Key words
amidiaztion - hydrazinolysis - carbohydrazide - carboxamide - click chemistry
Functionalized isoindole-1,3-dione derivatives exhibit a vast range of biological
activities[1] such as antibacterial,[2] teratogenic,[3] anticancer (multiple myeloma),[4] PPAR-γ agonist,[5] and anti-inflammatory activities.[6] Bioactive molecules containing an isoindol-1-3-dione moiety include Thalidomide
1, Pomalidomide 2, and Apremilast 3 (Figure [1]).
Figure 1 Representative examples of isoindol-1,3-dione containing bioactive molecules
Compounds containing the 1,2,3-triazole moiety also show antitubercular activity[7] and, phthalic anhydride derivatives also showed antitubercular activity.[8] Based on these findings, new molecules were designed, and the synthesis of 1,2,3-triazole
moieties connected to isoindole-1,3-dione derivatives via a hydrazide linkage is reported
herein. PASS Online predicts these compounds may be antimycobacterial or antineoplastic agents.[9] Thus, the synthesis of 1,2,3-triazole-isoindole-1,3-dione derivatives has been explored.
The desire to construct biologically relevant molecules starting from simple molecules
leads to a constant demand for new synthetic methodologies.[10]
[11]
[12] A simple and straightforward strategy to access the desired isoindole-1,3-dione-tethered
1,2,3-triazole derivatives would involve click chemistry (Scheme [1]), with the fragments being connected by following either path A or Path B. In the
present work, we followed Path A as it helps to generate and introduce diversity in
the final product. Diversity in the final products can be introduced at three points
by varying the azide, alkyne, and the phthalic anhydride, thus permitting access to
multifunctional, highly substituted derivatives.
Scheme 1 Strategy to generate derivatives 4 containing 1,2,3-triazole units connected to isoindole-1,3-dione
To start with, aromatic amines 9 were converted into the corresponding azides 6 via reaction of their respective diazonium salt with sodium azide by following reported
procedures (Scheme [2]).[13]
[14] The azides were used without further purification and were subjected to 1,3-dipolar
cycloaddition[15] with a ethyl propynoate 10 using Cu(OAc)2/sodium ascorbate (10 mol% and 20 mol%, respectively) in H2O/t-BuOH (1:1) to yield the corresponding cycloaddition products 5 in good to excellent yields (Scheme [2]).[16] These compounds were fully characterized by 1H and 13C NMR spectroscopy. For instance, compound 5a showed eleven resonances in its 13C NMR spectrum and, in its 1H NMR spectrum, a resonance at δ = 9.62 ppm could be assigned to the C-5 proton of
the triazole.
Scheme 2 Preparation of triazole ester 5a–d: Reagents and conditions: (a) HCl/H2O (1:1), sodium azide, sodium acetate, sodium nitrite, 0–5 °C; (b) t-BuOH/H2O (1:1), ethyl propynoate, copper acetate, sodium ascorbate.
Next, hydrazides 11 were prepared by reacting carboxylate derivatives 5 with hydrazine hydrate in ethanol at reflux (Scheme [3]).[17] The absence of resonances at δ = 61.6 and 14.3 ppm in the 13C NMR spectra of hydrazides 11 supported their formation. The 1H NMR spectra of hydrazides 11a–d still exhibited the characteristic resonance due to the C-5 proton of the triazole
moiety, but the ethyl ester resonances had been replaced by NH and NH2 resonances at δ = 9.91 (bs, 1H) and 4.53 ppm (bs, 2H).
Scheme 3 Preparation of hydrazide 11a–d
After synthesizing 1,2,3-triazole carbohydrazides 11, preparation of isoindole-1,3-dione derivatives 4 was performed (Scheme [4]). 1,2,3-Triazole carbohydrazides 11 were treated with the phthalic anhydride 8 under a range of reaction conditions; the results are summarized in Table [1]. These studies revealed that a catalytic amount of glacial acetic acid is required
for complete amidation. Reactions without glacial acetic acid were slower and lower
yielding. This sluggishness is presumably due to the lower nucleophilicity of the
NH2 group attached to a 1,2,3-triazole compared with aliphatic and aromatic amines.
Table 1 Reaction Conditions for Amidation Reaction
|
Solvent
|
Additive
|
Conditions
|
Time (h)
|
Yield (%)
|
|
DMF
|
–
|
reflux
|
24
|
no reaction
|
|
DMSO
|
–
|
reflux
|
24
|
no reaction
|
|
THF
|
–
|
reflux
|
24
|
no reaction
|
|
toluene
|
–
|
reflux
|
24
|
20
|
|
DMF
|
glacial AcOH (0.004 mmol)
|
reflux
|
24
|
no reaction
|
|
DMSO
|
glacial AcOH (0.004 mmol)
|
reflux
|
24
|
no reaction
|
|
THF
|
glacial AcOH (0.004 mmol)
|
reflux
|
24
|
no reaction
|
|
toluene
|
glacial AcOH (0.004 mmol)
|
reflux
|
2
|
63–79
|
Thus, the reaction of compounds 11 with phthalic anhydride in toluene using a catalytic amount of glacial acetic acid
at 110 °C to afford isoindole-1,3-dione derivatives 4 was found to be optimal (Scheme [4]).[18] All compounds were fully characterized spectroscopically.
Scheme 4 Preparation of triazole carboxamide 4a–d. Reagents and conditions: (a) ethanol, reflux (b) Glacial acetic acid, toluene.
Table [2] summarizes the yields of the various compounds synthesized. The infrared spectra
of carboxylates 5 exhibited a characteristic peak for an ester carbonyl group; whereas there was a
sharp decrease in the IR frequency for the carbohydrazide carbonyl group in 11 due to the amide linkage.
Table 2 Melting Points of Compounds 5, 11, and 4
|
Substituent R
|
Melting point (°C)
|
|
5
|
11
|
4
|
|
O-Me
|
oil
|
80–82
|
256–258 (decomp.)
|
|
O-NO2
|
78–80
|
136–138
|
276–275 (decomp.)
|
|
p-NO2
|
166–168
|
260–262 (decomp.)
|
296–298 (decomp.)
|
|
m-NO2
|
110–112
|
182–184
|
258–260 (decomp.)
|
These molecules were subjected to in vitro antibacterial activity against Mycobacterium smegmatis and were found to be inactive.[19]
In conclusion, a methodology to prepare triazole-isoindole-1,3-dione derivatives is
described. The methodology tolerates various functional groups and provides a way
to introduce three points of diversity into the core skeleton. The molecules were
designed to be active against tuberculosis; however, the experimental results did
not show the predicted activity.
