Selective cross-dehydrogenative C – O coupling of N -hydroxy compounds with pyrazolones. Introduction of the diacetyliminoxyl radical into the practice of organic synthesis †

Oxidative C – O coupling of pyrazolones with N -hydroxy compounds of di ﬀ erent classes ( N -hydroxyphthalimide, N -hydroxybenzotriazole, oximes) was achieved; both one-electron oxidants (Fe(ClO 4 ) 3 , (NH 4 ) 2 Ce(NO 3 ) 6 ) and two-electron oxidants (PhI(OAc) 2 , Pb(OAc) 4 ) are applicable, and the yields reach 91%. Apparently, the coupling proceeds via the formation of N -oxyl radicals from N -hydroxy compounds. One of the N -oxyl intermediates, the diacetyliminoxyl radical, was found to be exclusively stable in solution in spite of being sterically unhindered; it was isolated from an oxidant and used as a new reagent for the synthesis and mechanism study. The products of C – O coupling of pyrazolones with N -hydroxyphthalimide can be easily transformed into aminooxy compounds, valuable substances for combinatorial chemistry.


Introduction
The development of C-C and C-heteroatom cross-dehydrogenative coupling (CDC) methods is one of the major trends in modern organic synthesis and green chemistry. Such methods avoid prefunctionalization of coupling partners (with -Hal, -OTf, -SnBu 3 , -B(OH) 2 , and other groups) and thus afford high atom and step economy (Scheme 1). 1 C-O bonds are abundant in natural and synthetic organic compounds, which makes the development of C-O cross-dehydrogenative coupling (C-O CDC) desirable. Nevertheless, C-O CDC remains one of the most challenging types of oxidative couplings 1c-f due to the ease of side oxidation processes.
Usually a new C-O bond between two molecules is formed via reductive elimination in a metal catalyzed process or as a result of the reaction of an O-nucleophile with a C-electrophile (Scheme 2). 1c O-Reagents are frequently used in excess amounts to maintain the selectivity, which limits the scope of O-reagents to simple molecules. To overcome the mentioned limitations and open new coupling possibilities, we focused our attention on O-radicals as intermediates for C-O bond formation. N-Oxyl radicals derived from the N-hydroxy compounds proved to be useful for intramolecular cyclizations, 2 CvC bond functionalization, 3 oxidation, 4 C-O CDC with alkylarenes, 5a,b β-dicarbonyl compounds, 5c,d and aldehydes. 5e,f Nevertheless, structural diversity of C-reagents for the coupling and N-oxyl intermediates remains limited. In the present study we demonstrated the applicability of N-oxyl radicals for oxidative coupling with heterocyclic compounds. Pyrazolones were chosen as heterocycle representatives because they are both challenging substrates for radical coupling due to the easiness of their oxidation and oxidative dimerization 6 and important compounds for medicinal chemistry.
Methods for pyrazolone functionalization have been intensively developed in the last few years, but almost all of them are conceptually based on the same principle, namely, electrophilic attack on position 4 of the heterocycle (Scheme 3).
Diaryliodonium salts, 12a nitroalkenes, 12b 4-oxo-4-arylbutenoates, 12c alkynones, 12d azodicarboxylates, 12e isatin-derived N-Boc ketimines 12f and diacyl peroxides 12g were used as electrophiles. A rare example of free-radical oxidative C-S coupling of pyrazolones with thiophenols was reported recently (Scheme 3). 12h In the present study free-radical oxidative C-O coupling of pyrazolones with N-hydroxy compounds is reported (Scheme 3). Typical problems for O-centered radicals, harsh generation conditions and low selectivity, were successfully circumvented. A substantial insight into the nature of a free-radical coupling mechanism was achieved by the discovery of a new freeradical reagent, the diacetyliminoxyl radical, which previously was known as the only plausible intermediate. 5d
When oxime 2b was used instead of NHPI 2a, a different order of oxidant efficacy was observed (runs 11-20), Fe(ClO 4 ) 3 being still the best. In the case of (NH 4 ) 2 Ce(NO 3 ) 6 , the low yield of 4 can be attributed to the instability of iminoxyl radicals derived from oxime 2b in the presence of (NH 4 ) 2 Ce (NO 3 ) 6 . 5d With the optimized conditions in hand we tested the scope of the discovered coupling (Table 2). Under universal reaction conditions (Fe(ClO 4 ) 3 as the oxidant, 60°C, 10 min) pyrazolin-5-ones 1 reacted smoothly with N-hydroxy compounds of different classes: NHPI ( products 3a-3i), oximes ( products 4-16), and N-hydroxybenzotriazole ( products [17][18]. Lower yields were obtained in the reaction of NHPI with pyrazolones containing a phenyl substituent ( products 3h and 3i). We pro- (NH 4 ) 2 Ce(NO 3 ) 6 (2) 10 60 24 19 Pb(OAc) 4 (1) 10 60 43 20 PhI(OAc) 2 (1) 10 60 30 a AcOH was used as the solvent. posed that these pyrazolones are oxidized faster than NHPI with the formation of side products. Indeed, when the reagent addition order was changed and NHPI was mixed with an oxidant to generate N-oxyl radicals before the addition of pyrazolones, the yields of products 3h and 3i substantially increased (Table 2, yields with notes c and d).
In the row of N-hydroxy compounds the yield depends on the stability of the corresponding N-oxyl radicals. The lowest yield was obtained with the oxime of ethyl pyruvate (18%, product 9).
A plausible mechanism of the oxidative coupling of pyrazolones with N-hydroxy compounds is depicted in Scheme 5. N-Oxyl radicals are generated from N-hydroxy compounds under the action of an oxidant. Then two sequences are possible: the attack of an N-oxyl radical on pyrazolone (A) followed by oxidation or oxidation of pyrazolone (B) followed by the addition of the radical.
The formation of N-oxyl radicals from NHPI under the action of used oxidants was confirmed by EPR spectroscopy (Scheme 6 and ESI †). The formation of iminoxyl radicals from oxime 2b under analogous conditions was reported earlier. 5d

Diacetyliminoxyl free radical
The detection of a free radical under the reaction conditions does not prove its participation in the process and does not reveal its exact role. It is desirable to directly observe the "individual" reactivity of radicals in the absence of other reagents, such as oxidants used for their generation, which is usually impossible due to the high reactivity of free radicals, including sterically unhindered N-oxyl radicals with acceptor groups. To solve this problem, a method for the synthesis of diacetyliminoxyl radical 21, 13 a plausible intermediate, was developed (Scheme 7).
Oxidation of 2b with Pb(OAc) 4 gave rise to oxime radical 21 with almost quantitative yield based on EPR (see the ESI †). Radical 21 turned out to be surprisingly stable despite being sterically unhindered; it tolerated column chromatography on silica gel and the resulting dark red solution of 21 in CH 2 Cl 2 (ca. 0.04 M) was stored at room temperature for 2-5 days without a significant decomposition detectable by EPR or FTIR spectroscopy. As far as we know it is record stability for the unhindered oxime radical that was not reported previously. 13 Oxime radical 21 reacted with pyrazolones 1a, c, i, and h giving C-O coupling products 4, 12, 15, and 16, respectively, and oxime 2b (Scheme 8). Apparently, one equivalent of 21 formed the product and another one played the role of the oxidant. The yields are close to that obtained with in situ generation of iminoxyl radicals using Fe(ClO 4 ) 3 (see Table 2). These results are convincing evidence in favor of the mechanism depicted in Scheme 5.
It should be noted that the structure of the synthesized radical 21 has little in common with known stable N-oxyl radicals (Chart 2). The majority of the stable N-oxyl radicals are amine-N-oxyl radicals. Only some representatives of this extensive type of radicals are depicted. This class includes both cyclic structures (TEMPO, 14 AZADO, 15 ABNO, 16 IAPNO, 17 nitronyl nitroxides 18 ) and acyclic structures (Fremy's salt, 19 bis (trifluoromethyl)nitroxide, 20 TIPNO and others 21 ). These N-oxyl radicals found wide use in various fields 22a,b including oxidation processes, 15b,16a,17,22a-d "living" radical polymerization, 21b,c,22a spin-labeling 22e and synthesis of magnetic materials. 18b,c,22f Stable oxime radicals (imine-N-oxyl type) are very rare and highly hindered, examples are di-tert-butyliminoxyl radical and di(1-adamantyl)iminoxyl radical (Chart 2). 23 An important feature of radical 21 is its synthetic accessibility: the parent oxime can be prepared in one simple step from acetylacetone, NaNO 2 and H 2 SO 4 . 24 Synthetic application of the coupling products Finally, the synthetic utility of some of the synthesized products was tested (Scheme 9). Novel O-substituted hydroxyl-amines 24a, c, d, and f were synthesized from products 3a, c, d, and f without the need for chromatographic purification. In the case of the product 3a one-pot deprotection/condensation sequence was demonstrated to obtain oxime ether 25.

Conclusions
In conclusion, a new type of oxidative C-O coupling was realized, the method was applied to a wide range of N-hydroxy compounds and pyrazolones. N-Oxyl radicals are identified as key intermediates that selectively add to position 4 of the pyrazolone ring. The first method for the synthesis of the diacetyliminoxyl radical in solution was proposed. This radical can be used as an easily available reagent and a model radical for mechanistic studies.

General reaction conditions for
General procedure b (experiments in Table 2 with note b): to a mixture of pyrazolone (1.5 mmol), N-hydroxy compound (1.5 mmol) and MeCN (5 mL) stirred at room temperature, (NH 4 ) 2 Ce(NO 3 ) 6 (3 mmol) was added; stirring was continued for 20 min at room temperature.
General procedure c (experiments in Table 2 with note c): to a mixture of N-hydroxyphthalimide (1.5 mmol) and MeCN (5 mL) stirred at room temperature, (NH 4 ) 2 Ce(NO 3 ) 6 (3 mmol) was added for 5-10 seconds, stirring was continued for 4 min, and then pyrazolone (1.5 mmol) was added portion wise for 7-10 min; after the complete addition of pyrazolone, stirring was continued for 5 min at room temperature.
The products 3a-i, 4-18, 20a, b, and h were isolated as described for 3a in experiment in Table 1.
Generation and characterization of diacetyliminoxyl radical 21 (experimental details for Scheme 7) All experiments with diacetyliminoxyl radical 21 were conducted at room temperature (18-23°C).
Diacetyl oxime 2b (258 mg, 2 mmol) was dissolved in CH 2 Cl 2 (4 mL) at 18-23°C, and then Pb(OAc) 4 (467 mg, 1 mmol) was added with vigorous stirring. The mixture immediately turned dark red, stirring was continued for 10 min, and then the mixture was transferred to the chromatographic column, prepared by suspending the silica gel (12 g) in excess of CH 2 Cl 2 . CH 2 Cl 2 was used as an eluent, and the fraction corresponding to the dark-red spot was collected, so that the volume of the fraction was 50 mL. The obtained solution of diacetyliminoxyl radical 21 in CH 2 Cl 2 (50 mL, C ≈ 0.04 mmol mL −1 according to quantitative EPR measurement, see the ESI †) was used for experiments described below. The stability and purity of 21 in solution was confirmed by EPR, FT-IR spectroscopy and ICP-MS (to confirm separation from the lead compounds); for spectral data and discussion, see the ESI. † Reactions of diacetyliminoxyl radical 21 with pyrazolin-5-ones 1a, 1c, 1h, and 1i (experimental details for Scheme 8) To a stirred solution of diacetyliminoxyl radical 21 in CH 2 Cl 2 (50 mL, ca. 0.04 mol L −1 , ≈2 mmol, prepared as described above), pyrazolin-5-one (1 mmol; 1a: 188.2 mg; 1c: 140.2 mg; 1h: 188.2 mg; 1i: 174.2 mg) was added at room temperature (18-23°C). Stirring was continued for 3 h, and gradual dissolution of pyrazolin-5-one and the decrease in the intensity of the red color of the solution were observed. The mixture was rotary evaporated under water-jet vacuum, an aliquot (20 mg) of the residue was analyzed by 1 H and 13 C NMR, and the rest was transferred to a silica gel chromatographic column and eluted with EtOAc/CH 2 Cl 2 (EtOAc content was increased gradually from 0 to 30 vol%) to isolate the reaction products. In the case of pyrazolin-5-one 1h, an additional experiment was performed with a reaction time of 24 h (instead of 3 h), and the same product yields were observed.
The 1 H and 13 C NMR spectra of the reaction mixtures of diacetyliminoxyl radical 21 with pyrazolones 1a, c, h, and i are given in the ESI. † Signals were assigned to the coupling pro-ducts (4, 12, 15 and 16) and oxime 2b by comparing the spectra of reaction mixtures with the spectra of individual compounds. No significant impurity signals were observed.

Experimental details for Scheme 9
General procedure for the synthesis of hydroxylamines 24.
The product of C-O coupling 3 (180-210 mg, 0.6 mmol), NH 2 OH·HCl (83.4 mg, 1.2 mmol), MeCN (3 mL) and H 2 O (0.5 mL) were placed in a 10 mL round-bottom flask. Then NaHCO 3 (101 mg, 1.2 mmol) was added with vigorous stirring at room temperature; stirring was continued for 1 h. The mixture was rotary evaporated to dryness, and the residue was extracted with CH 2 Cl 2 (3 × 7 mL). Combined extracts were washed with NaHCO 3 (2 × 3 mL), dried over MgSO 4 , and rotary evaporated. Et 2 O (1-2 mL) was added to the residue to cause crystallization, and then was rotary evaporated. Hydroxylamines 24a, c, d, and f were obtained as white powders.

Conflicts of interest
There are no conflicts of interest to declare.