On the reactions of tertiary carbanions with some nitroindazoles and nitrobenzotriazoles

The vicarious nucleophilic substitution in some nitroindazole and nitrobenzotriazole derivatives with tertiary carbanions leads almost exclusively to products substituted para to the nitro group. As results from the theoretical calculations and structural evidences, such reaction outcome is due mainly to the stereoelectronic reasons in combination with the considerable shortening of the C ortho –CNO 2 bond. The presence of the chiral and prochiral centres (the methine and N-methylene groups, respectively) often gives rise to additional splitting of the methylene protons signal that is transmitted on a long distance provided there is no pyridinic nitrogen in the pathway of coupling.


Introduction
Ortho-substituted nitroarenes are useful starting materials for the synthesis of many heterocyclic compounds.One of the most practical methods that lead to the ortho-substituted derivatives of nitroarenes is the vicarious nucleophilic substitution (VNS).The VNS is a two-step reaction consisted in the addition of a carbanion, containing a leaving group X at the carbanionic centre, to a nitroarene followed by the base-induced -elimination of HX from the  H -adduct formed in the first step. 1The reaction is the best practical method that allow introduction of a new substituent into an azole or benzazole ring by using nucleophilic reagents. 2,3The VNS products with a functional alkyl substituent ortho to the nitro group are particularly useful for the synthesis of indole and quinoline derivatives. 1,4,5Some VNS products are useful starting materials for the synthesis of biologically active compounds, like recently reported potent and selective 5-HT6 antagonists. 6We employed such VNS products to the synthesis of indazole and condensed pyrazole derivatives that showed promising anticancer activity and were screened for anxiolytic effect. 7,8However, in the synthesis of some ortho-substituted nitroderivatives, we encountered severe problems when using tertiary carbanions or secondary carbanions containing poorer leaving groups than the chloride or thiophenoxide ions. 9,10In this paper we report our findings concerning the factors responsible for the VNS orientation in some nitrobenzazoles.Our results bear some relationship with those about the electrophilicity of nitroarenes and nitrohetroarenes published recently by the Mąkosza group. 11,12

Results and Discussion
The starting materials for the reactions described in the next paragraph were obtained by ethylation of nitroindazoles 1, 5, and 7, as well as 4-nitrobenzotriazole 10 (Scheme 1).

Scheme 1
The structures of benzotriazole derivatives 11-13 were confirmed by comparison of their 1 H and 13 C NMR spectra with the spectra for the corresponding N-methyl derivatives 13 and the NOE difference experiment performed for the amino derivative 14; the latter was obtained by hydrogenation of 13 (Scheme 1).Irradiation of the amino protons resulted in enhancements of the neighbouring signals, namely 6-H doublet of doublets, CH2 quartet and CH3 triplet.

Scheme 2
In one of our initial experiments, we tried to obtain an ortho-substituted 4-nitroindazole derivative 18.Under the typical for ortho substitution conditions, i.e. t-BuOK as a soluble base, DMF as a solvent and low temperature (-45 °C), 1 the synthesis led to a single isolable product (Scheme 2) but the reaction mixture contained a significant amount of tars.With only the 1 H NMR spectrum at hand, we were convinced that compound 18 was the desired ortho isomer.However, when the reaction was repeated under the conditions favourable for the para orientation (KOH/DMSO at room temperature), its outcome was identical.
The 1 H NMR spectrum of compound 18 (Figure 1) displays several signals in the aromatic region confirming the disubstituted benzene part of the indazole ring, namely a singlet at 8.58 ppm for the 3-H proton, a doublet at 8.20 ppm for the 5-H proton and two multiplets between 7.57 and 7.78 ppm for the PhSO2 group; the latter multiplet overlaps with the doublet for the remaining 6-H proton.The coupling constant for the doublet at 8.20 ppm ( 3 J 8.2 Hz) could not be conclusive whether the benzene part of the indazole ring is ortho-or para-substituted, thus we decided to register a NOE difference spectrum.Irradiation of the methine proton at 5.22 ppm, gave a significant NOE on the N-CH2 protons at 4.57-4.77ppm as well as on the CH-CH2 (2.24-2.33 ppm) and C-CH 2 CH3 (0.82 ppm) protons.A weak enhancement of the CH 3 triplet of the Nethyl group (1.43 ppm) was also observed.This clearly shows that the methine proton and Nethyl group are in close proximity and the benzene ring is para-substituted.The signal for the N-CH2 protons is particularly interesting due to its atypical splitting: instead of the expected quartet it appears as a complex multiplet (Figure 1).Also the methine signal is observed as a triplet with some residual splitting instead of a doublet of doublets.A part of the mystery was resolved by registering the NMR spectra for 18 at higher temperatures (Figure 2).At 60 °C the signal for methine proton appeared as a doublet of doublets and several lines disappeared from the complex N-CH2 multiplet.The latter one was then observed as a clean nonet.The unusual splitting of the N-CH2 signal is thus due to two factors: (i) hindered rotation and (ii) the presence of the chiral centre (the methine proton) in close proximity.The latter factor renders the N-methylene protons diastereotopic and not equivalent, and therefore they exhibit further splittings as they couple to each other.
To verify such reasoning, we obtained several indazole and benzotriazole derivatives with or without the chiral centre (Schemes 2 and 3).
Similarly to the starting material 3, the VNS in 1-methyl-4-nitroindazole (2) using the carbanion precursor 15 led to a single product 17 (Scheme 2) whereas, as expected, the reaction of compound 3 with 16 gave two isomers 19 and 20.Compound 17 as well as isomers 19 and 20 contain neither prochiral methylene protons (17) nor a chiral centre (19 and 20).A normal singlet is observed for the N-methyl group in 17 and a typical quartet is seen for the methylene protons both in 19 and 20.Only the para isomer 22 was detected and isolated from the reaction mixture containing compounds 4 and 15 as starting materials and KOH/DMSO as a base/solvent system (Scheme 2).Its 1 H NMR spectrum shows a similar pattern concerning the signals for the N-methylene protons like that for compound 18, i.e. a symmetrical multiplet, consisting this time of ten lines, instead of a typical quartet.However, in contrast to compounds 2 and 3, the starting material 4 gave two isomers 21 and 22 when treated with the carbanion precursor 15 in t-BuOK/DMF at low temperature (Scheme 2).Moreover, the ortho isomer 21 was the major product of the reaction: 25% vs. 10% for isomer 22.Such change in the VNS orientation is primarily caused by the presence of the peri unshared electron pair on the nitrogen atom N1.This electron pair retards both the approach of the carbanion to position 7 and the base attack in the elimination step, and thus forces the VNS at position 5.It is noteworthy that the 1 H NMR spectrum of 21 reveals an identical multiplet for the N-methylene protons like for the para isomer 22 regardless of the fact that the distance between these protons and the chiral centre is quite long.1a).
The VNS reaction of compound 6 with 15 did not lead to any isolable product.Despite using a variety of reaction conditions, we were able to recover only the starting material 6 (32-57%) from the reaction mixtures that contained usually significant quantities of tarry products.The most apparent rationale for the reaction failure is the stereoelectronic hindrance caused by the nitro group and unshared electron pair at N1, both in close proximity to the reaction site.Likewise reactant 3, compound 8 gave only the para substituted product 23 regardless of the conditions applied (Scheme 2).Strikingly, in the 1 H NMR spectrum of 23, the signal for N-CH2 protons appears as a typical quartet rather than a complex multiplet as opposed to the N-CH2 signals for indazoles 18, 21, and 22 described above (albeit some residual lines can be seen within this quartet), and the same signal in the spectrum of benzotriazole 24.The latter compound was the sole product obtained from the reaction of nitrobenzotriazole 11 with the carbanion precursor 15 in both base/solvent systems (Scheme 3).In its 1 H NMR spectrum, an AB systemdoublets at 7.72 and 8.33 ppm with ortho coupling 3 J 8.4 Hzindicates a parasubstituted benzene ring in benzotriazole rather than ortho as the coupling constant for the latter is substantially larger and close to 9 Hz. 14The 1 H NMR spectrum of 24 shows similar diastereotopism like the spectra for indazoles 18, 21, and 22, i.e. the N-methylene protons signal takes shape of a symmetrical multiplet, this time consisting of 12 lines.The difference in number of lines present in the multiplets for N-methylene protons in compounds 18, 21, 22, and 24 may be due not only to the hindered rotation (compound 18) but also to overlapping of some lines within the multiplets.

Scheme 3
The effect of diastereotopic N-methylene protons is not observed for other benzotriazole derivatives 25-27 (Figure 1) obtained by the VNS from starting materials 12 and 13 (Scheme 3, we were unable to isolate an analytically pure sample of 26 but the 1 H NMR of the reaction mixture showed its presence in an about 21% yield).In the 1 H NMR spectra registered for compounds 25-27, the signal for these protons appears as a typical quartet.
The suppression of the additional splitting of N-methylene signal in the spectra of benzotriazole derivatives 25-27 is due to the presence of the pyridinic nitrogen N3 in the pathway of possible coupling.We tried to quantify the effect using theoretical calculations.Although we have not overly been successful, some of our findings are worthy of mention.The Natural Bond Orbitals (NBO) analysis showed the presence of a high-energy molecular Rydberg orbital RY* on N3 with the following contribution of atomic orbitals: s 2.17%, p 93.10%, and d 4.73%.This analysis revealed also the presence of a two-centre Lewis orbital BD with a high occupancy value that connected atoms N2 and N3.The above features can be useful in the interpretation of the UV spectra of some benzotriazoles.
In summary, the presence of the chiral centre within a molecule of N-ethylindazole and Nethylbenzotriazole often gives rise to further splitting of the N-methylene signal.The effect is transmitted through the  system on a long distance, even through seven bonds (compound 21), provided that there is no pyridinic ring nitrogen in the way of possible coupling.To determine which factors are responsible for the practical lack of the substitution ortho to nitro group in nitroindazoles and nitrobenzotriazoles, we referred to theoretical calculations and X-ray crystallography.In nitroindazoles 3, 4 and nitrobenzotriazoles 11, 12, the charge distribution obtained by the calculations is characterized by a noticeable withdrawal of the electron density from the benzene ring into the nitro group (Table 1).The electrons tend to accumulate on the oxygen atoms and ring nitrogens.A particular low electron density is found on the carbons neighbouring the nitrogen atoms, i.e. the ipso carbon C4, bridge carbons C7a and C3a (the latter one only in benzotriazoles), and carbon C3 in indazoles.The calculations reveal small differences in charges between the ortho and para carbons, both in indazole and benzotriazole derivatives.Even though these dissimilarities, favouring the para positions by only 0.04 electrons, are not enough large to alter significantly the direction of carbanion attack, they may add some impact to the stereochemical discrimination between these positions described in the next paragraph.Figure 3 shows the X-ray structure of compound 18.As expected, the indazole ring is planar but the nitro group is not coplanar with the ring; it is twisted of the ring plane by 3.58°.The nitrobenzene ring of indazole derivative 18 reveals considerable deviations concerning some bonds in comparison with nitrobenzene.The C4-C5 bond is particularly short (1.35 Å vs. 1.3989Å in nitrobenzene 15 ).As a similar value for the C4-C5 bond length can be predicted for nitroindazole 3, this bond shortening may be crucial for the orientation in the nucleophilic substitution.The other exo bond, namely C6-C7 is also significantly shorter than the C5-C6 endo bond (1.367 Å vs. 1.411Å).This means that the antiperiplanar conformation required for the elimination is severely hindered in the ortho  H adduct, hence the ortho substitution involving bulky tertiary carbanions is usually not observed for nitroindazole derivatives even when the reaction is carried out under the conditions more favourable for the kinetic ortho product (t-BuOK/DMF/low temperature).Only when using the 2-substituted nitrobenzazoles of dienoid structure 4 and 12 as starting materials, we were able to detect both ortho and para isomers in the reaction mixture (compounds 21 and 22 as well as 25 and 26).This change in the VNS orientation is mainly due to the stereoelectronic hindrance of the peri unshared electron pair on N1.   16 Worth mentioning is considerable lengthening of the bond between methine carbon and proton: 1.20 Å in comparison with the standard length for a Csp 3 -H bond -1.083Å. 17 The intermolecular hydrogen bonds keep the molecules of 18 in a three-dimensional aggregation (Figure 4a).The unit cell contains four molecules.The indazole and phenyl rings from separate molecules are arranged alternatively forming infinite stacks.The extent of stacking is significant.Moreover, the stacking between the phenyl and pyrazole rings is considerably larger than the stacking between the phenyl and benzene rings (Figure 4b).Both above depicted interactionsthe weak hydrogen bonding and - stackingmay have an important value in the molecular recognition involving indazole ring.

Experimental Section
General.Flash chromatography (FC) was performed using silica gel 60, 230-400 mesh (Merck), Low Pressure Liquid Chromatography (LPLC)the Michael-Miller system and 15-40 silica gel (Merck), gradient chromatographysilica gel 60, 60-230 mesh (Merck).Melting points were determined on a Boetius apparatus and are uncorrected. 1H NMR were recorded at 300 (Varian Mercury 300), 400 (Varian VNMR-S), or 600 MHz (Bruker Avance 600) in DMSO-d6 with TMS as an internal standard.When necessary, the position of the phenylsulfonyl substituent attachment at the hetarene ring was proved by NOE differential spectra. 13C NMR spectra were registered at 100 or 150 MHz using Varian VNMR-S or Bruker Avance 600 spectrometers, respectively.Low resolution mass spectra were recorded on an AMD Intectra Mass AMD 402 instrument operating at 75 eV.IR spectra were run in KBr on a Specord 75-IR apparatus.Elemental analyses were performed on a Vario EL III instrument.Starting materials, apart from those described below, were obtained by known procedures (2 18 , 15 and 16 19 ) or were commercially available.

(a) compound 18 (b) compound 26 Figure 1 .
Figure 1.Examples of the 1 H NMR spectra with expanded regions containing the signals for methine and N-methylene protons: (a) revealing the interaction between the chiral and prochiral centres; (b) devoid of this interaction due to suppression by the pyridinic nitrogen.

Figure 2 .
Figure 2. The 1 H NMR spectra for compound 18 registered at 40, 60, and 80 °C, showing signals for the methine proton and N-methylene protons (the spectrum recorded at ambient temperature is shown in Figure1a).

Figure 4 .
Figure 4. (a) Cross section through the stacks of 18 (hydrogen atoms are omitted).(b) Superimposition of pyrazole and benzene rings in the stacks.