A novel acid-catalyzed rearrangement of 2-substituted-3-(2-nitrophenyl)oxiranes for the synthesis of di- and mono-oxalamides

A. E. Arbuzov Institute of Organic and Phys the Russian Academy of Sciences, Arbuzov s E-mail: mamedov@iopc.ru Kazan National Research Technological Uni Russian Federation † Electronic supplementary information ( and MALDI mass-spectra of the products 3 4a,b (CIF), description of quantum comparison of X-ray and DFT compute 1417946 (for 4a) and 1015263 (for 4b). Fo or other electronic format see DOI: 10.103 Cite this: RSC Adv., 2016, 6, 27885


Introduction
Oxiranes are one of the most versatile classes of organic compounds available to the synthetic chemist. 1 They can be prepared by a wide variety of methods. 2 One of the most frequently used atom economical reactions of oxiranes is their rearrangement to carbonyl compounds, and a number of reagents including a variety of Lewis acids 3 have been elaborated for this purpose.In principle, for trisubstituted oxiranes two types of rearrangements are possible depending on the migration pathways following the Lewis acid promoted C-O bond cleavage (Scheme 1).The rearrangement of I with hydride (path a) or the alkyl/aryl migration (path b) would lead to ketone II or aldehyde III, respectively.3a,4 The synthetic applications of oxiranes have been the subject of a number of reviews.1a,2,5 The promise of increased chemo-, regio-, and stereoselectivity available via transition metal catalysis 6 has led investigators to study the interactions of oxiranes with transition metal complexes, and a number of interesting and useful isomerization reactions have been reported.Notably, oxiranes activated by adjacent aryl, vinyl, silyl, or carbonyl substituents are isomerized to carbonyl compounds or allylic alcohols by complexes of Rh, 7 Pd, 8 Mo, 9 Sm, 10 Fe 11 and In. 12 Unlike all the considered reactions proceeding depending on the structure of oxirane and applied conditions of rearrangement on the path a or b, our strategy included the use of oxiranes, containing substituents with functional groups instead of the usual alkyl or aryl substituents.These functional groups promote an intramolecular condensation (cyclization) of intermediate ketone II or aldehyde III formed as a result of the above two transformations.Recently, our group reported a novel metal-free transannulation reaction of N,3diaryloxirane-2-carboxamides (AOCAs) involving a one-pot acidcatalyzed Meinwald rearrangement and intramolecular Friedel-Cras alkylation processes allowing to synthesize various 3-Scheme 1 Possible rearrangements of the trisubstituted oxiranes.
During our studies on the ring-opening/ring-closure reactions of AOCAs, we attempted to use N-aryl-3-(2-nitroaryl) oxirane-2-carboxamides (obtained from 2-nitrobenzaldehydes and 2-chloro-N-arylacetamides) with the aim of expanding the scope of the reaction.We found that compounds with a newly formed oxalamide chain were obtained instead of expected 3-(2nitroaryl)quinolin-2(1H)-ones when the reactions were carried out in reuxing AcOH in the presence of H 2 SO 4 .As far as we know, there has been no report on the synthesis of unsymmetrical oxalamides via the rearrangement yet.Herein, we report this novel acid-catalyzed rearrangement of AOCAs in AcOH, which proceeds through a cascade of the ring-opening/ ring-closure/ring-closure/ring-opening/ring-opening processes.
The salient features of our method are as follows: (1) a variety of aldehydes 1 and chloroacetamides 2 are readily available and the rapid synthesis of 3 with diverse substitution patterns are possible; (2)

Results and discussion
The procedure of the Darzens condensation is the same as that described for AOCAs, 13 except that only 2-nitrobenzaldehydes instead of variously substituted aromatic aldehydes with chloroacetamides were used and the reactions were carried out at room temperature for 7 h.The mixtures of cis-and transisomers of 3-(2-nitroaryl)oxirane-2-carboxamides (3) with the predominance of the trans-isomer were easily puried from the cis-isomer by washing with ether (Table 1).
The structures of 3a-h were proved by variety of 1D/2D NMR correlation methods (see ESI †). 15 First of all to clarify the optimal reaction conditions we examined the rearrangement of trans-3-(2-nitrophenyl)-N-phenyloxirane-2-carboxamide (3a).Aer a brief survey of the reaction conditions, we have found that the product 4a is obtained in almost quantitative yield at reux for 3 h in AcOH with 1 equiv. of H 2 SO 4 (Table 2, entry 1).The reux of 3a in both MeCN (with 1 equiv.H 2 SO 4 ) and AcOH for 3 h resulted in the mixtures containing 30 and 10% (determined by 1 H NMR) of the desired product 4a, respectively.Further optimization of the reaction conditions was carried out with trans-3-(2-nitrophenyl)oxirane-2-carboxamide (3h).The reux of 3h in H 2 O with 1 equiv.H 2 SO 4 for 5 h or its storage at room temp in AcOH with 1 equiv. of H 2 SO 4 for 24 h gave 57 and 75% of the product 4h, respectively.However, an almost quantitative yield of the rearrangement product was achieved when 1 equiv. of H 2 SO 4 was used in boiling AcOH for 3 h (entry 8).The latter condition was used for the rearrangement of all the compounds 3. The rearrangement proceeds equally well with the compounds 3 containing various substituents in an anilide moiety, no matter whether it is a strong electron donating (entry 4) or a strong electron withdrawing (entry 5) group.Interestingly, under the rearrangement conditions the    ester group (entry 6) is not subjected to hydrolysis and it can be used in further transformations.The presence of the chlorine atom with the ÀI and +M electronic effects in the aldehyde component does not inuence the yield of the rearrangement product (entry 7).
To our delight 3-(2-nitrophenyl)oxirane-2-carboxamides undergo the rearrangement with the formation of compounds which can be considered both as anthranilic acid and as unsymmetrical oxalamide derivatives.Anthranilic acid derivatives are potential anticancer agents 16 and the ligands for farnesoid X receptor. 17Oxalamides also represent a key framework of many bioactive compounds. 18They have been developed as acetylcholine esterase inhibitors, 19 C5a inhibitors, 20 nitric oxide synthase inhibitors, 21 anti-HIV agents, 22 antiepileptic drugs, 23 HIV integrase inhibitors, 24 HIV-1 proteas inhibitors, 25 cephalosporin bactericides 26 and chemioterapic agents. 27Considering the well documented medicinal utility of anthranilic acid and oxalamide derivatives, these tethered combinations of the two scaffolds afford new opportunities to probe their biological activity.
Based on above results and literature reports, 3a,4,28a-c a plausible mechanism for the rearrangement was proposed.First, the process was believed to proceed through the classical Meinwald rearrangement (Scheme 1, path a) of 3-( 2  involving hydration and dehydration processes (E / F / G / H / 4 through pathway 1 and F / G / H / 4 through pathway 2) with the participation of nitro-group and a-methylene functionalities.As a result, the reduction of the nitro-group and the transformation of the C3 atom of epoxide to the carboxylic functionality occurs (Scheme 3).
The structures of 4a-h were established unambiguously by various 1D/2D NMR correlation methods. 15First, the proton spin systems of the Ar1 and Ar2 moieties were identied by COSY/TOCSY methods.Aer that, the structures of both halves up to carbonyl groups (C 1 and C 2 ) were established (boldfaced on Fig. 1) from the 1 H- 13 C and 1 H- 15 N HSQC/HMBC connectivities.Finally, both halves were linked into a single whole on the basis of the NOEs between protons of these two fragments: Structures of the compounds 4a,b were further conrmed by single-crystal X-ray analyses (Fig. 2).
It should be pointed out that a series of synthetic methods for oxalamides have been described in the past decades. 29However, only ve examples of the synthetic methods for unsymmetrical oxalamides are known.The rst is traditional and based on the condensation of corresponding carboxylic acids with amines, which needs either activating agents or conversion into more reactive derivatives. 30The next three methods include the direct amidation of isocyanates, 31 a-keto benzotriazole 32 and trichloropyruvamides with amines. 33The h method is a novel one and is based on green H 2 O 2promoted oxidative amidation of 2-oxoaldehydes with amines. 34evertheless, these methods have several drawbacks, such as harsh conditions, expensive reagents, poor atom-efficiency and limited substrate scope.Method proposed in this study demonstrated a new, efficient and metal-free synthesis of unsymmetrical oxalamides via novel rearrangement of easily available 3-(2-nitroaryl)-oxirane-2-carboxamides.
With this result in hand, we proceeded with the study of the scope of the rearrangement.As can be seen from the suggested mechanism of the rearrangement (Scheme 3) the transformation of 3-(2-nitroaryl)oxirane-2-carboxamides to the oxalamides involves the 3-(2-nitroaryl)oxirane fragment only.Thus, seeking to expand accessible skeletal diversity using the same reaction conditions, we anticipated that use of ( 3 3).It should be pointed out that in this case, in contrast to the reactions of chloroacetanilides 2, 13 the process proceeds with high stereoselectivity with the formation of only transisomers of oxiranes 6a-d as the only products.
The structures of all compounds were proved by variety of 1D/2D NMR correlation methods (see ESI †). 15

Conclusion
In conclusion, we have discovered a new rearrangement of 3-(2nitrophenyl)-oxirane-2-carboxamides proceeding in boiling AcOH in the presence of H 2 SO 4 .The rearrangement quantitatively produces the N-(2-carboxyaryl)oxalamides as a result of cascade processes involving (a) the classical Meinwald rearrangement in its initial stage with the formation of ketone bearing an active a-methylene group, (b) transformation of carbonyl group of the ketone to the carboxylic functionality, (c) migration of active a-methylene group to the nitrogen atom of already reduced nitro group.The simple reaction conditions offer a potential for employing this method in the synthesis of complex molecules.It is anticipated that this methodology will have versatile applications in the practical syntheses of biologically important pharmaceutical molecules with anthranilic acid and oxalamide moieties.The methodology is applicable to synthesis of N-(2-carboxyphenyl)aryloxalmonoamides from (3-(2-nitrophenyl)oxiran-2-yl)(aryl)methanones.Further extension of the reaction scope and the synthetic applications of this methodology are in progress at our laboratory.

General methods
All reagents and solvents were used as purchased, without further purication melting points were determined on a hotstage apparatus.Infrared (IR) spectra samples in Nujol were recorded on a FT-IR spectrometer Bruker Vector-22 in the 400-4000 cm À1 range at optical resolution of 4 cm À1 .The high resolution MALDI mass-spectra were obtained on UltraFlex III TOF/TOF instrument in positive reectron mode; 2,5-DHB and p-NA were used as matrix and PEG-400 was used for calibration of accurate masses.All NMR experiments were performed with 600, 500 and 400 MHz (600 MHz for 1 H NMR; 150.9, 125 and 100.6 MHz for 13 C NMR;60.8 and 50.7 MHz for 15 N NMR) spectrometers equipped with 5 mm diameter gradient inverse broad band probehead and a pulsed gradient unit capable of producing magnetic eld pulse gradients in the z-direction of 53.5 G cm À1 .NMR experiments were carried out at 303 K. DPFGROE 35 and TOCSY spectra were obtained using a Hermiteshaped pulse for selective excitation.Chemical shis (d in ppm) are referred to the solvent DMSO-d 6 (d ¼ 2.49 ppm for 1 H and 39.5 ppm for 13 C NMR), to external CD 3 NO 2 (380.2ppm) for 15 N NMR spectra (conversion factor to NH 3 : À380.2 ppm). 1 H-1 H coupling constants were computed according to Bally & Rablen's recommendations. 36First the geometry was optimized at the B3LYP/6-31G(d) level.Then NMR single-point calculation of the Fermi contact J values was run at the B3LYP/6-31G(d,p) level.These values were scaled then by a factor of 0.9117.The quantum chemical calculations were performed using a Gaussian 03 soware package. 37eneral procedure for the Darzens condensation.A solution of EtONa obtained when dissolving Na (0.73 g, 0.032 g-atom) in EtOH (20 mL) was added at room temperature to the stirred solution of 2-nitrobenzaldehyde (4.08 g, 0.027 mol) with the corresponding compound 2 (0.027 mol) in EtOH (70 mL).The stirring is continued for 7 h.Treatment of the reaction mixtures as is usual for previous cases 13 led to the products 3.
only two steps are necessary beginning with the starting materials to the products 4; (3) the facile isolation of 3 and 4 are accomplished by a simple aqueous workup.

Scheme 2
Scheme 2 Our previous work and this work.

a 2 -
Chloro-N-arylacetamides 2b-f were obtained on a 0.1 mol scale at 0-15 C by reacting chloroacetylchloride with an equimolar amounts of corresponding aniline and Et 3 N.The compounds 2a and 2g are commercially available.b Ratio was determined by 1 H NMR of the crude products.c Yields refer to isolated trans-isomers of 3. d cis-Isomer of this compound was obtained early.14 Scheme 3 Proposed mechanisms of the rearrangement.

Fig. 2
Fig. 2 ORTEP plot of compounds 4a (a) and 4b (b) partial numbering scheme.Displacement ellipsoids are drawn at the 50% probability level.Hatoms are represented in stick mode for clarity.