Remarkable stereoselectivity switch in synthesis of carbonyl substituted N2-arylamidrazones with low lipophilicity

Article abstract of DOI:10.1016/j.tetlet.2012.06.032

Reaction of carbonyl substituted hydrazonoyl chlorides with amines usually leads to Z-configured amidrazone derivatives via nucleophilic substitution of the chlorine atom. Surprisingly, N,N-dimethylcarboxamide substituted hydrazonoyl chlorides yielded E-a

Full text of DOI:10.1016/j.tetlet.2012.06.032

Tetrahedron Letters 53 (2012) 4507–4509
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Tetrahedron Letters
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Remarkable stereoselectivity switch in synthesis of carbonyl substituted
N2-arylamidrazones with low lipophilicity
⇑
Petra Frohberg , Ingo Schulze, Christian Donner, Fabian Krauth
Institute of Pharmacy, Martin-Luther-University Halle-Wittenberg, Wolfgang-Langenbeck-Str. 4, 06120 Halle, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Reaction of carbonyl substituted hydrazonoyl chlorides with amines usually leads to Z-configured amid-
razone derivatives via nucleophilic substitution of the chlorine atom. Surprisingly, N,N-dimethylcarbox-
amide substituted hydrazonoyl chlorides yielded E-amidrazones when dialkylamines were used as
nucleophilic reagent. The lipophilicities of the obtained amidrazones were found to be drastically
reduced compared to their corresponding carboxanilides.
Received 10 April 2012
Revised 29 May 2012
Accepted 1 June 2012
Available online 15 June 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Stereoselective synthesis
Amidrazone
Configuration
Isomer
Lipophilicity
N2-Arylamidrazones 1 (Fig. 1) provide a highly variable source
for the synthesis of nitrogen containing heterocycles.1 Moreover,
they exhibit a great variety of biological activities, among which
are corticotropin releasing factor receptor antagonists, insecticides,
or sphingosine-1-phosphate receptor 3 (S1P3) antagonists as well.2
A general application of amidrazones in heterocyclic chemistry is
Table 1
Correlation of the substitution pattern and the lipophilicity of oxanilo-N2-arylamid-
razones 1a–e: estimated logP values (logPcalc) and retardation factors (Rf values) are
given
a
R
R1/R2
Ar
LogPcalc
Rf valueb
1a
1b
1c
1d
1e
PhNH
PhNH
PhNH
PhNH
PhNH
H/H
H/CH3
(CH2)5
(CH2)5
Ph
Ph
Ph
4-Cl-C6H4
4-Cl-C6H4
2.3
2.6
3.3
4.4
2.8
0.50
0.56
0.66
0.67
0.53
achieved by inserting a carbonyl substituent at the
a-position of
the amidrazone moiety.3 Compounds 1 containing ester, anilido,
or keto groups have already been synthesized and characterized.
Recently, we reported the synthesis of (Z)-oxanilo-N1-dialkyl-N2-
arylamidrazones (1 with R = PhNH, R1R2 = dialkyl).4 We observed
that during the preparation procedure including recrystallization,
these compounds undergo an isomerization to the E-isomer. This
(CH2)2O(CH2)2
a
LogP values were estimated with ACD ChemSketch 12.01 freeware.
Rf values were determined using thin layer chromatography with silica gel
b
sheets and solvent system heptane/ethyl acetate (1:1, v/v).
isomerization process could yield compounds with altered
biological activities. The high lipophilicity of these compounds
(Table 1) limits their evaluation in biological assays.5
Based on these findings we aimed to synthesize more polar
compounds containing an amide structure in order to investigate
spectroscopic properties of E/Z-amidrazones. In this Letter, we re-
port a stereoselectivity switch in the preparation of N,N-dimethyl-
carboxamido-N2-arylamidrazones from hydrazonoyl chlorides
depending on the nature of the N1 substitution.
Access to hydrazonoyl chlorides could be realized via a Japp–
Klingemann cleavage.6 b-Chlorinated dicarbonyl compounds, such
as 2-chloro-3-oxobutanoic acid derivatives couple with diazotized
anilines and concomitant acetic acid cleavage. Nevertheless, this
versatile reaction is limited to compounds containing ester, anilido,
or keto structures so far. We aimed to synthesize hydrazonoyl
Figure 1. General structure of
according to IUPAC nomenclature.
a-carbonyl substituted amidrazones. Numbering is
⇑
Corresponding author.
E-mail address: petra.frohberg@pharmazie.uni-halle.de (P. Frohberg).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.06.032

4508
P. Frohberg et al. / Tetrahedron Letters 53 (2012) 4507–4509
Scheme 1. Synthesis of hydrazonoyl chlorides 2.
Table 2
Substitution patterns, melting points (mp, °C), and yields (%) of hydrazonoyl chlorides
(CH3)2NCOC(Cl) @NNHAr 2
Scheme 2. Synthesis of amidrazones 3. Reagents and conditions: (a) R1 = H:
2.5 equiv NH3, dioxane; R1 = CH3: 2.0 equiv CH3NH2, dioxane; R1 = Ph: 1.0 equiv
PhNH2, 1.0 equiv NEt3, dioxane; (b) 2.0 equiv R1R2NH, dioxane.
Ar
Mp
Yield
(Z)-2a
(Z)-2b
(Z)-2c
(Z)-2d
Ph
107–109 (Ethanol)
104–106 (Methanol)
125–130 (Methanol)
78–80 (Methanol)
32
58
40
54
4-CH3-C6H4
4-Cl-C6H4
4-F-C6H4
in the product mixture as well. These compounds were isolated
as mixed crystals of the Z- and E-isomers, with the E-isomer be-
tween 20% and 30%. Surprisingly, disubstituted amines such as
pyrrolidine, piperidine, and morpholine, respectively, gave exclu-
sively E-amidrazones 3g–m (Scheme 2, Table 3).
chlorides 2 by reaction of 2-chloro-3-oxo-N,N-dimethylbutana-
mide with diazotized anilines (Scheme 1).
Yet, the compounds of interest could not be isolated from the
reaction mixture by filtration because they did not precipitate.
Also, after bringing the reaction mixture to room temperature
decomposition of the desired products was observed. When keep-
ing the aqueous reaction mixture at 5–10 °C overnight, compounds
2a–d (Table 2) were successfully isolated.
According to hydrazonoyl chlorides described in the literature,
which exist in the Z-form,7 the obtained compounds 2a–d were de-
tected as Z-isomers by NMR experiments. In particular, the chem-
ical shift of the C@NNH signal in the 1H NMR spectra recorded in
DMSO-d6 was found in the prescribed region of 9–10 ppm. In 13C
NMR spectra the signal of the C@N moiety was observed at approx.
115 ppm.
The formation of E/Z-isomers was monitored by 1H NMR in
DMSO-d6 due to the very slow isomerization in solution in the range
of days. Isomers were assigned using NOE NMR experiments. For 3b,
irradiation at the frequency of the NH2 protons causes an NOE to the
hydrazone proton @NNH. In contrast, the NOE spectrum of 3h dis-
plays an NOE signal for the amide CH3 protons, when irradiating at
the frequency of the amidrazone N1 methylene protons. In addition,
the 13C NMR signal corresponding to the C@N group changes
depending on the configuration of this group4 resulting in a ca.
10 ppm downfield shift for the E-isomer (Table 3).
Reaction of hydrazonoyl chlorides with ammonia in dioxane or
methanol solution yielded Z-configured amidrazones 3a–c
(Scheme 2, Table 3).
The reaction conditions have to be carefully chosen using an ex-
cess of ammonia. Otherwise, particularly if triethylamine is used as
a proton acceptor, formation of dimer 4 is preferred, which decom-
poses during heating or recrystallization to give the triazole deriv-
atives 5 (Scheme 3).
Treating hydrazonoyl chlorides
amines, that is, methylamine or aniline, afforded mostly Z-amid-
razones 3d–f (Scheme 2, Table 3), but the E-isomer was detected
2 with monosubstituted
Scheme 3. Side reaction observed during synthesis of 3b: Reagents and conditions:
(a) 1.0 equiv ammonia, 1.0 equiv NEt3, dioxane, rt.
Table 3
Substitution patterns, melting points (mp, °C), yields (%), and characteristics (13C NMR signals of C@N (ppm), logPcalc and Rf values) of prepared amidrazones (CH3)2NCOC(NR1R2)
@NNHAr 3a–m
R1/R2
Ar
Mp
Yield
13C NMR signal of C@Na
LogPcalc
Rf valuec
b
(Z)-3a
(Z)-3b
(Z)-3c
(E,Z)-3d
(E,Z)-3e
(E,Z)-3f
(E)-3g
(E)-3h
(E)-3i
H/H
H/H
H/H
H/CH3
H/CH3
H/Ph
(CH2)4
(CH2)5
(CH2)5
(CH2)5
(CH2)5
(CH2)2O(CH2)2
(CH2)2O(CH2)2
Ph
132–134 (Heptane/ethyl acetate)
126–129 (Heptane/ethyl acetate)
155–158 (Methanol)
166–172 (Water)
175–178 (Methanol)
140–147 (Chloroform)
141–143 (Methanol)
110–115
125–127 (Methanol)
149–151 (Methanol)
102–105 (Methanol)
148–149
27
31
38
46
58
67
71
53
48
86
78
33
55
138.3
137.8
139.4
0.50
0.96
1.49
1.29
1.82
3.58
1.99
1.56
2.02
2.55
2.01
0.02
1.01
0.19
0.20
0.17
0.05
0.04
0.35
0.11
0.29
0.29
0.31
0.26
0.13
0.14
4-CH3-C6H4
4-Cl-C6H4
4-CH3-C6H4
4-Cl-C6H4
4-Cl-C6H4
4-Cl-C6H4
Ph
4-CH3-C6H4
4-Cl-C6H4
4-F-C6H4
Ph
143.5 (153.3)d
144.7 (153.9)d
135.1 (146.0)d
153.5
153.0
153.4
154.0
156.6
150.7
151.2
(E)-3j
(E)-3k
(E)-3l
(E)-3m
4-Cl-C6H4
160–162 (Methanol)
a
b
c
100 MHz, solvent DMSO-d6.
Values were estimated with ACD ChemSketch 12.01 freeware.
Rf values were determined using thin layer chromatography with silica gel sheets and solvent system heptane/ethyl acetate (1:1, v/v).
Signal of E-isomer.
d

P. Frohberg et al. / Tetrahedron Letters 53 (2012) 4507–4509
4509
LogP values were estimated with ACD software, yet, the configu-
ration is not considered in this calculation program. The lipophilicity
of amidrazones with the N,N-dimethylcarboxamide structure 3 (Ta-
ble 3) was found to be drastically reduced by ca. two log units com-
pared to the corresponding carboxanilide derivatives 1 (Table 1).
Calculated logP values were compared with Rf values from thin
layer chromatography using a solvent system of heptane/ethyl ace-
tate 1:1 (v/v). Likewise, Rf values for 3 were found to be only half of
these of amidrazones 1 (compare Tables 1 and 3).
associated with this article can be found, in the online version, at
http://dx.doi.org/10.1016/j.tetlet.2012.06.032.
References and notes
1. (a) Al-Noaimi, M. Z.; Abdel-Jalil, R. J.; El-Abadelah, M. M.; Haddad, S. F.; Baqi, Y.
N. H.; Voelter, W. Monatsh. Chem. 2006, 137, 745–750; (b) Sabri, S. S.; El-Abadla,
N. S.; El-Abadelah, M. M.; Voelter, W. Z. Naturforsch., B: J. Chem. Sci. 2006, 61, 65–
68; (c) Frohberg, P.; Nuhn, P. Heterocycles 1996, 43, 2549–2552.
2. (a) Wilson, D. M.; Termin, A. P.; Mao, L.; Ramirez-Weinhouse, M. M.; Molteni, V.;
Grootenhuis, P. D. J.; Miller, K.; Keim, S.; Wise, G. J. Med. Chem. 2002, 45, 2123–
2126; (b) Kawata, Sh.; Okui, Sh.; Suzuki, Sh.; Fukuchi, T. Patent: EP1470752,
2004.; (c) Ohnuma, Sh.-Y.; Hasegawa, T.; Sada, T. Patent: EP1935874, 2008.
3. Krauth, F.; Dahse, H. M.; Ruttinger, H. H.; Frohberg, P. Bioorg. Med. Chem. 2010,
18, 1816–1821.
In summary, we present a promising strategy to synthesize
amidrazones stereoselectively, which will be beneficial to study
their physical and biophysical properties, in more detail.
4. Frohberg, P.; Wagner, Ch.; Meier, R.; Sippl, W. Tetrahedron 2006, 62, 6050–6060.
5. Lipinski, C. A.; Lombardo, F.; Dominy, B. W.; Feeney, P. J. Adv. Drug Delivery Rev.
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Supplementary data
6. Phillips, R. R. Org. React. 1959, 10, 143–178.
7. Frohberg, P.; Drutkowski, G.; Wagner, Ch. Eur. J. Org. Chem. 2002, 10, 1654–1663.
Supplementary data (experimental procedures and character-
ization data such as 1H, 13C NMR, MS, microanalyses data)