An unprecedented rearrangement of salicylanilide derivatives: imidazolinone intermediate formation

Article abstract of DOI:10.1016/j.tetlet.2009.10.084

The preparation of new prodrug forms of anti-tuberculosis active salicylanilide esters with amino acids led to an unexpected rearrangement. The isolation and the structure determination of 2-(5-chloro-2-hydroxyphenyl)-3-(3-chlorophenyl)-5-substituted-3,5-

Full text of DOI:10.1016/j.tetlet.2009.10.084

Tetrahedron Letters 51 (2010) 23–26
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Tetrahedron Letters
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An unprecedented rearrangement of salicylanilide derivatives:
imidazolinone intermediate formation
b,c
a
a
a
Jarmila Vinšová a, , Aleš Imramovsky , Martin Krátky , Juana Monreal Férriz , Karel Palát ,
*
´
´
c,d
e
ˇ
ˇ ˇ
Antonín Lycka , Aleš Ru˚ zicka
a Department of Inorganic and Organic Chemistry, Faculty of Pharmacy, Charles University in Prague, Heyrovského 1203, 500 05 Hradec Králové, Czech Republic
b Institute of Organic Chemistry and Technology, Faculty of Chemical Technology, University of Pardubice, Studentská 573, 532 10 Pardubice, Czech Republic
c Department of Chemistry, Faculty of Education, University of Hradec Králové, Rokytanského 62, 500 03 Hradec Králové, Czech Republic
d Research Institute for Organic Syntheses, Rybitví 296, 533 54 Pardubice, Czech Republic
e Department of General and Inorganic Chemistry, Faculty of Chemical Technology, University of Pardubice, 532 10 Pardubice, Czech Republic
a r t i c l e i n f o
a b s t r a c t
Article history:
The preparation of new prodrug forms of anti-tuberculosis active salicylanilide esters with amino acids
led to an unexpected rearrangement. The isolation and the structure determination of 2-(5-chloro-
2-hydroxyphenyl)-3-(3-chlorophenyl)-5-substituted-3,5-dihydro-4H-imidazol-4-ones unambiguously
confirm one of the two proposed reaction mechanisms.
Received 17 August 2009
Revised 2 October 2009
Accepted 16 October 2009
Available online 22 October 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Multi-drug resistance to antimicrobial agents is an unavoidable
side effect of their use and goes hand-in-hand with the relentless
drive of bacterial evolution. Ongoing combat against drug-resistant
bacteria leads to the search for new types of active molecules with
different or novel mechanisms of action. Salicylanilides are promis-
ing candidates for this purpose, due to their wide range of pharma-
cological activity, including antifungal and antibacterial.1,2 In a
series of publications, Waisser and co-workers described their sig-
nificant in vitro antimycobacterial activity against Mycobacterium
tuberculosis as well as against the non-tubercular strainsMycobacte-
rium avium and Mycobacterium kansasii.3–5 The presence of phenolic
hydroxy groups seems to be necessary for the activity of these com-
pounds,6 but also converts them into non-bioavailable drugs.
In order to improve physico-chemical and pharmacokinetic
properties, including metabolic stability, a new prodrug form of
salicylanilide was proposed. Substituted salicylanilides 1 were
esterified with different N-protected amino acids. In the course
of our research, we found that N-benzyloxycarbonyl glycine 1
(R3 = H) or (S)-alanine (R3 = CH3), when esterified with salicylani-
lides 2 (R1 = 5-Cl, R2 = 4-Cl, 4-Br, 4-CF3, 3-Cl) gave cyclic seven-
membered benzoxazepine-2,5-diones 3,7 while other N-protected
amino acids 2, such as (R)- or (S)-phenylalanine or valine, afforded
the required esters 4 in high yields8,9 (Scheme 1).
alkylbenzamide (diamide) 6 (Scheme 2). The rearrangement also
occurs with unsubstituted salicylanilides or with electron-activat-
ing methyl (6f) or methoxy groups on the aniline moiety (6e). This
process is not limited to salicylanilide esters of Cbz-protected
amino acids. We have used Boc-protected valine and the Leuch
anhydride of phenylalanine7 for esterification, and the appropriate
salicylanilide esters, gave after N-deprotection, the rearranged
diamides which were isolated and characterized. A series of
compounds 6a, b, d–f were prepared (Table 1).
In a previous publication7, we proposed a possible mechanism
for this rearrangement where the deprotected amino group imme-
diately attacks the carbonyl of the amide and forms a cyclic seven-
membered ester which is ring-opened by the action of the released
aniline to produce the diamide.7
With the aim of confirming the above-proposed mechanism, we
have carried out a number of experiments where activated anilines
bearing a stronger nucleophilic substituent at position 4, were
added to the reaction mixture. No rearranged diamides containing
the added anilines were isolated, only the product containing the
original aniline moiety. Therefore, an alternative mechanism
involving reorganization of the molecule without liberation of
the aniline moiety was investigated. We report in this Letter the
elucidation of this mechanism.
Acidic N-deprotection of 4 with hydrogen bromide in acetic acid
gave the corresponding hydrobromide salts 5. Subsequent libera-
tion of the amino group with triethylamine under anhydrous
conditions yielded the rearranged hydroxy-N-(phenylamino)-oxo-
The free amino group attacks the amidic carbonyl and the ami-
dic nitrogen attacks the ester carbonyl to generate the bicyclic
intermediate 7 which is spontaneously transformed into a five-
membered hydroxyimidazolinone 8 which then ring-opens to form
diamide 6 (Scheme 3).
Support for a five-membered imidazoline ring as an intermediate
in this rearrangement came from our experimental results. During
* Corresponding author.
E-mail address: vinsova@faf.cuni.cz (J. Vinšová).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.10.084

24
J. Vinšová et al. / Tetrahedron Letters 51 (2010) 23–26
Scheme 1. Synthesis of benzoxazepine-2,5-diones 3 or Cbz-amino acids esters 4. Reagents and condition: (a) DCI, DMF, À15 °C.
Scheme 2. Unexpected rearrangement of amino acid esters. Reagents: (a) HBr, CH3COOH; (b) Et3N.
Table 1
List of prepared compounds
Product
R1
R2
R3
R4
O
N
R2
4a
4b
4c
4d
4e
4f
4-Cl
4-Cl
4-Cl
H
H
H
3-Cl
3-Cl
3-Cl
4-Cl
4-OCH3
4-CH3
–CH(CH3)2
–CH2C6H5
–CH(CH3)2
–CH(CH3)2
–CH(CH3)2
–CH(CH3)2
–CH2C6H5
–CH2C6H5
–C(CH3)3
–CH2C6H5
–CH2C6H5
–CH2C6H5
R1
H
O
H
N
O
O
R4
R2
R3
O
O
O
5a
5b
5d
5e
5f
4-Cl
4-Cl
H
H
H
3-Cl
3-Cl
4-Cl
4-OCH3
4-CH3
–CH(CH3)2
–CH2C6H5
–CH(CH3)2
–CH(CH3)2
–CH(CH3)2
N
H
R1
NH3Br
O
R3
R2
6a
6b
6d
6e
6f
5-Cl
5-Cl
H
H
H
3-Cl
3-Cl
4-Cl
4-OCH3
4-CH3
–CH(CH3)2
–CH2C6H5
–CH(CH3)2
–CH(CH3)2
–CH(CH3)2
R3
HN
O
O
NH
OH
R1
R1
9a
9b
5-Cl
5-Cl
H
H
H
3-Cl
3-Cl
4-Cl
4-OCH3
4-CH3
–CH(CH3)2
–CH2C6H5
–CH(CH3)2
–CH(CH3)2
–CH(CH3)2
9da
9ea
9fa
HO
R2
N
N
R3
O
a
Compound was not isolated, molecular weights were detected by GC–MS.

J. Vinšová et al. / Tetrahedron Letters 51 (2010) 23–26
25
Scheme 3. Proposed mechanism for the rearrangement.
purification of the diamide 6a by column chromatography, we iso-
lated a side-product that proved to be a dehydrated form of this
five-membered ring intermediate as a racemic mixture, 2-(5-
chloro-2-hydroxyphenyl)-3-(3-chlorophenyl)-5-isopropyl-3,5-dihy-
dro-4H-imidazol-4-one 9a (Fig. 1). The structure of 9a [R1 = 5-Cl,
R2 = 3-Cl, R3 = CH(CH3)2] was confirmed by MS, IR and 2D NMR and
by X-ray crystallography. The same type of substituted 3,5-dihydro-
4H-imidazol-4-one was isolated during the purification of 6b, 5-ben-
zyl-2-(5-chloro-2-hydroxyphenyl)-3-(3-chlorophenyl)-3,5-dihydro-
4H-imidazol-4-one 9b (Fig. 1) and its structure was determined by IR,
1H NMR and 13C NMR spectroscopy.
P21/c. No important short contacts,
p
–
p
stacking or intermolecular
H-bonds were present in the crystal lattice of 9a. The ORTEP view
of the structure of 9a (Fig. 2, the unit cell plot is available in Sup-
plementary data) shows the almost planar arrangement of the imi-
dazolinone ring together with the phenyl rings mutually twisted
by 70.6(2)°. The imidazolinone moiety contains two localized dou-
ble bonds O1–C1 1.201(4) Å and N1–C2 1.275(4) Å (see Fig. 2), the
lengths of which are in good agreement with the literature data10
and similar ring systems found in the CSD database where related
species contain very close,11,12 bicyclic,13 fused hetero,14,15 or spi-
rocyclic16 systems. A similar structure has also been determined
for imidazolinone rings coupled to a pyridine moiety and used as
ligands in iron(III)17 or copper(II)18 complexes.
The negative and positive ion electrospray ionization (ESI) mass
spectra of 9a showed [M]+ and deprotonated molecular ions
[MÀH]+, respectively, which confirmed the molecular weight. The
fragment ions observed in the MS spectra correspond to the sug-
gested structure.
The crystal structure has been deposited at the Cambridge Crys-
tallographic Data Centre and allocated the deposition number
CCDC 695861.
Additional structural determination of 9a was made by 1H NMR,
13C NMR and 15N NMR 2D experiments (gradient-selected (gs)-
COSY, gs-HMQC, gs-HMBC) as well as by construction of a com-
puter model using DFT (B3LYP/6-31G(d)). The IR, 1H and 13C
NMR spectra were calculated based on this model.
In conclusion, we have elucidated the mechanism of the unex-
pected rearrangement of amino acid esters of salicylanilides. The
isolated dehydrated form of the imidazolinone 9a strongly sup-
ports the proposed mechanism for the formation of compounds
6. The results of the X-ray study are in excellent agreement with
the proposed structure and 2D NMR experiments. The above-men-
tioned rearrangement has provided new types of potential antitu-
bercular compounds originating from salicylanilides. Their
antimycobacterial activity is under investigation.
Finally, compound 9a was also studied by X-ray diffraction
techniques. It crystallized in the monoclinic achiral space group
Acknowledgements
This study was supported by MSM 0021620822, MSM
0021627501, GAUK 76807/2007 and IGA NS 10367-3.
Supplementary data
Figure 1. Isolated dehydrated reaction intermediates.
Supplementary data (general experimental information, exper-
imental details, characterization data for compounds 4–6 and 9
and scans of NMR and MS spectra for compounds 9a and 9b, calcu-
lated IR-spectra, 1H, 13C NMR and 2D spectra of compound 9a and
the solid state study details for compound 9a as well as Quantum-
chemical calculations for 9a) associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2009.10.084.
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