En route towards α-benzotriazoyl nitroso derivatives

Abstract

A new class of geminally-substituted nitroso compounds, i.e. α-benzotriazoyl nitroso derivatives, is presented. These compounds display a rather different behavior than other related nitroso compounds bearing a geminal electron-withdrawing group. An unexpected and spontaneous oxidation to the nitro analog is observed in solution.

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1 Introduction

Nitroso compounds have emerged during the last decades as prominent reagents for the hydroxylation and amination of a wide variety of substrates, leading to useful 1,2-oxazines, nitrones and other aminohydroxylated building blocks.^1a–e Numerous examples of nitroso Diels–Alder cycloaddition (nDA),^2a–c nitroso-ene^3a–c and nitroso-aldol^4a–b reactions are already known. Recently, Srivastava and coworkers reported a promising gold-catalyzed annulation of nitroso arenes and alkynes.⁵ The nDA has been one of the most successfully incorporated nitroso reactions as the key step in the total synthesis of a broad range of biologically active molecules.^1a,6a–m A wide variety of nitroso reagents have emerged, ranging from the very reactive (transient) acyl nitroso compounds to the rather stable nitroso arenes.^7a,b Among these, geminally functionalized nitroso compounds (α-EWG-NO) are of particular interest: they have offered synthetic advantages in affording free 1,2-oxazines upon solvolysis of the initial Diels–Alder cycloadduct,^7b and also found biological applications for the release of nitrogen oxide (NO) and nitroxyl (HNO).^8a–e α-Chloro-⁹ and α-acetoxy nitroso^10a–c derivatives are amongst the most commonly used α-EWG-NO dienophiles, although α-cyanonitroso dienophiles have been also reported.¹¹

Their in vitro and in vivo NO/HNO-related vasodilating activities were spotlighted in 2000 by Gasco and coworkers.^8e A few years later, a seminal study by King^8d led to the development of a series of promising α-acetoxy nitroso compounds which slowly release HNO upon hydrolysis under physiological conditions and have been proven to be vasorelaxant.^8a,b In 2009, Toone et al. demonstrated that α-cyano nitroso compounds behave as NO donors.^8c

This context has prompted us to assess α-benzotriazoyl nitroso derivatives as a new class of reagents. 1H-Benzotriazole has been shown to be an extremely versatile synthetic auxiliary in organic chemistry.^12a–d We now document the synthesis, properties and reactivity of a new class of α-EWG nitroso compounds. X-ray, kinetic and computational studies rationalise the phenomena observed.

2 Results and discussion

2.1 Preparation of α-benzotriazoyl nitroso derivatives

Our first attempt to synthesize α-benzotriazoyl nitroso derivatives from their corresponding oximes 1a–c (Scheme 1) utilized 1-chloro-1H-benzo[d][1,2,3]triazole (1-CBT, 2) as an oxidizer.^13a–d

Scheme 1 Reactivity of 1-CBT and preparation of α-benzotriazoyl nitroso derivatives.

1-CBT (2) was prepared on a large scale according to a reported procedure¹⁴ and obtained in high purity after recrystallization.¹⁵ 1-CBT (2) displays global^16a–h and local¹⁷ electronic properties of interest for an oxidizer (Fig. 1): a moderate electrophilicity (ω = 1.7 eV), in contrast with other commonly used oxidizers which often lead to the overoxidation of oximes to nitro,^18a,b and a strongly electropositive chlorine atom (f⁺_Cl = 0.64) combined with the potential release of the nucleophilic benzotriazolate anion in situ.

Fig. 1 Global and local electronic properties for a selected series of nitrosation reagents (see refs 18a,b and 19a–d for experimental details). The compounds are scaled according to their global electrophilicity (ω) and local Fukui functions f⁺_Cl are indicated for the chlorine atom. The global electrophilicity was computed according to the procedure introduced by Domingo^16a–h and the Fukui functions were obtained using the procedure of Contreras.¹⁷

Despite these very promising features, the reaction of several oximes (1 in Scheme 1) in the presence of 1-CBT led exclusively to the formation of the corresponding α-chloro nitroso derivatives 3a–c in quantitative yields (Scheme 1). The incorporation of various additives (1H-benzo[d][1,2,3]triazole, sodium benzotriazolate) in the protocol did not affect the reaction. Computed heterolytic and homolytic bond dissociation enthalpies of 1-CBT revealed that the likelihood of a radical mechanism is much higher (ΔH^homo = 48.4, 44.8 and 44.7 kcal mol⁻¹ in gas phase, THF and DCM, respectively) than the expected heterolytic mechanism (ΔH^hetero = 318.9, 206.8, 203.7 kcal mol⁻¹ in gas phase, THF and DCM, respectively), in agreement with our experimental observations (see Supporting Information† for details).

Recent work by King^8d and by Kouklovsky and Vincent^10b suggested Pb^IV(OAc)₄ and iodobenzene diacetate-based reagents, and we obtained the best results from a preformed mixture of lead tetraacetate and benzotriazole (10 equiv.). Alkyl oximes derived from acetone (1a), 2-butanone (1b), and cyclohexanone (1c) led to their corresponding α-benzotriazoyl nitroso derivatives 4a (55%), 4b (51%) and 4c (74%) in dry THF at room temperature (Scheme 1).²⁰ In dry dichloromethane, the corresponding yields were considerably lower.

2.2 Properties of α-benzotriazoyl nitroso derivatives

The behavior of nitroso compounds 4a,b differed from that of 4c. Compounds 4a,b formed white powders, but bright blue solutions, suggesting that the azodioxy dimer is the major form in the solid state but dissociates in solution into the monomeric nitroso derivative. This was confirmed by the observation of a signal at ∼1290 cm⁻¹ in the solid state IR spectra. Contrastingly, compound 4c was isolated as a monomeric nitroso derivative. The shelf-life of compound 4c was over 4 months at room temperature, in deep contrast with the short shelf-life of its chloro- and acetoxy-analogs. The chloro-analog 3c decomposed after 3 days at −10 °C.

Compound 4c was submitted for single crystal X-ray diffraction, resulting in interesting information about the solid state and confirming the monomeric nitroso structure (see Supporting Information†). The benzotriazoyl moiety appeared to be exclusively bonded at the quaternary carbon via the N² position. From the collected X-ray data sets, a single endo conformer of compound 4c was detected (with nitroso group in an equatorial position and endo versus the benzotriazoyl system). This specific conformation could result either from the emergence of favorable π-system interactions, electrostatic repulsion between the lone pair of the nitrogen and the aromatic benzotriazoyl system (exo lone pair effect),²¹ or a combination of both phenomena. Computations at the B3LYP/6-31+G* level of theory showed that the conformer bearing the ²Bt substituent in an axial position and the nitroso moiety in a relative equatorial endo position was indeed the most stable. This specific relative position allows for the antiperiplanar alignment of the NO nitrogen lone pair and the σ^*_C-Bt2 and therefore increased vicinal negative hyperconjugation.²² A NBO²³ analysis confirmed this assumption and showed that the nitrogen N² lone pair on the benzotriazole substituent was similarly involved in a strong stabilizing negative hyperconjugation with the σ^*_C-NO, consequently weakening the corresponding σ bond.

2.3 Reactivity of α-benzotriazoyl nitroso derivatives

The computed global electrophilicity (ω) of α-benzotriazoyl nitroso compound 4c allowed its ranking on the electrophilicity scale.^16a–h Compound 4c showed up in the same electrophilicity range (ω_Bt = 2.6 eV) as its chloro- and acetoxy-analogs (ω_Cl = 2.6 eV and ω_AcO = 2.9 eV), i.e. as a moderate electrophile. Interestingly, compound 4c was inactive as a dienophile even after prolonged reaction time in the presence of an excess of 2,3-dimethylbutadiene or cyclopentadiene in various solvents (see Supporting Information†), while its chloro- and acetoxy-congeners have been known as dienophiles for decades.^7b,9,10a-c This experimental observation contrasted with the rather similar computed activation barriers for the cycloaddition of model 2-nitrosopropane (A), benzotriazoyl- (B), chloro (C)- and acetoxy-derivatives (D) (Fig. 2). The cycloaddition step was computed for 2-nitrosopropane (A) in order to scout the impact of the leaving group on the cycloaddition step.

Fig. 2 Picture of the TSs associated with the cycloaddition of the selected model nitroso compounds onto butadiene. For each situation, 4 isomeric TSs have been isolated due to the relative endo/exo approach of the dienophile and the relative syn/anti orientation of the EWG group vs. N=O. The results presented are relative to the most stable TS (endo/anti; see details in the Supporting Information†). Activation free energies (ΔG^≠) are indicated in kcal mol⁻¹: A: 26.6; B 27.3; C 27.2; D: 26.5.

The activation barriers for the cycloaddition step (B3LYP/6-31+G*) were relatively independent of the nature of the leaving group (Fig. 2). To explain the observed lack of dienophile character for compound 4c, two main hypotheses have risen: (i) a more pronounced impact of the nature of the leaving group on the subsequent steps (i.e. elimination and solvolysis) (ii) the existence of a competitive reaction pathway for 4c in solution. The first hypothesis was dismissed on the basis of the excellent abilities of benzotriazole to act as leaving group in a plethora of reactions.^12a–d The second hypothesis materialized upon the observation of various side-products depending on the reaction conditions. When solutions of compound 4c in various solvents were left in an open flask for 15 h, compound 4c was quantitatively converted into 2-(1-nitrocyclohexyl)-2H-benzo[d][1,2,3]triazole 6 (Scheme 2), whereas in degassed and dry THF a complex mixture was observed after 15 h, likely arising from the spin-trapping of radicals by 4c.^8c,24 Addition of TEMPO to a degassed solution of 4c led to the progressive disappearance of the typical blue coloration of 4c and formed a complex mixture of spin-trapped compounds.^8c,24

Scheme 2 Proposed mechanism for the formation of 2-(1-nitrocyclohexyl)-2H-benzo[d][1,2,3]triazole 6 from 4c.

The rationale for the mechanism depicted in Scheme 2 was built on the following observations and computations: (i) apparent first order k_obs = 3.1, 2.0, 1.8 and 1.4 × 10⁻⁵ s⁻¹ were determined in methanol, acetonitrile–water, acetonitrile and dichloromethane, respectively (Fig. 3); (ii) the presence of a large excess of oxygen (bubbled through the solution) did not impact on the rate of disappearance; (iii) rather high one-electron redox potentials E° were computed and (iv) isodesmic heat (ΔH^iso) for radical exchange, radical stabilization energies (RSE)²⁵ as well as homolytic bond dissociation energies (BDE) for compounds 4c, 4d and 3c were computed (Tables 1–2).

Fig. 3 (A.) Apparent (k_obs) first order disappearance of 4c in different solvents (top) and of compounds 4a–c in dichloromethane (bottom). (B.) The kinetics for the disappearance of compounds 4a–c were determined by UV-spectrophotometry at 20 °C in different solvents by following the decrease of the typical nitroso signal (λ_max = 655.7 nm, 10 mg mL⁻¹).

Table 1 Isodesmic reactions for radical exchange on different cyclohexyl substrates and corresponding radical stabilization energy (RSE)

R	ΔH^iso (kcal mol^−1)	RSE (kcal mol^−1)
Me	−10.8	10.8
Cl	−10.2	10.2
Ph	−19.3	19.3
^2Bt	−30.9	30.9

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Table 2 Homolytic bond dissociation energies (BDE) for compounds 4c, 4d and 3c

X	BDE (kcal mol^−1)
^2Bt (4c)	22.4
CN (4d)	19.8
Cl (3c)	30.6

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The kinetics display only moderate dependency on solvent polarity which suggested implication of radical species rather than charged intermediates. An additional set of experiments using different concentrations (5 and 20 mg mL⁻¹) for compound 4c in acetonitrile gave different half times (t_1/2 = 266.6 and 495.1 min, respectively). This observation is consistent with the formation of an inactive reservoir of nitroso compound 4c as its azodioxy dimer at higher concentration. The second observation, i.e. the apparent lack of impact of an excess of oxygen in the reaction mixture, reinforced the mechanism proposed in Scheme 2. As per Fig. 2, the steric hindrance of the backbone on ^αC has a profound impact on the reactivity (t_1/2 = 223.6 (4a), 247.6 (4b) and 495.1(4c) min).

The one-electron redox potential E° was computed in methanol using standard procedures (see free energy cycles in the Supporting Information†).^26a,bE° (MeOH) = 5.5, 6.4 and 6.2 V for 4c, 4d and 3c, respectively (E° = 6.5 V for the reference MeNO) indicated that these compounds are quite resistant to oxidation and require strong oxidizers, in agreement with previously reported data.^27a–c

RSE emphasized that the ²Bt substituent stabilizes a radical much better than a phenyl does (Table 1). Further proof was obtained by computing homolytic bond dissociation energies (BDE) for the release of nitric oxide from compounds 4c, 4d and 3c (see Supporting Information† for heterolytic bond dissociation energies). These revealed that the homolytic bond rupture for the benzotriazoyl compound was very close to the value obtained for the reference 4d (Table 2),^8c emphasizing its propensity to release the radical intermediate 5 (Scheme 2). The release of NO was not detected by GC-MS; subsequent rapid oxidation of the side product NO by atmospheric oxygen led to nitrogen dioxide,^28a which very likely underwent recombination with the stabilized radical 5.^28a–d Compound 6, the structure of which has been unambiguously determined by X-ray diffraction, was exclusively formed under aerobic conditions.²⁹

3 Conclusion

In this communication, we have documented the synthesis, properties and reactivity of a new class of reagents, namely α-benzotriazoyl nitroso compounds. α-Benzotriazoyl nitroso compounds were conveniently obtained via the oxidation of the corresponding oximes in the presence of lead tetraacetate and a large excess of benzotriazole. The benzotriazole is anchored to the nitroso-substrate exclusively at the ²N position. Despite comparable activation barriers, α-benzotriazoyl nitroso compounds were not reactive towards dienes, in contrast with their α-chloro and α-acetoxy analogs. An unexpected oxidation – not observed for other α-EWG analogs – was found to occur in solution leading to the exclusive formation of α-benzotriazoyl nitro compounds. The mechanism most likely involves a rate-determining homolytic cleavage of the parent nitroso, releasing NO which is readily oxidized in solution, followed by subsequent recombination to yield the nitro analog.

Acknowledgements

This work was supported by the Research Foundation-Flanders (FWO-Vlaanderen; fellowship to JCMM). JCMM acknowledges the ICT Department of Ghent University for access to HPC facilities. The authors acknowledge the Kenan Foundation (University of Florida) and the King Abdulaziz University (Saudi Arabia) for their financial support.

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29. Procedure for the synthesis of 2-(1-nitrocyclohexyl)-2H-benzo[d][1,2,3]triazole 6 . A solution of 2-(1-nitrosocyclohexyl)-2H-benzo[d][1,2,3]triazole 4c (1.15 g, 5.0 mmol) in 50 mL dry methanol was stirred for 15 h in an open flask. The solvent was evaporated and the resulting white solid was recrystallized from a 10 : 1 hexanes–dichloromethane mixture. Yield: 92% (1.21 g, 4.9 mmol), white microcrystals. m.p. 143.0–145.0 °C. ¹H (300 MHz, CDCl₃): 1.30–1.72 (m, 4H), 1.86–1.99 (m, 2H), 2.72 (dt, J = 13.1, 13.1, 4.0 Hz, 1H), 3.44–3.44 (m, 2H), 7.41–7.49 (m, 2H), 7.86–7.95 (m, 2H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 22.6, 24.0, 34.1, 105.1, 119.1, 128.1, 145.0 ppm. Crystal data for compound 6: white crystal (rods), dimensions 0.55 × 0.29 × 0.26 mm, crystal system orthorhombic, space group P2₁2₁2₁, Z = 4, a = 5.9246(9), b = 11.7114(19), c = 16.898(3) Å, β = 90.00°, V = 1172.5(3) ų, ρ = 1.395 g cm⁻³, T = 100(2) K, Θmax = 31.73°, radiation Mo-Kα, λ = 0.71073 Å, 0.3 ω-scans with CCD area detector, covering a whole sphere in reciprocal space, 8626 reflections measured, 2124 unique (R_int = 0.0554), 2045 observed (I > 2σ(I)), intensities were corrected for Lorentz and polarization effects, an empirical absorption correction was applied using SADABS22 based on the Laue symmetry of the reciprocal space, m = 0.099 mm⁻¹, Tmin = 0.6747, Tmax = 0.7463, structure solved by direct methods and refined against F2 with a full-matrix least-squares algorithm using the SHELXL-97 software package, 163 parameters refined, hydrogen atoms were treated using appropriate riding models, goodness of fit = 1.071 for observed reflections, final residual values R1(F) = 0.0346, wR(F2) = 0.0888 for observed reflections. CCDC 883510†.

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Footnote

† Electronic Supplementary Information (ESI) available: Detailed computational procedures, cartesian coordinates for the isolated transitions states, kinetic data, ¹H and ¹³C NMR for compounds 4c and 6 and thermogravimetric analysis of 1-CBT. CCDC 883509-883510. See DOI: 10.1039/c2ra21311g/

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