RuO4-mediated oxidation of secondary amines. Part 1. Are hydroxylamines the main intermediates? J. Serb. Chem. Soc. 81 (5) 475–486 (2016) UDC 546.96+542.943+547.233.2:546.172–41 JSCS–4861 Original scientific paper 475 RuO4-mediated oxidation of secondary amines. Part 1. Are hydroxylamines the main intermediates? CRISTINA A. FLOREA* and HORIA PETRIDE Romanian Academy, “Costin D. Nenitzescu” Center of Organic Chemistry, Spl. Independenţei 202-B, RO-060023 Bucharest, Romania (Received 15 December 2015, revised 13 January, accepted 14 March 2016) Abstract: The RuO4-catalyzed oxidation of secondary amines Bn–NH–CH2R (1a and b; R=H, Me) gave mainly amides, but minute amounts of nitrones PhCH=N(O)–CH2R (9a and b) and traces of Bn–N(OH)–CH2R (R=H, 4a) were also detected. In the presence of cyanide, up to 22 reaction products were identified, but mainly α-aminonitriles. Comparison of the oxidation products of 1a and b with those of 4a and b and 9a and b, and Bn–N(O)=CHR (10a and b) showed that 4a and b cannot be the main reaction intermediates formed from 1a and b. Keywords: oxidation; secondary amines; ruthenium tetraoxide; hydroxyl- amines; nitrones. INTRODUCTION Ruthenium-based catalysts, ruthenium tetraoxide (RuO4) included, have been extensively used to oxidize a wide variety of organic compounds, such as aliphatic and aromatic hydrocarbons, alkenes, alkynes, alcohols, ethers, amines, or amides.1–11 The versatility, specificity, the high yields obtained in many cases, and the environmentally friendly reaction conditions have strongly recommended ruthenium-containing catalysts be successfully utilized in fine and green chem- istry.1–10 In the case of tertiary amines of the RCH2–NR1R2 type, earlier papers12–16 indicated that RuO4 attacks the N–CH2 positions to afford amides (RCO–NR1R2) and for about 30 years, this reaction was viewed as a highly regioselective oxidation. However, the RuO4-mediated oxidation of tertiary amines containing differ- ent types of N–CH2 groups, such as N-benzylazacycloalkanes,17,18 N,N-dialkyl- benzylamines19 or N-benzyl-2-azanorbornane derivatives,20,21 caused doubts on the previously claimed high regioselectivity. In the case of N,N-dialkylbenzyl- amines, the oxidation compounds were derived from both reactive N–CH2 sites * Corresponding author. E-mail: antonetaflorea@yahoo.com doi: 10.2298/JSC151215029F 476 FLOREA and PETRIDE (i.e., benzylic and alkylic). In addition, some N-oxides were also formed, indi- cating the existence of a third, minor oxidative route. In the presence of the cya- nide ion, only the first two routes were followed. Formation of two kinds of N-α- cyano derivatives suggested the transient existence of iminium cations as inter- mediates. The statistically corrected alkyl/benzyl regioselectivity of the oxidation reaction was relatively poor (4.1 for N,N-dimethyl- and 2.1 for N,N-diethyl- benzylamine).19 In continuation of previous work on the RuO4-mediated oxidation of tertiary amines,17–19 it was considered useful to extend the study on secondary amines, more precisely on N-methyl- (1a) and N-ethylbenzylamine (1b). By analogy with the behavior of tertiary amines presented before, the secondary amines 1a and b could suffer oxidative attack at three positions: 1) benzylic, 2) alkylic, and/or 3) at the nitrogen atom (Scheme 1). Depending on the followed path, the first oxid- ation step should give N-alkyl imines 2a and b, N-benzyl imines 3a and b, and/or hydroxylamines 4a and b, respectively. In this paper, it was analyzed whether 4a and b could be the main reaction intermediates. Bn-NH-CH2R PhCH=N-CH2R benzyl 2a-b 1a-b Bn-N=CH-R 3a-b attack at attack at N attack at alkyl 4a-b Bn:benzyla: R=H b: R=Me Bn-N(OH)-CH2R Scheme 1. Oxidative routes for 1a and b. EXPERIMENTAL Instrumentation The FT-IR spectra were registered on a Bruker Vertex 70 instrument, equipped with a diamond crystal ATR. The NMR spectra were recorded with a Varian Unity INOVA 400 spectrometer, operating at 400 MHz (1H) and 100 MHz (13C). The mass spectra were obtained using a GC 6890 Agilent Technologies gas chromatograph coupled with a MS 5975 B quad- rupole mass spectrometer, using the standard 70 eV ionization energy. NMR (1H and 13C) and MS data for 1, 2 and 4–28 are given in Supplementary material to this paper. Materials The formulae of all substrates and reaction products 1, 2 and 4–28 are given in Scheme 2. Compounds 1a, 2c, hydrated RuO2 (all from Aldrich), 1b, 5c, 6c, 7a, 11–13, 26, benzoic acid, NaIO4 (all from Merck) and the organic solvents (from Chemical Co., Iaşi, Romania) were used as purchased, except for CHCl3 and CH2Cl2, which were stored over anhydrous Na2CO3 and filtered prior to use. Derivatives 2a and b, 6a and b, 7b, 8a–e, 9a and b, 14, 15a and b, 16a and b, 17a–e, 18a and b, 19a and b, 20a and b, 21a and b, 22a and b, 23a and b, 24a and b and 25a and b were prepared and characterized previously.19,22 Compounds 4a and OXIDATION OF SECONDARY AMINES 477 b,23 9c,24,25 10a,26 10b,27 15c,28 2729 and 2830 are all known from the literature and were prepared according to the indicated procedures. The purity of all non-commercial chemicals was checked by FT-IR, NMR and GC–MS. NMR and MS spectroscopies were extensively used to identify the oxidation products. Even though the NMR characteristics of most of compounds depicted in Scheme 2 have been already reported19,22 or are widely known (i.e., 5c and 11–13), it was judged useful to present the corresponding NMR (and MS) spectral data of all these compounds (1, 2 and 4–28) as Supplementary material. Bn: benzyl 8, 17 R R1 a H H b Me Me c Me H d H Ph e Me Ph Bn-NH-CH2R 1a-b RuO4/NaIO4 (NaCN) imines (2), hydroxylamines (4) amides I (6, 7), amides II (8) nitrones (9, 10) others I (11-14) nitriles I (15, 16), nitriles II (17) cyanoimines (18-20) cyanonitrones (21, 22) others II (26-28) formamidines & related compounds (23-25) aldehydes (5) 2a-c: Ph-CH=N-CH2R 4a-b: Bn-N(OH)-CH2R 5a-c: R-CHO 6a-c: PhCO-NH-CH2R 7a-b: Bn-NH-CO-R 8a-e: Bn-N(CH2R)-CO-R 1 9a-c: Ph-CH=N(O)-CH2R 10a-b: Bn-N(O)=CH-R 12: PhCN 11: BnNH2 14: (Bn-NMe-)2CH2 13: PhCONH2 15a-c: Ph-CH(CN)-NH-CH2R 17a-e: Bn-N(CH2R)-CH(CN)-R 1 18a-b: Ph-C(CN)=N-CH2R 19a-b: Bn-N=C(CN)-R 20a-b: Ph-CH=N-CH(CN)-R 21a-b: Ph-C(CN)=N(O)-CH2R 22a-b: Bn-N(O)=C(CN)-R 28: Bn-NH-OH 26: Ph-CH=N-OH 27: Bn-N=N(O)-Bn 23a-b: Bn-N(CH2R)-C(=NH)-CN 24a-b: Bn-N(CH2R)-CN 25a-b: Bn-N(CH2R)-CONH2 16a-b: Bn-NH-CH(CN)-R 1, 2, 4-7, 9, 10, 15, 16, 18-25 R a H b Me c Ph Scheme 2. Oxidation products of 1a and b. Oxidation by RuO4/NaIO4 (± NaCN). General procedure To a heterogeneous mixture of CHCl3 (5 mL) and aqueous solution of NaIO4 (0.4 M; 10 mL, 4 mmol) was added solid RuO2·xH2O (10–15 mg), followed by the substrate (1 mmol), 478 FLOREA and PETRIDE previously dissolved in CHCl3 (5 mL) (reaction conditions A). In the case of the cyano-trap- ping experiments (reaction conditions B), to the NaCN solution [196 mg (4 mmol) in water (10 mL)] was added RuO2, the substrate (1 mmol in 10 mL of CHCl3), and the co-oxidant NaIO4 solution (10 mL, as before), in this order. Several other organic solvents (CH2Cl2, Me2CO3 and AcOEt) were tried with no significant differences. In all cases the heterogeneous reaction mixture was magnetically stirred at room temperature for 3–5 h and then worked up as described in a previous paper.22 Identification of the various reaction products was made by comparison of the NMR and GC–MS spectra before and after the addition of pure compounds into the analyzed samples. 1,4-Dimethoxybenzene (DMB) was employed as an internal stan- dard for quantitative analyses.22 Work-up losses were determined on synthetic mixtures and then used to correct the experimentally found amounts. These corrected amounts were used to calculate the yields given in Table I (see below). Oxidation of 1a and b by H2O2/Na2WO4 Hydrogen peroxide (30 %; 1 mL, 9.8 mmol) was added dropwise into a magnetically stirred methanolic solution (10 mL) of 1a (0.53 mL, 4 mmol) and Na2WO4·2H2O (132 mg, 0.4 mmol), maintaining the temperature within 25–30°C with a water bath. The mixture was stirred at room temperature for another 4–5 h and then filtered. The clear filtrate was eva- porated to dryness, the residue taken up in CHCl3, the solution filtered again, and the organic solvent eliminated in vacuo. The obtained liquid residue was analyzed by NMR, as such and with a known amount of DMB. Besides benzaldehyde and other compounds, 9a and 10a resulted in about 32 and 17 % yield, respectively. Treatment of this oxidation residue with LiAlH4/ether23 transformed both nitrones into hydroxylamine 4a. Analogously, 9b (≈31 %) and 10b (≈25 %) were formed from 1b; reduction of the nitrones gave 4b. RESULTS AND DISCUSSION The oxidations were performed in the absence/presence of cyanide (A- and B-conditions, respectively) and the corresponding results are shown in Table I. The yield of benzaldehyde 5c in Table I actually refers to the yield of 5c+benzoic acid. This is allowed because benzoic acid is always derived from 5c, merely by air oxidation during the reaction mixture work-up. To gain in simplicity, the desired entries (let them be x and y) of Table I will be cited as TI-x,y throughout this paper. Oxidation of amines 1a–b. Reaction products The various components of the oxidation mixtures obtained from 1a–b in the absence of cyanide (TI-1,2) can be divided into imines (2a–c), hydroxylamines (only 4a was detected), aldehydes (only 5c was detected as such), amides (6–8), nitrones (9), benzonitrile (12), and benzamide (13). In the case of 1a, diamine 14 was also present. Some reaction products contain more carbon atoms than in the starting amines. Whatever the following oxidation route, they cannot be primary reaction products. Thus, amides 8a–e (amides II in Scheme 2) should be formed in two steps, as depicted in Scheme 3: i) the condensation of the appropriate amine 1 with aldehyde 5 affords the intermediate 29, which ii) is oxidized further at the OXIDATION OF SECONDARY AMINES 479 OH level.31,32 Besides oxidation to 8a, the hemiaminal 29a could also react with 1a to give the diamine 14. It should be noted that 8a and 8d resulted from 1a (TI- -1), but 8b, 8c, and 8e from 1b (TI-2). According to Scheme 3, this implies the formation of aldehydes 5a and 5c during the oxidation of 1a and of 5a, 5b, and 5c during the analogous reaction of 1b. TABLE I. Oxidation of selected compounds Entry No. Compd. (conversion, %)a Reaction productsb (yield, %)c 0 1 2 A) Oxidations in the absence of cyanided 1 1a (55) 2a (2.2), 2c (8.6), 4a (0.2), 5c (8.0), 6a (2.2), 6c (1.8), 7a (3.8), 8a (30.0), 8d (7.4), 9a (2.4), 12 (2.0), 13 (0.6), 14 (1.3) 2 1b (81) 2b (2.1), 2c (4.1), 5c (34.3), 6b (3.9), 6c (3.1), 7a (1.7), 7b (4.1), 8b (3.5), 8c (15.2), 8e (3.8), 9b (0.3), 12 (7.4), 13 (0.5) 3 4a (100) 5c (55.0), 6a (1.9), 7a (1.8), 12 (7.7), 13 (4.1), 26 (2.3), 27 (1.4) 4 4b (100) 5c (40.8), 6b (3.6), 7b (4.0), 12 (8.6), 13 (10.9), 26 (4.7), 27 (2.8) 5 9a (100) 5c (75.6), 6a (0.8), 12 (0.4), 13 (0.8) 6 9b (100) 5c (78.1), 6b (0.6), 12 (9.6), 13 (0.3) 7 10a (100) 5c (48.7), 7a (4.6), 9c (0.6), 12 (7.1), 13 (5.8), 26 (5.7), 27 (3.0) 8 10b (100) 5c (50.1), 7b (4.0), 9c (0.5), 12 (7.0), 13 (6.0), 26 (3.1), 27 (1.8) 9 28 (100) 5c (10.7), 9c (4.0), 12 (4.3), 13 (0.5), 26 (34.7), 27 (8.7) B) Oxidations in the presence of cyanided 10 1a (13)e 2c (1.2), 5c (0.9), 6a (0.4), 7a (0.7), 8a (1.8), 8d (8.9), 11 (2.5), 12 (0.9), 15a (6.3), 16a (2.2), 17a (18.2), 17d (15.3), 18a (0.6), 20a (0.3), 21a (0.4), 22a (0.8), 23a (2.9), 24a (1.0), 25a (4.5) 11 1b (37)e 2b (5.2), 2c (1.8), 5c (0.5), 6b (0.5), 7b (0.6), 8b (1.0), 8c (0.6), 8e (2.7), 9b (7.8), 12 (1.5), 15b (15.6), 16b (10.9), 17b (9.9), 17c (1.0), 17e (8.1), 18b (0.8), 20b (0.5), 21b (0.5), 22b (0.9), 23b (4.2), 24b (0.9), 25b (8.0) 12 4a (100) 5c (2.5), 6a (0.7), 7a (2.7), 9a (28.8), 9c (1.2), 12 (4.0), 13 (6.0), 18a (7.3), 21a (7.6), 22a (2.0), 26 (0.3) 13 4b (100) 5c (1.8), 6b (0.3), 9b (39.4), 10b (25.8), 12 (8.8), 13 (3.6), 18b (1.1), 21b (3.0), 22b (5.8) 14 9a (20) 5c (34.7), 6a (1.2), 12 (6.9), 18a (22.0), 21a (9.7) 15 9b (22) 5c (37.5), 6b (1.5), 12 (6.0), 18b (20.2), 21b (8.1) 16 10a (100) 5c (14.0), 7a (2.5), 9c (5.0), 12 (8.7), 13 (2.9), 22a (11.9), 26 (2.9), 27 (3.6) 17 10b (93) 5c (12.3), 7b (1.5), 9c (5.1), 12 (8.3), 13 (5.9), 22b (12.1), 26 (4.3), 27 (2.0) aConversion calculated against the reacted substrate; bformulae in Scheme 2; cyields (mole ratios of product/ /reacted substrate) were calculated from the NMR and MS spectra, regardless of the stoichiometry; dreaction conditions (for 1 mmol of substrate): A – RuO2⋅xH2O(10–15 mg), NaIO4 (4 mmol), CHCl3/water = = 10/10 (mL/mL), room temperature, 3–5 h; B – as in A, but NaCN (4 mmol) in water (10 mL) was also added; eliterature data22 480 FLOREA and PETRIDE Secondary reaction products could also be the derivatives 2c and 6c, their existence implying the transient formation of benzylamine 11. Thus, benzamide 6c might be formed by a sequence similar to that depicted in Scheme 3 (i.e., 11+5c → Bn–NH–CH(OH)–Ph → 6c). Moreover, unlike 29, the generated hemi- aminal has an N–H proton (in italics) thus allowing the concurrent dehydration to imine 2c. As presented in a forthcoming paper,33 compounds 5c (some of it), 12 and 13, were also derived from benzylamine. It is worth mentioning that the ori- gin of 6a and b and 7a and b (amides I in Scheme 2) will be clarified else- where.33 Bn-N(CH2R)-CO-R 1 ox 8a-e 8, 17, 29 R R1 a H H b Me Me c Me H d H Ph e Me Ph Bn-N(CH2R)-CH(OH)R 1 HCN 14 ox: oxidation + 1a (R=R1=H) (Bn-NMe-)2CH2 Bn-NH-CH2R + R 1-CHO 1a-b 5a-c 29a-e Bn-N(CH2R)-CH(CN)R 1 30a-c1a-b 17a-e -H2O Bn-NH-CH2R + R 1-CH(OH)-CN 1, 5, 30 R/R1 a H b Me c Ph Scheme 3. Formation of 8, 14 and 17. These considerations are also supported by the results obtained in the pre- sence of cyanide (TI-10,11). In this case, along with some compounds encount- ered in the corresponding cyanide-free reactions, most of the starting amine was consumed in the formation of new, cyano-containing products: nitriles 15–17, cyanoimines 18 and 20, cyanonitrones 21 and 22, as well as derivatives 23–25. Identification of benzylamine 11 in the oxidation mixture derived from 1a (TI-10) confirmed the preceding deductions on its formation. As already reported,22 formamidines 23 and their hydrolysates 24 and 25 are side products, which do not involve oxidation of 1a and b. Therefore, they are not important for the present discussion. In general, all nitriles (15–17) could be formally derived by substituting the C=O function in the analogous amides 6–8 with the CH–CN group. As depicted in Scheme 3, nitriles 17a–e might result from 1a and b and cyanohydrins 30a–c, OXIDATION OF SECONDARY AMINES 481 formed in turn from 5a–c. It is well known that cyanohydrins result easily by adding an aldehyde (or aliphatic ketone) to a cyanide-containing medium. Compounds 18 and 20–22 are not primary oxidation products of 1a and b. As presented below, some of them might derive from the oxidation of 4a and b, via 9a and b and 10a and b. The existence of nitrones 9a and b (TI-1,2,11) implies the transient formation of 4a and b in all oxidations of 1a and b, res- pectively. In fact, it is well known that nitrones are usually prepared by oxidation of hydroxylamines under various conditions.34–36 It is also known that secondary amines can give nitrones directly, especially under tungsten catalysis,37 but low- -valent ruthenium compounds can also be used under certain conditions (for instance, with catalytic tetra-n-propylammonium perruthenate).38 The possible oxidation of imines to nitrones (such as 2a–c → 9a–c) can be excluded in the present case, because it requires peracids.39 The oxidation of 1a and b was performed with the H2O2/Na2WO4 system and the expected mixtures of nitrones 9a+10a and 9b+10b, respectively, were obtained. The cumulated yields of about 50 % (see Experimental) were in con- trast to the very modest values obtained under RuO4-catalysis (TI-1,2,10,11). This raises doubts about the implication of nitrones (and by extension of hydro- xylamines) as the main intermediates during the RuO4-oxidation of 1a and b. A detailed comparison of oxidation products would clarify this supposition. Oxidation of hydroxylamines 4a and b and related nitrones Under cyanide-free conditions (TI-3,4), 4a and b gave mainly benzaldehyde (5c) and small amounts of 6a+7a/6b+7b, 12 and 13. In both cases, two new com- pounds appeared, which were identified as benzaldoxime (26) and 1,2-bis(phe- nylmethyl)diazene 1-oxide (27). In the presence of cyanide (T1-12), the oxidation of 4a gave mainly nitrone 9a, but cyano-containing derivatives 18a, 21a, and 22a were also formed. More informative was the behavior of 4b (T1-13). Analogously with 4a, compounds 9b, 18b, 21b, and 22b were present, but accompanied by another nitrone, 10b. The two nitrones, 9b and 10b, accounted for 65 % of the reacted 4b. The form- ation of the nitrones 9b and 10b suggested that 4b was attacked at both N-α-posi- tions, namely benzylic and alkylic, respectively (Scheme 4). This is probably the first reaction step in all RuO4-mediated oxidations of 4a and b, but, usually, only the most stable nitrones (under the considered conditions) are observed. The behavior of all four nitrones was verified and it was found that the N-alkylic ones (9a and b) were completely transformed under conditions A (con- version of 100 % in TI-5,6), but only partially under conditions B (≈21 % in TI-14,15). At the same time, the N-benzyl nitrones 10a and b were completely transformed under both A (TI-7,8) and B conditions (TI-16,17), meaning that they are less stable than their N-alkyl analogs 9a and b. 482 FLOREA and PETRIDE 21a-b 9a-b 4a-b Ph-CHO + HO-NH-CH2R Bn:benzyl ox: oxidation X: OH, CN (X=OH) 5c +HX (X=CN) (X=OH) 22a-b Bn-NH-OH + OHC-R 28 5a-b 9c + 5c Ph-CH=N(O)-CH2R Bn-N(OH)-CH2R Ph-C(CN)=N(O)-CH2R Bn-N(O)=C(CN)R Ph-CH=N(O)-Bn 10a-b 7a-b Bn-NH-CO-R +HX -H2O Bn-N(O)=CH-R R a H b Me (X=OH) tautom. 6a-b PhCO-NH-CH2R X=OH: 36a-b X=CN: 19a-b Bn-N=CX-R X=OH: 34a-b X=CN: 35a-b Bn-N(OH)-CHX-R X=OH: 31a-b X=CN: 32a-b Ph-CHX-N(OH)-CH2R (X=CN) 27 +H2O Bn-N=N(O)-Bn X=OH: 33a-b X=CN: 18a-b Ph-CX=N-CH2R -H2O (X=OH) 5c37 PhCHO + H2N-OH 26 Bn-NO Ph-CH=N-OH (Bn-NO)2 (37)2 ox ox ox ox ox + 37 Scheme 4. Oxidation of 4a and b, 9a anb b, 10a and b and 28. The behavior of 9a and b and 10a and b is more consistent with hydrolysis than with oxidation, at least in the first step. For instance, 9a and b gave large (≈77 %) or medium (≈33 %) amounts of benzaldehyde (5c) under conditions A and B, respectively. The imagined formations of the corresponding intermediates 31a and b and 32a and b are presented in Scheme 4. Under A-conditions, 31a and b can be either broken to a mixture of 5c + an aliphatic hydroxylamine, or dehydrated to 33a and b, the enolic form of the most stable benzamides 6a and b. Under B-conditions, the intermediates 32a and b can suffer either oxidation to cyanonitrones 21a and b, or dehydration to the corresponding cyanoimines 18a and b. Actually, it is well known that, under non-oxidative conditions, imines 18a and b can easily be obtained from 9a and b and sodium cyanide in aqueous ethanol.40 A similar reaction scheme was imagined also for 10a and b (Scheme 4). Nucleophilic addition of HX affords 34a and b (X=OH) or 35a and b (X=CN). Analogously to 31a and b, the intermediates 34a and b can give 28+5a and b OXIDATION OF SECONDARY AMINES 483 and/or amides 7a and b (via 36a and b). Similarly to 32a and b, the intermediates 35a and b could be the sources of cyanonitrones 22a and b and/or cyanoimines 19a and b. However, no explanation can offered for the absence of 19a and b. Turning back to the reactions of 10a and b (TI-7,8), it was noted that about 50 % of the substrate was consumed towards benzaldehyde 5c. Why 5c and not benzyl- hydroxylamine 28, the logical output of hydrolyzed 10a and b, as expected from Scheme 4? To understand these transformations, the oxidation of 28 was studied separ- ately. In the reaction mixture (TI-9), 5c, nitrone 9c, benzaldoxime 26, and the azoxy compound 27 were found; a similar composition was obtained under B-conditions (absent in Table I). Remember that all these compounds were also present in the oxidation mixtures of 10a and b. The reaction was interpreted as depicted in Scheme 4, where 28 is oxidized first to the nitroso derivative 37, which is in equilibrium with its dimer (37)2. The key intermediate 37 could give 26 (by tautomerization), but also 27 by condensation with unreacted 28. Benzal- dehyde 5c, generated from 26 by hydrolysis, could be the source of nitrone 9c, after condensation with 28. The dimer (37)2 was not synthesized, but a rapid NMR scan of the analyzed sample showed the presence of a transient compound with NMR characteristics (a CH2–singlet at 5.37 ppm (63.1 ppm) long-range coupled with peaks at 129.4 (ortho-arom. CH) and 134.1 ppm (ipso-arom. C), similar to those given in the literature for 1,2-bis(phenylmethyl)diazene 1,2-di- oxide ((37)2).41,42 Moreover, in the absence of 28 and directly in the NMR tube, it gave 26 quantitatively, in a few hours. This is not surprising, since trans- formations such 37 → 26 are well known for about 125 years; the reaction is catalyzed by acids or bases.43,44 The presence of 9c, 26 and 27 in an oxidation mixture might be considered as a fingerprint for the previous existence of nitrones 10a and b. The fact that some of them are absent in the reaction mixtures of 4a and b (TI-3,4,12) is probably due to their relative amounts, presumably too small to be detected. The same reason could be invoked for entry 13, when all three compounds were missing, probably because too little 10b underwent hydrolysis. It is now clear that the behavior of 4 is the sum of that of corresponding nitrones 9 and 10. Comparison of results Now it is possible to compare the reaction products formed from 1a and b with those derived from 4a and b. In these comparisons, compounds 8a–e (amides II in Scheme 2), 14 and 17a–e (nitriles II) were not considered, as they could not result from 4a and b, because their formation requires the presence of amines 1a and b. However, if 4a and b are the main reaction intermediates, their oxidative outputs should explain the formation of benzylamine 11, as well as of aldehydes 5a+5c and 5a+5b+5c, respectively. 484 FLOREA and PETRIDE Comparison of the reaction products derived from 1a (TI-1,10) with those resulting from 4a (TI-3,12) and/or 9a+10a (TI-5,14 + TI-7,16) shows that 2a, 2c, 6c, 11, 15a, 16a and 20a were derived from 1a only. On the contrary, 9c, 26 and 27 resulted from 4a only. Similar observations could be made comparing the outputs of 1b (TI-2,11) with those of 4b (TI-4,13) and 9b+10b (TI-6,15 + TI-8,17): 2b, 2c, 5a, 6c, 15b, 16b and 20b came from 1b only, but the unique source of 9c, 26 and 27 was 4b (or 9b+10b). This means that, under conditions A, the oxidation of 4a and b cannot explain the formation of imines 2a and b and benzylamine (source of 2c and 6c). In the case of 4b, it must add also the lack of any species implying formaldehyde (5a), used by 1b to generate 8c, as in Scheme 3. Moreover, under conditions B, the oxidation of 4a and b does not imply the formation of nitriles 15a and b and 16a and b (the HCN-trapped forms of 2a and b and 3a and b, respectively).33 At the same time, although 18+21+22 are gener- ated from hydroxylamines 4 as well as from amines 1, the cyanoimines 20 are formed only from 1. This causes doubts regarding the route followed to generate all cyanoderivatives 18 and 20–22. Actually, it will be shown33 that during the oxidation of 1a and b, the real source of 18+20+21+22 is just the oxidation of 15a and b and 16a and b. At the same time, no 9c, 26, nor 27 seemed to be ever formed from 1a and b. All these considerations do not favor 4a and b as the main intermediates during the RuO4-mediated oxidation of 1a and b. However, this route does exist, but its minor role consists only in the formation of small amounts of nitrones 9a and b and 10a and b. CONCLUSIONS Hydroxylamines Bn–N(OH)–CH2R (4a and b; R=H and Me) and nitrones PhCH=N(O)–CH2R (9a and b) are present in minute amounts in the RuO4-medi- ated oxidation mixtures derived from the secondary amines Bn–NH–CH2R (1a and b). Careful comparative analysis of the complex reaction mixtures showed that 4a and b, 9a and b, as well as nitrones Bn–N(O)=CH–R (10a and b) cannot be the main oxidation intermediates of 1a and b. SUPPLEMENTARY MATERIAL NMR (1H and 13C) and MS data for 1, 2 and 4–28 are available electronically from http://www.sbd.org.rs/JSCS/ or from the corresponding author on request.. OXIDATION OF SECONDARY AMINES 485 И З В О Д ОКСИДАЦИЈА СЕКУНДАРНИХ АМИНА УЗ ПОСРЕДОВАЊЕ RuO4. ДЕО 1. ДА ЛИ СУ ХИДРОКСИЛАМИНИ ГЛАВНИ ИНТЕРМЕДИЈЕРИ? CRISTINA A. FLOREA и HORIA PETRIDE Romanian Academy, “Costin D. Nenitzescu” Center of Organic Chemistry, Spl. Independen�ei 202-B, RO-060023 Bucharest, Romania Оксидација секундарних амина Bn–NH–CH2R (1a и b; R=H, Me) RuO4 катали- затором даје као главне производе амиде, али и незнатне количине нитрона PhCH=N(O)–CH2R (9a и b) и Bn–N(OH)–CH2R (R=H, 4a) у траговима. У присуству цијанида идентификована су 22 производа, углавном α-аминонитрили. Поређењем производа оксидације 1a и b са производима оксидације 4a и b, 9a и b и Bn–N(O)=CHR (10a и b) закључено је да производи 4a и b не могу бити главни реакциони интермеди- јери који се формирају из полазних једињења 1a и b. (Примљено 15. децембра 2015, ревидирано 13. јануара, прихваћено 14. марта 2016) REFERENCES 1. N. Ishito, H. Kobayashi, K. Nakajima, Y. Maegava, S. Inagaki, K. Hara, A. Fukuoka, Chem. Eur. J. 21 (2015) 15564 2. K. N. T. Tsenq, N. K. Szymczek, Synlett. 25 (2014) 2385 3. N. J. 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