4)
1.379(4)
1.368(5)
1.380(5)
1.364(5)
1.423(4)
1.787(3)
1.403(5)
1.232(4)
1.311(4)
1.370(4)
1.371(5)
1.348(4)
1.426(4)
1.456(4)
1.479(5)
1.382(5)
1.370(4)
1.489(5)
S(1)−O(4)
S(1)−C(14)
N(1)−C(9)
N(1)−C(13)
O(2)−C(10)
O(3)−C(11)
C(1)−C(6)
C(3)−C(4)
C(5)−C(6)
C(7)−C(8)
C(8)−C(10)
C(14)−C(19)
C(15)−C(16)
C(17)−C(18)
C(18)−C(19)
S(1)−O(5)
S(1)−C(7)
N(1)−C(1)
O(1)−C(9)
O(3)−C(10)
C(1)−C(2)
C(2)−C(3)
C(4)−C(5)
C(6)−C(7)
C(8)−C(9)
C(11)−C(12)
C(14)−C(15)
C(16)−C(17)
C(17)−C(20)
TABLE 2. Valence Angles (ω) in the Tosylquinoline Structure 2
Angle
ω, deg
Angle
ω, deg
108.8(2)
119.3(2)
109.0(2)
106.6(2)
124.1(2)
118.9(2)
121.1(2)
118.8(2)
119.9(3)
122.5(2)
118.1(2)
121.5(2)
120.3(2)
128.0(2)
122.8(2)
116.9(2)
122.5(2)
107.5(3)
118.3(3)
119.4(2)
118.1(3)
120.2(2)
118.7(3)
O(4)−S(1)−O(5)
O(5)−S(1)−C(14)
O(5)−S(1)−C(7)
C(9)−N(1)−C(1)
C(1)−N(1)−C(13)
C(2)−C(1)−N(1)
N(1)−C(1)−C(6)
C(4)−C(3)−C(2)
C(4)−C(5)−C(6)
C(1)−C(6)−C(7)
C(8)−C(7)−C(6)
C(6)−C(7)−S(1)
C(7)−C(8)−C(10)
O(1)−C(9)−N(1)
N(1)−C(9)−C(8)
O(2)−C(10)−C(8)
O(3)−C(11)−C(12)
C(19)−C(14)−S(1)
C(16)−C(15)−C(14)
C(16)−C(17)−C(18)
C(18)−C(17)−C(20)
C(18)−C(19)−C(14)
O(4)−S(1)−C(14)
O(4)−S(1)−C(7)
C(14)−S(1)−C(7)
C(9)−N(1)−C(13)
C(10)−O(3)−C(11)
C(2)−C(1)−C(6)
C(1)−C(2)−C(3)
C(5)−C(4)−C(3)
C(1)−C(6)−C(5)
C(5)−C(6)−C(7)
C(8)−C(7)−S(1)
C(7)−C(8)−C(9)
C(9)−C(8)−C(10)
O(1)−C(9)−C(8)
O(2)−C(10)−O(3)
O(3)−C(10)−C(8)
C(19)−C(14)−C(15)
C(15)−C(14)−S(1)
C(15)−C(16)−C(17)
C(16)−C(17)−C(20)
C(19)−C(18)−C(17)
108.6(2)
103.4(1)
117.0(2)
116.1(3)
120.0(2)
121.1(3)
119.8(3)
116.6(3)
125.3(2)
118.2(2)
120.3(3)
111.6(2)
120.3(3)
125.6(3)
111.7(3)
120.4(2)
121.3(2)
121.4(3)
121.7(3)
122.1(2)
679

toluenesulfonyl substituent is likely additionally stabilized by a weak intramolecular hydrogen bond (C(5)–
H(5)···O(4), H···O 2.38 Å. C–H···O 123º) and results in a shortened intramolecular contact H(5)···C(15) 2.78 Å (sum
of van der Waal radii 2.87 Å [6]). A marked repulsion between the rather bulky substituents at atoms C(7) and
C(8) (shortened intramolecular contact O(5)···C(10) 2.55 Å (3.00 Å)) results in an increase in the valence angle
C(7)–C(8)–C(10) to 128.0(2)º and twists the ester substituent practically perpendicular to the quinolone plane
(torsional angle C(7)–C(8)–C(10)–O(2) -85.6(3)). The ethyl group has an ap-orientation relative to the C(8)–C(10)
bond (torsional angle C(11)–O(3)–C(10)–C(8) 177.1(2)º) and the C(11)–C(12) bond an ap-conformation relative to the
C(10)–O(3) bond (torsional angle C(10)–O(3)–C(11)–C(12) -169.7(2)º).
A marked repulsion between the N-methyl substituent, the neighboring carbonyl group, and the benzene
ring atoms of the quinolone (shortened intramolecular contacts H(2)···C(13) 2.47 (2.87), H(2)···H(13c) 2.15 (2.34),
(13b)···O(1 2.28 (2.46), and H(13c)···C(2) 2.63 Å (2.87 Å)) leads to some deviation of the N-methyl group from the
H
bicyclic fragment plane (torsional angle C(13)–N(1)–C(1)–C(2) -6.0(3)º) with preservation of the trigonal planar
configuration of the nitrogen atom.
Hence the investigation we have carried out has broadened the boundaries of the practical use of
p-toluenesulfonylhydrazide and adds a tosylating ability to its already known properties. Even though the
mechanism of the unusual reaction we report remains unclear its theoretical and perhaps wider practical use is
not in doubt.
EXPERIMENTAL
1
The H NMR spectrum of the tosylquinoline 2 was recorded on a Varian Mercury VX-200 instrument
(200 MHz) using DMSO-d6 solvent and TMS as internal standard. Mass spectra were registered on a Varian
1200L spectrometer in full scan mode in the range 35-700 m/z with EI ionization of 70 eV and with direct
sample introduction. Commercial p-toluenesulfonylhydrazide and anhydrous acetonitrile were used from the
Aldrich company and anhydrous THF from Riedel-de Haën.
Ethyl 1-Methyl-2-oxo-4-tosyl-1,2-dihydroquinoline-3-carboxylate (3). A solution of the 4-chloro-
substituted ester 1 (2.65 g, 0.01 mol), p-toluenesulfonylhydrazide (1.86 g, 0.01 mol, triethylamine (1.4 ml,
0.01 mol), and anhydrous acetonitrile (or THF) (30 ml) was refluxed for 48 h. The reaction mixture was cooled
and diluted with cold water. The precipitate was filtered off, washed with water, and dried. Yield 2.66 g (69%);
1
mp 249-251ºC (DMF). H NMR spectrum, δ, ppm (J, Hz): 8.35 (1H, d, J = 8.3, H-5); 7.99 (2H, d, J = 8.4,
H-2',6'); 7.66 (2H, m, H-7,8); 7.47 (2H, d, J = 8.4, H-3',5'); 7.32 (1H, td, J = 7.6, 1.6, H-6); 4.38 (2H, q, J = 7.0,
OCH2); 3.65 (3H, s, NCH3); 2.35 (3H, s, CH3); 1.33 (3H, t, J = 7.0. OCH2CH3). Mass spectrum, m/z (Irel, %):
385 [M]+ (92), 340 [M-OEt]+ (91), 312 [M-OEt-CO]+ (32), 292 (24), 276 (51), 262 (55), 248 (55), 234 (100).
Found, %: C 62.32; H 4.97; N 3.63. C20H19NO5S. Calculated, %: C 62.24; H 4.86; N 3.69.
X-ray Structural Investigation. Crystals of the tosylquinoline 2 are monoclinic (DMF), at 20ºC: a =
8.91(2), b = 13.54(4), c = 15.36(2) Å. β = 101.5(2)º, V = 1804(8) Å3, Mr = 385.42, Z = 4, space group P21/c,
d
calc = 1.419 g/cm3, µ(MoKα) = 0.212 mm-1, F(000) = 808. The parameters of the unit cell and intensities of
12554 reflections (5099 independent, Rint = 0.084) were measured on an Xcalibur-3 diffractometer (MoKα
radiation, CCD detector, graphite monochromator, ω scanning to 2θmax = 60º).
The structure was solved by a direct method using the SHELXTL program package [7]. The positions of
the hydrogen atoms were revealed using electron density difference synthesis and refined using the "riding"
model with Uiso = nUeq (n = 1.5 for a methyl group and n = 1.2 for remaining hydrogen atoms). The structure
was refined in F2 full matrix least squares analysis in the anisotropic approximation for non-hydrogen atoms to
wR2 = 0.114 for 5099 reflections (R1 = 0.051 for 2007 reflections with F>4σ(F), S = 0.849). The full
crystallographic information has been placed in the Cambridge structural database (reference No. CCDC
650599). Interatomic distances and valence angles are given in Tables 1 and 2.
680

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