Photoredox Synthesis of Arylhydroxylamines from Carboxylic Acids and Nitrosoarenes

Published as part of the Bürgenstock Special Section 2017 Future Stars in Organic Chemistry

Abstract

Hydroxylamines are found in biologically active compounds and serve as building blocks for the preparation of nitrogen-containing molecules. Here the direct conversion of carboxylic acids into the corresponding alkylhydroxylamines using organo-photoredox catalysis is reported. The process relies in the generation of alkyl radicals via photoinduced oxidation-decarboxylation and their following reaction with nitrosoarenes. We have successfully applied this method to the late-stage modification of complex and biologically active acids and applied it in novel radical cascade processes.

Key words

hydroxylamines - radical addition - nitrosoarenes - late-stage functionalization - radical cascade - photoredox

Hydroxylamines and their derivatives are a privileged class of compounds with applications spanning from active pharmaceutical ingredients and agrochemicals to versatile building blocks for the synthesis of complex molecules (Scheme [1], A).[1] Despite this relevance, their preparation can still be troublesome and the development of novel strategies able to selectively introduce the hydroxylamine functionality on structurally complex molecules under mild reaction conditions is a relevant goal.

Scheme 1 Relevance of hydroxylamines, previous ionic and radical approaches using nitrosoarenes, and this work

Visible-light photoredox catalysis is now an established and powerful technique to perform single-electron transfer (SET)[2] reactions under mild conditions.[3] In particular, the ability of harvesting carboxylic acids for the generation of sp³-C-radicals by oxidative decarboxylation has enabled the development of many C–C and C–X (X = F, N₃, S…) bond-forming processes.[4]

Owing to our ongoing interest in the preparation of hydroxylamine derivatives as nitrogen-radical precursors,[5] we wondered if a visible-light-mediated protocol for their direct assembly from simple feedstock chemicals could be developed. In particular, we were interested in the possibility of using carboxylic acids as source of sp³-C-radicals and to exploit them in the reaction with nitrosoarenes.[6] Such an approach would be complementary to the more established ionic pathways where nitrosoarenes are used as electrophiles in conjunction with organometallic reagents,[7] enolates,[8] and enamine[9]/NHC[10]-based catalytic systems (Scheme [1], B).[11] Furthermore, the preparation of hydroxylamines via radical addition onto nitrosoarenes has been considerably overlooked and only few protocols are available.[12] Most notably, de Alaniz[13] and Selander[14] have recently developed Cu(II)-catalyzed protocols for the coupling of nitrosoarenes with radical deriving from α-bromo­carbonyls and sodium triflinate, respectively (Scheme [1], C).

In this paper, we describe the development of the first approach for the generation of hydroxylamines from readily available carboxylic acids and its use in the functionalization of complex and biologically active molecules (Scheme [1], D).

At the outset, we envisioned a catalytic cycle starting with the visible-light-promoted excitation of a photo­catalyst and the following oxidative SET decarboxylation of acid A upon in situ deprotonation A → B (Scheme [2], A).[4] This step would deliver the C-radical C that would react with a nitrosoarene D forging the required C–N bond and delivering the persistent nitroxyl radical E.[15] At this point, we speculated that the final hydroxylamine G could be obtained by reductive SET of E with the reduced photoredox catalyst (to give F) and protonation.

Scheme 2 Proposed photoredox cycle and computational studies on the reaction of nitrosobenzene I with the adamantyl radical J

In order to obtain information regarding the feasibility of our proposed process, preliminary DFT studies were conducted (Scheme [2], B). We were in fact concerned about the potential addition of the C-radical at both the N (path a – to give E) and the O atom (path b – to give H) of the nitroso­arene, an issue frequently encountered in ionic processes.[7a] [8c] We started by characterizing nitrosobenzene I in terms of electron donor properties by calculating its adiabatic ionization potential (IP), electron affinity (EA), and absolute electronegativity (χ_DB).[16] These values are in line with I being a competent radical acceptor. The preferred site of radical attack was then assessed by calculating the N and O atom Mulliken spin densities (MSDs) in the triplet state (ππ*).[16] According to this study, I should display a slight preference for the reaction at the N-atom owing to its higher MSD. Further support for this reactivity was obtained upon determination of the activation parameters for the reaction of I with the adamantyl radical J (nucleophilic radical; ω_+rc = 0.34).[17] According to our study both radical pathways ( a : attack at the N-atom and b : attack at the O-atom) are very exergonic but there is a slight preference for path a , which would support our proposed process.[16] The very low |δ^TS| values also indicate that these radical additions are not influenced very much by polar effects in the transition state and should be predominantly enthalpy controlled.[18]

To assess our working hypothesis, the reaction of adamantane carboxylic acid (1a) and nitrosobenzene was investigated using various photoredox catalysts (Figure [1]) and bases in CH₂Cl₂ (0.05 M) at room temperature. As illustrated in Table [1], we were pleased to find out that using mesityl acridinium perchlorate 2a (Fukuzumi’s acridinium, E*_1/2 = +2.06 V vs SCE)[19] as the photoredox catalyst and Cs₂CO₃ as the base under blue LEDs irradiation, the product 3a was obtained in good yield (Table [1], entry 1). We then changed the stoichiometry of the reaction (entries 2–4) and found out that a slight excess of nitrosobenzene (2.0 equiv with respect to 1a) was optimum, providing 3a in 90% yield (entry 3). Other bases were evaluated and while K₂CO₃ gave 3a in a useful 62% yield (entry 5); 2,6-lutidine was not compatible and completely suppressed the reactivity (entry 6). We also tried to run the reaction under more concentrated conditions (entries 7 and 8) but this was detrimental. Other photocatalysts 2b–d were screened but they generally provided 3a in considerably lower efficiency (if any) (entries 9–11). Lastly, control experiments confirmed the requirement for base, light, and 2a (entries 12–14).

Figure 1 Photoredox catalysts used

With the optimized reaction conditions in hand, the scope of the process using nitrosobenzene and a series of structurally different carboxylic acids was evaluated (Scheme [3]). In general, tertiary carboxylic acids worked well and provided the desired hydroxylamines 3b–g in good yields. This approach tolerated several functional groups like alkyl halides, terminal olefins, carbamates and was effective for accessing C-3 and C-4 aminopiperidines, which are a frequent structural motif in many commercially available drugs (e.g., the antidiabetic alogliptin and the opioid analgesic sufentanil). Secondary carboxylic acids were tried next but unfortunately the use of a secondary mono-benzylic 3h and a primary alkylic 3i was not possible, thus representing the limitation of the strategy. Lastly, we evaluated the use of functionalized nitrosoarenes in conjunction with adamantine carboxylic acid (1a) and found them compatible. Both electron-rich 3j and ortho-substituted 3k derivatives reacted well. Substrates containing an electron-withdrawing CF₃-group 3l could also be employed, albeit in lower yield.

Table 1 Optimization of the Visible Light-Mediated Synthesis of Hydroxylamine 3a from Carboxylic Acid 1a

Entry	PCa	1a/PhNO	Base	[M]	Yield (%)
1	2a	1:1	Cs2CO3	0.05	58
2	2a	1:1.1	Cs2CO3	0.05	72
3	2a	1:2	Cs2CO3	0.05	90
4	2a	2:1	Cs2CO3	0.05	70
5	2a	1:2	K2CO3	0.05	62
6	2a	1:2	2,6-lutidine	0.05	–
7	2a	1:2	Cs2CO3	0.1	50
8	2a	1:2	Cs2CO3	0.2	36
9	2b	1:2	Cs2CO3	0.05	75
10	2c b	1:2	Cs2CO3	0.05	–
11	2d c	1:2	Cs2CO3	0.05	–
12	2a	1:2	Cs2CO3	0.05	–
13b	2a	1:2	Cs2CO3	0.05	–
14	–	1:2	Cs2CO3	0.05	–

^a Photoredox catalyst.

^b 1,2,3,5-Tetrakis(carbazol-9-yl)-4,6-dicyanobenzene.

^c [Ir{dF(CF₃)ppy}₂(dtbpy)]PF₆ {[4,4′-bis(1,1-dimethylethyl)-2,2′-bipyridine-N ¹,N ^1′]bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-N]phenyl-C]iridium(III) hexafluorophosphate}.

^d The reaction was carried out in the dark.

Scheme 3 Scope of the process for the synthesis of hydroxylamines 3

We were particularly keen in showcasing the utility of the methodology by using high-value and structurally complex carboxylic acids in order to provide access to the corresponding hydroxylamines. As reported in Scheme [3], this approach was successfully used to modify the blockbuster drug gemfibrozil (1j → 3m), which is used to lower lipid levels. Furthermore, we were able to selectively introduce the hydroxylamine functionality on the core of the highly complex hepatoprotective oleanoic acid (1k → 3n) and the antiulcer drug enoxolone (1l → 3o). Overall, these examples show that the methodology can be used as a late-stage modification techniques, which tolerates redox active functionalities such as electron rich aromatics (which could undergo SET oxidation), enones (which can be photo-excited upon visible-light irradiation as demonstrated by Lectka)[20] as well as free hydroxyl groups.

We then decided to evaluate if this radical decarboxylative process could be part of a cascade sequence leading to the concomitant formation of two C–N bond across an olefin. We have recently developed a divergent photoredox imino-functionalization strategy for the assembly of polyfunctionalized pyrroline-based heterocycles.[5b] Specifically, we envisaged a cascade process starting with the SET oxidation-fragmentation of the oxime M (Scheme [4]). This would deliver an iminyl radical O (M → N → O) that would undergo fast 5-exo-trig cyclization resulting in the C-radical P. At this point, radical attack onto the nitrosoarene and SET reduction and protonation of the persistent nitroxyl radical Q would enable the formation of R. Also in this case, we have evaluated the key radical reaction between nitrosobenzene I and the Ph-dimethyl-substituted C-radical S (to give T) by DFT and found it feasible.[16]

Scheme 4 Proposed cascade for the imino-hydroxylamination of olefins via iminyl radicals and preliminary DFT studies

The implementation of this strategy was assessed using the oxime 6a, which was prepared by condensation of the ketone 4 with commercially available 2-(aminooxy)-2-methylpropanoic acid (5) on a gram-scale (Scheme [5]).

Scheme 5 Preparation of oxime 6a from ketone 5

As illustrated in Table [2], we were pleased to find out that by irradiating (blue LEDs) a solution of 6a and nitrosobenzene (1:2) using 2a as the photoredox catalyst, Cs₂CO₃ as the base in CH₂Cl₂ (0.1 M), the product 7a was obtained in 48% (Table [2], entry 1). In this case however, increasing the amount of nitrosobenzene with respect to 6a was detrimental (entries 2 and 3) and eventually a ratio of 1:1.1 (entry 4) and a reaction concentration of 0.05 M were identified to be optimum for this transformation (entry 5). Also in this case control experiments confirmed the requirement for base, 2a, and blue LEDs for irradiation (entries 6–8).

Table 2 Optimization of the Imino-Hydroxylamination Cascade Using Oxime 6a

Entry	6a/PhNO	[M]	Yield (%)
1	1:2	0.1	48
2	1:3	0.1	26
3	1:4	0.1	16
4	1:2	0.05	53
5	1:1.1	0.05	60
6	1:1.1	0.05	67
7a	1:1.1	0.05	–
8b	1:1.1	0.05	–
9c	1:1.1	0.05	–

^a The reaction was run in the dark.

^b The reaction was run without 2a.

^c The reaction was run without Cs₂CO₃.

With this optimized conditions in hand, other iminyl radical precursors were tested (Scheme [6]). We were able to engage substrate containing pyridine 6b and ester 6c functionalities giving access to pyrrolines 7b and 7c that can be used for the preparation of nicotine and proline analogues. Interestingly, in this case we were able to engage a secondary α-ester radical 7d in the cascade cyclization-functionalization reaction.

Scheme 6 Scope of the process for the synthesis of hydroxylamines 7

Other nitrosoarenes were compatible with the process as shown by the formation of products 7a–h in good to moderate yields. Also in this case, the use of highly electron poor nitrosoarene 7i as well as the trapping primary C-radicals (e.g., following cyclization onto a terminal olefin 7j) was not possible representing the limit of the strategy. Overall, this cascade process generates molecules containing two nitrogen functionalities, imine and hydroxylamines, which can be orthogonally functionalized and further modified.

In conclusion we have developed a photoredox decarboxylative approach for the formation of hydroxylamines and demonstrated its application in late-stage functionalizations and radical imino-hydroxylamination cascades.

All required fine chemicals were used directly without purification, unless stated otherwise. All air and moisture sensitive reactions were carried out under N₂ atmosphere using standard Schlenk manifold technique. ¹H and ¹³C NMR spectra (abbreviations: M = major; m = minor) were acquired at various field strengths as indicated and were referenced to CHCl₃(7.27 and 77.0 ppm for ¹H and ¹³C, respectively). High-resolution mass spectra were obtained using a JEOL JMS-700 spectrometer or a Fissions VG Trio 2000 quadrupole mass spectrometer. Spectra were obtained using electron impact ionization (EI) and chemical ionization (CI) techniques, or positive electrospray (ES). IR spectra were recorded using a JASCO FT/IR 410 spectrophotometer or using an ATI Mattson Genesis Seris FTIR spectrometer as evaporated films or liquid films. Flash column chromatography was performed using Merck Silica Gel 60 (40–63 μm). All the reactions were conducted in CEM 10 mL glass microwave tube using the EvoluChem PhotoRedOx Box.

The syntheses of the precursor ketones and oximes 6a–e are described in the Supporting Information.

Hydroxylamines 3a–o; General Procedure 1 (GP1)

A dry tube equipped with a stirring bar was charged with the carboxylic acid 1a–l (0.2 mmol, 1.0 equiv), 2a (4.0 mg, 10 μmol, 5 mol%), Cs₂CO₃­ (66 mg, 0.1 mmol, 1.0 equiv), and the requisite nitrosoarene (0.4 mmol, 2.0 equiv). The tube was capped with a Supelco aluminum crimp seal with septum (PTFE/butyl) and it was evacuated and refilled with N₂(3 ×). CH₂Cl₂ (anhydrous and degassed by bubbling through with N₂ for 20 min; 4.0 mL) was added. The N₂ inlet was then removed and the cap sealed with parafilm. The mixture was stirred at r.t. for 1 h in front of blue LEDs. The tube was opened to air and the mixture was diluted with CH₂Cl₂ (5 mL) and brine (5 mL). The layers were separated and the aqueous layer was extracted with CH₂Cl₂ (3 × 5 mL). The combined organic layers were dried (MgSO₄), filtered, and evaporated. Purification by column chromatography on silica gel gave 3a–o.

N-[(3s,5s,7s)-Adamantan-1-yl]-N-phenylhydroxylamine (3a)

Following GP1, 1-adamantanecarboxylic acid (1a; 36 mg, 0.2 mmol) gave 3a (44 mg, 90%) as a brown solid, purified by column chromatography (CH₂Cl₂).

IR (film): 2905, 2850, 1595, 1486, 1451, 1357, 1306, 1209, 1209, 1103, 1074 cm^–1.

¹H NMR (CDCl₃, 400 MHz): δ = 7.21 (4 H, dt, J = 15.4, 7.7 Hz), 7.10 (1 H, t, J = 7.0 Hz), 6.58 (1 H, br s), 2.04 (2 H, br s), 1.77–1.71 (6 H, d, J = 2.0 Hz), 1.57 (6 H, q, J = 12.0 Hz).

¹³C NMR (CDCl₃, 101 MHz): δ = 147.9, 127.3, 125.1, 124.9, 60.5, 38.5, 36.5, 29.4.

MS (EI): m/z = 227 (MH – OH), 170, 135, 107.

HRMS (ASAP): m/z [M + H]⁺ calcd for C₁₆H₂₂NO: 244.1696; found: 244.1691.

N-(1-Methylcyclohexyl)-N-phenylhydroxylamine (3b)

Following GP1, 1-methyl-1-cyclohexanecarboxylic acid (1b; 28 mg, 0.2 mmol) gave 3b (26 mg, 64%) as a brown solid, purified by column chromatography (pentane/CH₂Cl₂ 1:1).

IR (film): 2925, 2857, 2361, 1596, 1487, 1449, 1372, 1120, 1028 cm^–1.

¹H NMR (CDCl₃, 400 MHz): δ = 7.33 (2 H, br d, J = 7.8 Hz), 7.28 (2 H, t, J = 7.8 Hz), 7.17 (1 H, t, J = 7.1 Hz), 1.73–1.65 (3 H, m), 1.58–1.51 (3 H, m), 1.42–1.27 (4 H, m), 1.09 (3 H, s).

¹³C NMR (CDCl₃, 126 MHz): δ = 128.6, 127.4, 125.8, 124.3, 34.4, 29.4, 25.44, 22.3, 17.5.

MS (EI): m/z = 205 [M]⁺, 189, 146, 109.

HRMS (HESI): m/z [M + H]⁺ calcd for C₁₃H₂₀NO: 206.1539; found: 206.1540.

N-Phenyl-N-(1-phenylcyclohexyl)hydroxylamine (3c)

Following GP1, 1-phenylcyclohexane-1-carboxylic acid (1c; 41 mg, 0.2 mmol) gave 3c (38 mg, 71%) as an orange solid, purified by column chromatography (pentane/CH₂Cl₂ 1:1).

IR (film): 2929, 2861, 1593, 1484, 1456, 1447, 1204, 1152, 1037 cm^–1.

¹H NMR (CDCl₃, 400 MHz): δ = 7.32–7.11 (5 H, m), 7.15–6.99 (3 H, m), 6.71 (2 H, d, J = 7.6 Hz), 5.98 (1 H, br s), 2.41 (2 H, d, J = 12.6 Hz), 1.90 (2 H, t, J = 11.7 Hz), 1.66 (2 H, d, J = 9.5 Hz), 1.49 (1 H, d, J = 4.7 Hz), 1.39–1.12 (3 H, m).

¹³C NMR (CDCl₃, 101 MHz): δ = 148.6, 138.0, 129.1, 127.5, 127.1, 126.9, 125.1, 124.9, 68.1, 33.4, 26.1, 22.7.

MS (EI): m/z = 267 [MH – OH], 251, 208, 182, 159.

HRMS (HESI): m/z [M + H]⁺ calcd for C₁₈H₂₂NO: 268.1696; found: 268.1699.

N-[(1r,3s,5R,7S)-3-Chloroadamantan-1-yl]-N-phenylhydroxylamine (3d)

Following GP1, 3-chloroadamantane-1-carboxylic acid (1d; 43 mg, 0.2 mmol) gave 3d (50 mg, 90%) as a brown solid, purified by column chromatography (pentane/CH₂Cl₂ 1:1).

IR (film): 2913, 2859, 1595, 1487, 1450, 1349, 1328, 1303, 1204, 1154, 1074 cm^–1.

¹H NMR (CDCl₃, 400 MHz): δ = 7.25 (2 H, t, J = 7.5 Hz), 7.17 (2 H, d, J = 7.7 Hz), 7.13 (1 H, t, J = 7.2 Hz), 6.93 (1 H, br s), 2.21 (1 H, br s), 1.97 (4 H, q, J = 12.0 Hz), 1.72 (2 H, d, J = 11.7 Hz), 1.68 (2 H, q, J = 11.7 Hz), 1.58–1.37 (2 H, m).

¹³C NMR (CDCl₃, 101 MHz): δ = 147.4, 127.7, 125.7, 124.8, 68.5, 63.4, 47.8, 46.7, 37.2, 34.5, 31.5.

MS (EI): m/z = 261 [MH – OH], 227 (MH – OH – Cl), 204, 170, 133.

HRMS (HESI): m/z [M + H]⁺ calcd for C₁₆H₂₁NO: 278.1306; found: 278.1304.

N-(2-Methylbut-3-en-2-yl)-N-phenylhydroxylamine (3e)

Following GP1, 2,2-dimethylpent-4-enoic acid (1e; 26 mg, 0.2 mmol) gave 3e (21 mg, 54%) as an orange solid, purified by column chromatography (CH₂Cl₂).

IR (film): 3070, 2976, 2933, 1639, 1596, 1487, 1450, 1382, 1362, 1260, 1230, 1206, 1151, 1077, 1027 cm^–1.

¹H NMR (CDCl₃, 400 MHz): δ = 7.31–7.23 (4 H, m), 7.19–7.08 (1 H, m), 5.93 (1 H ddt, J = 15.8, 10.9, 7.4 Hz), 5.79 (1 H, br s), 5.08 (1 H, d, J = 1.4 Hz), 5.07–4.99 (1 H, m), 2.34 (2 H, d, J = 7.3 Hz), 1.08 (6 H, s).

¹³C NMR (CDCl₃, 101 MHz): δ = 149.2, 135.6, 127.6, 125.2, 124.8, 117.2, 63.0, 43.6, 23.2.

MS (EI): m/z = 190 [M]⁺, 150, 133, 109.

HRMS (HESI): m/z [M + Na]⁺ calcd for C₁₂H₁₇NONa: 213.1124; found: 213.1125.

tert-Butyl 3-[Hydroxy(phenyl)amino]-3-methylpiperidine-1- carboxylate (3f)

Following GP1, 1-N-Boc-3-methylpiperidine-3-carboxylic acid (1f; 49 mg, 0.2 mmol) gave 3f (34 mg, 56%) as a brown solid, purified by column chromatography (CH₂Cl₂).

IR (film): 3350, 2975, 2359, 1692, 1661, 1597, 1488, 1453, 1425, 1392, 1365, 1284, 1161, 1087 cm^–1.

¹H NMR (CDCl₃, 400 MHz): δ (rotamers) = 7.26 (4 H, m), 7.15 (1 H s), 7.12–7.07 (1 H, m), 4.35 (0.8 H, d, J = 13.8 Hz), 4.02 (0.8 H d, J = 12.9 Hz), 3.78–3.70 (0.2 H, m), 3.57 (0.2 H, br s), 3.32–3.17 (0.4 H, m), 2.88 (0.8 H, t, J = 12.2 Hz), 2.65 (0.8 H, d, J = 13.9 Hz), 2.15 (0.8 H, q, J = 12.2 Hz), 1.93 (0.2 H, br s), 1.68 (1.2 H, d, J = 13.3 Hz), 1.47 (9 H, s), 1.43–1.28 (2 H, m), 0.94 (3 H, m).

¹³C NMR (CDCl₃, 101 MHz): δ (rotamers) = 157.2 (M), 154.9 (m), 149.3 (M), 148.8 (m), 127.8 (M + m), 125.4 (m), 125.0 (M), 124.5 (m), 124.4 (M), 80.2 (M + m), 61.6 (m), 61.1 (M), 53.1 (M + m), 46.3 (M), 44.3 (m), 34.9 (M), 34.4 (m), 28.6 (M + m), 21.7 (M), 21.6 (m), 17.3 (M), 16.7 (m).

MS (EI): m/z = 290 [MH – OH], 217, 190, 160, 132.

HRMS (HESI): m/z [M + H]⁺ calcd for C₁₇H₂₇N₂O₃: 307.2016; found: 307.2016.

tert-Butyl 4-[Hydroxy(phenyl)amino]-4-methylpiperidine-1- carboxylate (3g)

Following GP1, 1-N-Boc-4-methylpiperidine-4-carboxylic acid (1g; 49 mg, 0.2 mmol) gave 3g (50 mg, 82%) as a brown oil, purified by column chromatography (CH₂Cl₂ → CH₂Cl₂/MeOH 99:1.)

IR (film): 3390, 2973, 2929, 1692, 1669, 1596, 1486, 1425, 1391, 1366, 1348, 1279, 1262, 1245, 1153, 1125, 1092, 1026 cm^–1.

¹H NMR (CDCl₃, 400 MHz): δ (rotamers) = 7.31–7.21 (4 H, m), 7.19–7.11 (1 H, m), 3.78 (2 H, br s), 3.18–3.04 (2 H, m), 1.94–1.74 (2 H, m,), 1.57–1.37 (11 H, m), 1.09 (3 H, s).

¹³C NMR (CDCl₃, 101 MHz): δ (rotamers) = 154.9, 148.6, 127.7, 125.5, 124.8, 79.4, 61.2, 34.8, 31.0, 28.5, 17.3.

MS (EI): m/z = 290 [MH – OH]⁺, 233, 189, 141.

HRMS (HESI): m/z [M + H]⁺ calcd for C₁₇H₂₇N₂O₃: 307.2016; found: 307.2018.

N-[(3s,5s,7s)-Adamantan-1-yl]-N-(4-methoxyphenyl)hydroxylamine (3j)

Following GP1, 1-adamantanecarboxylic acid (1a; 36 mg, 0.2 mmol) gave 3j (32 mg, 59%) as a red solid, purified by column chromatography (CH₂Cl₂ → CH₂Cl₂/MeOH 99.5:0.5).

IR (film): 2905, 2850, 1502, 1454, 1298, 1245, 1210, 1182, 1106, 1034 cm^–1.

¹H NMR (CDCl₃, 400 MHz): δ = 7.11 (2 H, d, J = 8.2 Hz), 6.78 (2 H, d, J = 8.2 Hz), 3.82 (3 H, s), 2.05 (3 H, s), 1.74 (6 H, s), 1.59 (6 H, q, J = 12.1 Hz).

¹³C NMR (CDCl₃, 101 MHz): δ = 156.3, 140.1, 125.3, 111.8, 59.6, 54.7, 44.7, 37.8, 35.8, 35.34 30.0, 28.7.

MS (EI): m/z = 257 (MH – OH), 242 (M – OMe), 214, 200, 163, 135.

HRMS (ASAP): m/z [M]⁺ calcd for C₁₇H₂₃NO₂: 273.1723; found: 273.1726.

N-[(3s,5s,7s)-Adamantan-1-yl]-N-(o-tolyl)hydroxylamine (3k)

Following GP1, 1-adamantanecarboxylic acid (1a; 36 mg, 0.2 mmol) gave 3k (28 mg, 55%) as a red solid, purified by column chromatography (pentane/CH₂Cl₂ 3:1 → 1:1).

IR (film): 2905, 2850, 1487, 1452, 1356, 1307, 1103, 1080 cm^–1.

¹H NMR (CDCl₃, 400 MHz): δ = 7.48 (1 H, d, J = 8.0 Hz), 7.18 (1 H, t, J = 7.5 Hz), 7.14 (1 H, d, J = 7.3 Hz), 7.08 (1 H, t, J = 7.3 Hz), 5.11 (1 H, br s), 2.32 (3 H, s), 2.06 (3 H, s, br), 1.83 (6 H, br s).

¹³C NMR (CDCl₃, 101 MHz): δ = 147.1, 135.1, 130.1, 127.0, 125.6, 125.3, 61.5, 38.2, 36.7, 29.5, 19.1.

MS (EI): m/z = 257 [M]⁺, 241, 184, 135.

HRMS (ASAP): m/z [M + H]⁺ calcd for C₁₇H₂₄NO: 258.1852; found: 258.1845.

N-[(3s,5s,7s)-Adamantan-1-yl]-N-[3-(trifluoromethyl)phenyl]- hydroxylamine (3l)

Following GP1, 1-adamantanecarboxylic acid (1a; 36 mg, 0.2 mmol) gave 3l (24 mg, 39%) as an orange solid, purified by column chromatography (pentane/CH₂Cl₂ 2:1 → 1:1).

IR (film): 2907, 2853, 1439, 1325, 1306, 1164, 1068, 1123, 1094, 1068 cm^–1.

¹H NMR (CDCl₃, 400 MHz): δ = 7.41 (1 H, s), 7.30 (4 H, m), 6.55 (1 H, br s), 2.08 (3 H, br s), 1.75 (6 H, s), 1.63 (3 H, d, J = 11.6 Hz), 1.55 (3 H, d, J = 11.5 Hz).

¹³C NMR (CDCl₃, 101 MHz): δ = 148.5, 129.8 (q, J = 31.9, 31.3 Hz), 127.9, 127.7, 124.0 (q, J = 273.1 Hz), 121.7, 121.4, 60.8, 38.4, 36.4, 29.3.

¹⁹F NMR (CDCl₃, 376 MHz): δ = –62.5.

MS (EI): m/z = 311 [M]⁺, 295, 275, 238, 135.

HRMS (ASAP): m/z [M + H]⁺ calcd for C₁₇H₂₁F₃NO: 312.1570; found: 312.1566.

N-[5-(2,5-Dimethylphenoxy)-2-methylpentan-2-yl]-N-phenyl­hydroxylamine (3m)

Following GP1, gemfibrozil (1j; 50 mg, 0.2 mmol) gave 3m (42 mg, 68%) as a brown solid, purified by column chromatography (CH₂Cl₂).

IR (film): 2923, 1615, 1585, 1508, 1486, 1451, 1413, 1384, 1361, 1284, 1264, 1208, 1156, 1129, 1077, 1046, 1002 cm^–1.

¹H NMR (CDCl₃, 400 MHz): δ = 7.26–7.21 (4 H, m), 7.15–7.07 (1 H, m), 7.00 (1 H, d, J = 7.4 Hz), 6.66 (1 H, d, J = 7.4 Hz), 6.60 (1 H, br s), 3.86 (2 H, t, J = 6.3 Hz), 2.32 (3 H, s), 2.16 (3 H, s), 1.95–1.77 (2 H, m), 1.78–1.62 (2 H, m), 1.08 (6 H, s).

¹³C NMR (CDCl₃, 101 MHz): δ = 157.0, 149.3, 136.4, 130.3, 127.6, 125.1, 124.7, 123.5, 120.6, 112.1, 68.3, 62.8, 35.6, 24.5, 23.0, 21.4, 15.8.

MS (EI): m/z = 296 [M – OH], 282, 204, 160, 135.

HRMS (HESI): m/z [M + Na]⁺ calcd for C₂₀H₂₆NO₂Na : 335.1856; found: 335.1860.

N-[(4aS,6aS,6bR,8aS,12aS,12bR,14bS)-2,2,6a,6b,9,9,12a-Heptamethyl-1,3,4,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicen-4a(2H)-yl)-N-phenylhydroxylamine (3n)

Following GP1, oleanoic acid (1k; 91 mg, 0.2 mmol) gave 3n (36 mg, 35%) as a red solid, purified by column chromatography (CH₂Cl₂).

IR (film): 2945, 1486, 1463, 1386, 1364, 1263, 1028 cm^–1.

¹H NMR (CDCl₃, 400 MHz): δ = 7.42–7.33 (2 H, d, J = 7.7 Hz), 7.26 (2 H, t, J = 7.7 Hz), 7.08 (1 H, t, J = 7.3 Hz), 5.21 (1 H, t, J = 3.4 Hz), 4.76 (1 H, br s), 3.32–3.13 (1 H, m), 2.49 (1 H, d, J = 13.0 Hz), 2.26–2.15 (1 H, m), 2.16–2.04 (1 H, m), 2.05–1.88 (2 H, m), 1.82–1.69 (2 H, m), 1.68–1.54 (7 H, m), 1.53–1.46 (2 H, m), 1.45–1.40 (2 H, m), 1.39–1.29 (2 H, m), 1.28–1.24 (2 H, m), 1.21 (3 H, s), 1.17–1.09 (2 H, m), 1.05 (3 H, s), 1.02 (3 H, s), 0.96 (3 H, s), 0.83 (3 H, s), 0.81 (3 H, s), 0.62 (3 H, s).

¹³C NMR (CDCl₃, 101 MHz): δ = 149.6, 146.2, 127.5, 124.3, 124.2, 122.5, 79.1, 65.4, 55.3, 53.5, 48.3, 48.0, 43.0, 42.0, 39.6, 38.8, 38.4, 37.2, 37.1, 35.4, 32.6, 32.8, 30.8, 28.3, 27.3, 26.6, 26.4, 24.4, 23.9, 23.7, 23.6, 18.4, 17.6, 15.7, 15.3.

MS (EI): m/z = 410, 406, 395, 392.

HRMS (HESI): m/z [M + H]⁺ calcd for C₃₅H₅₄NO₂: 520.4149; found: 520.4157.

(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-Hydroxy-2-[hydroxy (phenyl)amino]-2,4a,6a,6b,9,9,12a-heptamethyl-1,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,14b-octadecahydropicen-13(2H)-one (3o)

Following GP1, enoxolone (glycyrrhetinic acid, 1l; 91 mg, 0.2 mmol) gave 3o (82 mg, 77%) as an orange solid, purified by column chromatography (CH₂Cl₂ → CH₂Cl₂/MeOH 98:2); dr = 5:1.

IR (film): 3351, 2927, 1651, 1486, 1455, 1386, 1260, 1206, 1112, 1037 cm^–1.

¹H NMR (CDCl₃, 400 MHz): δ (diastereomers) = 7.24 (4 H, m), 7.13 (1 H, t, J = 6.9 Hz), 5.63 (0.2 H, d), 5.55 (0.8 H, s), 3.23 (1 H, dd, J = 10.6, 5.6 Hz), 2.79 (1 H, dt, J = 13.5, 3.5 Hz), 2.16–1.98 (2 H, m), 1.86–1.72 (2 H, m), 1.74–1.55 (8 H, m), 1.49–1.32 (5 H, m), 1.33 (3 H, s), 1.12 (7 H, m), 1.09 (3 H, s), 1.01 (3 H, s), 0.95 (2 H, m), 0.86–0.68 (6 H, m).

¹³C NMR (CDCl₃, 126 MHz): δ (diastereomers) = 199.8 (m), 199.7 (M), 169.8 (m), 168.8 (M), 149.4 (m), 147.7 (M), 127.8 (M), 127.7 (m), 127.3 (m), 127.1 (M), 125.0 (M), 124.4 (M + m), 123.5 (m), 78.3 (m), 78.2 (M), 63.3 (M), 61.8 (m), 61.6 (m), 61.2 (M), 54.5 (m), 54.4 (M), 47.4 (M), 45.8 (m), 44.8 (M + m), 42.9 (m), 42.7 (M), 41.4 (m), 39.3 (M), 38.7 (M + m), 38.6 (M + m), 36.6 (M + m), 36.3 (M), 35.4 (m), 32.5 (m), 32.3 (M), 32.2 (M + m), 31.7 (M), 31.2 (m), 29.1 (M), 28.1 (m), 27.8 (M + m), 27.7 (M + m), 27.6 (M + m), 26.8 (M), 26.4 (m), 26.0 (m), 25.8 (M), 22.9 (M), 22.8 (m), 18.2 (M), 17.0 (M + m), 16.4 (m), 15.8 (M + m), 15.1 (M + m).

MS (EI): m/z = 515 (M – OH₂), 424 (M–H – NOHPh), 257, 216, 175, 135, 91.

HRMS (ASAP): m/z [M + H]⁺ calcd for C₃₅H₅₂NO₃: 534.3942; found: 534.3949.

Hydroxylamines 7; General Procedure 2 (GP2)

A dry tube equipped with a stirring bar was charged with the carboxylic acid 6a–d (0.1 mmol, 1.0 equiv), 2a (2.0 mg, 5 μmol, 5 mol%), Cs₂CO₃ (33 mg, 0.1 mmol, 1.0 equiv), and the requisite nitrosoarene (0.11 mmol, 1.1 equiv). The tube was capped with a Supelco aluminum crimp seal with septum (PTFE/butyl) and it was evacuated and refilled with N₂(3 ×). CH₂Cl₂ (anhydrous and degassed by bubbling through with N₂ for 20 min) (2.0 mL) was added. The N₂ inlet was then removed and the cap sealed with parafilm. The mixture was stirred at r.t. for 1 h in front of blue LEDs. The tube was opened to air and the mixture was diluted with CH₂Cl₂ (5 mL) and brine (5 mL). The layers were separated and the aqueous layer was extracted with CH₂Cl_2­ (3 × 5 mL). The combined organic layers were dried (MgSO₄), filtered, and evaporated. Purification by column chromatography on silica gel gave 7a–h.

N-Phenyl-N-[2-(5-phenyl-3,4-dihydro-2H-pyrrol-2-yl)propan-2-yl]hydroxylamine (7a)

Following GP2, 6a (58 mg, 0.2 mmol) gave 7a (39 mg, 67%) as a brown solid, purified by column chromatography (CH₂Cl₂ → CH₂Cl₂/MeOH 99.8:0.2).

IR (film): 3212, 2978, 1618, 1596, 1576, 1486, 1448, 1342, 1168, 1063 cm^–1.

¹H NMR (CDCl₃, 101 MHz): δ = 7.89 (2 H, dd, J = 8.0, 1.4 Hz), 7.49–7.39 (5 H, m), 7.30 (2 H, t, J = 7.9 Hz), 7.13 (1 H, t, J = 7.3 Hz), 4.37 (1 H, t, J = 8.2 Hz), 3.04 (1 H, dddd, J = 16.8, 10.3, 3.0, 2.5 Hz), 2.83 (1 H, dtd, J = 11.6, 9.5, 2.3 Hz), 2.07 (1 H, dddd, J = 11.3, 9.8, 8.0, 3.3 Hz), 1.85–1.74 (1 H, (m), 1.27 (3 H, s), 1.11 (3 H, s).

¹³C NMR (CDCl₃, 101 MHz): δ = 173.3, 149.2, 133.5, 131.2, 128.7, 129.0, 127.8, 125.2, 125.0, 78.6, 65.1, 34.1, 25.4, 25.1, 18.2.

MS (EI): m/z = 278 (MH – OH), 170, 144, 134, 77.

HRMS (APCI): m/z [M + H]⁺ calcd for C₁₉H₂₂N₂O: 294.1727; found: 294.1725.

N-Phenyl-N-{2-[5-(pyridin-3-yl)-3,4-dihydro-2H-pyrrol-2-yl]- propan-2-yl}hydroxylamine (7b)

Following GP2, 6b (29 mg, 0.1 mmol) gave 7b (15 mg, 51%) as a brown oil, purified by column chromatography (CH₂Cl₂ → CH₂Cl₂/MeOH 99.5:0.5).

IR (film): 2979, 1620, 1594, 1485, 1413, 1377, 1358, 1342, 1168, 1071, 1026 cm^–1.

¹H NMR (CDCl₃, 400 MHz): δ = 9.00 (1 H, d, J = 2.2 Hz), 8.70 (1 H, dd, J = 4.8, 1.7 Hz), 8.25 (1 H, dt, J = 7.9, 2.0 Hz), 7.41–7.35 (3 H, m), 7.33–7.24 (2 H, m), 7.15–7.10 (1 H, m), 4.43 (1 H, tt, J = 8.2, 2.4 Hz), 3.05 (1 H, dddd, J = 17.3, 10.4, 3.5, 2.3 Hz), 2.93–2.79 (1 H, m), 2.11 (1 H, dddd, J = 13.2, 9.8, 8.0, 3.5 Hz), 1.87 (1 H, ddt, J = 13.1, 10.3, 8.6 Hz), 1.24 (3 H, s), 1.08 (3 H, s).

¹³C NMR (CDCl₃, 101 MHz): δ = 171.1, 151.8, 149.3, 149.1, 135.0, 129.4, 127.8, 125.1, 125.1, 123.6, 79.0, 65.3, 34.2, 25.1, 23.9, 18.3.

MS (EI): m/z = 279 (MH – OH), 236, 171, 147, 134, 118, 91, 77.

HRMS (ASAP): m/z [M + H]⁺ calcd for C₁₈H₂₂N₃O: 296.1757; found: 296.1758.

Methyl 2-{2-[Hydroxy(phenyl)amino]propan-2-yl}-3,4-dihydro-2H-pyrrole-5-carboxylate (7c)

Following GP2, 6c (54 mg, 0.2 mmol) gave 7c (20 mg, 36%) as a brown oil, purified by column chromatography (CH₂Cl₂ → CH₂Cl₂/MeOH 99.5:0.5).

IR (film): 2952, 1723, 1596, 1488, 1439, 1325, 1243, 1167, 1111 cm^–1.

¹H NMR (CDCl₃, 400 MHz): δ = 7.29 (4 H, m), 7.13 (1 H, t, J = 6.7 Hz), 6.45 (1 H, br s), 4.55 (1 H, tt, J = 8.2, 2.8 Hz), 3.88 (3 H, s), 2.92 (1 H, ddt, J = 17.7, 10.4, 3.4 Hz), 2.83–2.69 (1 H, m), 2.10–2.00 (1 H, m), 1.94 (1 H, dq, J = 13.4, 8.6 Hz), 1.23 (3 H, s), 0.96 (3 H, s).

¹³C NMR (CDCl₃, 101 MHz): δ = 167.8, 163.2, 149.0, 127.8, 125.3, 125.1, 124.0, 80.5, 65.5, 52.8, 35.6, 24.3, 21.5, 19.2.

MS (EI): m/z = 260 (MH – OH), 185, 134, 77.

HRMS (ASAP): m/z [M + H]⁺ calcd for C₁₅H₂₁N₂O₃: 277.1547; found: 277.1547.

Methyl 2-[Hydroxy(phenyl)amino]-2-(5-phenyl-3,4-dihydro-2H-pyrrol-2-yl)acetate (7d)

Following GP2, 6d (34 mg, 0.2 mmol) gave 7d (29 mg, 45%) as a brown oil, purified by column chromatography (CH₂Cl₂ → CH₂Cl₂/MeOH 99.5:0.5); dr = 3:2.

IR (film): 3059, 2950, 1737, 1614, 1597, 1578, 1520, 1489, 1447, 1434, 1342, 1259, 1197, 1155 cm^–1.

¹H NMR (CDCl₃, 400 MHz): δ = 7.85–7.79 (2 H, m), 7.48–7.36 (4 H, m), 7.32–7.27 (1 H, m), 7.14 (0.8 H, d, J = 7.9 Hz), 7.09 (1.2 H, d, J = 7.8 Hz), 7.00–6.87 (1 H, m), 4.97–4.88 (1 H, m), 4.48 (0.6 H, d, J = 6.4 Hz), 4.33 (0.4 H, d, J = 7.4 Hz), 3.72 (1.2 H, s), 3.71 (1.8 H, s), 3.11 (1 H, dddd, J = 19.8, 10.2, 4.2, 2.2 Hz), 3.03–2.92 (1 H, m), 2.40–2.31 (1 H, m), 2.09–1.96 (1 H, m).

¹³C NMR (CDCl₃, 101 MHz): δ = 174.7 (M), 174.3 (m), 171.8 (m), 171.1 (M), 151.2 (M), 150.9 (m), 134.0 (m), 133.8 (M), 130.9 (M), 130.8 (m), 129.0 (m), 128.8 (M), 128.5 (M), 128.4 (m), 127.9 (M), 127.9 (m), 121.8 (m), 121.5 (M), 115.3 (M + m), 72.9 (m), 72.2 (M), 71.6 (M), 70.7 (m), 52.1 (M), 52.0 (m), 35.4 (M), 35.0 (m), 26.7 (M), 26.5 (m).

MS (EI): m/z = 308 (MH – OH), 249, 145, 104, 77.

HRMS (APCI): m/z [M + H]⁺ calcd for C₁₉H₂₁N₂O₃: 325.1547; found: 325.1534.

N-(4-Methoxyphenyl)-N-[2-(5-phenyl-3,4-dihydro-2H-pyrrol-2-yl)propan-2-yl]hydroxylamine (7e)

Following GP2, 6a (29 mg, 0.1 mmol) gave 7e (18 mg, 56%) as a brown oil, purified by column chromatography (CH₂Cl₂ → CH₂Cl₂/MeOH 99.5:0.5).

IR (film): 3285, 2970, 1615, 1502, 1463, 1447, 1342, 1296, 1245, 1160, 1033 cm^–1.

¹H NMR (CDCl₃, 400 MHz): δ = 7.91 (2 H, d, J = 6.8 Hz), 7.52–7.44 (3 H, m), 7.37 (2 H, d, J = 8.8 Hz), 6.86 (2 H, d, J = 8.8 Hz), 4.41 (1 H, t, J = 8.1 Hz), 3.82 (3 H, s), 3.06 (1 H, ddt, J = 16.4, 10.4, 2.8 Hz), 2.92–2.79 (1 H, m), 2.15–2.03 (1 H, m), 1.90–1.73 (1 H, m), 1.26 (3 H, s), 1.08 (3 H, s).

¹³C NMR (CDCl₃, 101 MHz): δ = 173.3, 157.1, 142.0, 133.5, 131.1, 128.6, 128.0, 126.5, 113.0, 78.5, 65.1, 55.5, 34.2, 25.3, 24.7, 18.0.

MS (EI): m/z = 308 (MH – OH), 265, 164, 115, 91.

HRMS (ASAP): m/z [M]⁺ calcd for C₂₀H₂₄N₂O₂: 324.1832; found: 324.1836.

N-(4-Chlorophenyl)-N-[2-(5-phenyl-3,4-dihydro-2H-pyrrol-2-yl)propan-2-yl]hydroxylamine (7f)

Following GP2, 6a (29 mg, 0.1 mmol) gave 7f (23 mg, 70%) as a brown oil, purified by column chromatography (CH₂Cl₂ → CH₂Cl₂/MeOH 99.5:0.5).

IR (film): 3184, 2977, 1618, 1576, 1482, 1448, 1379, 1360, 1343, 1169, 1090, 1011 cm^–1.

¹H NMR (CDCl₃, 400 MHz): δ = 9.27 (1 H, br s), 7.87 (2 H, d, J = 7.4 Hz), 7.46 (3 H, m), 7.33 (2 H, d, J = 8.6 Hz), 7.25 (2 H, d, J = 8.7 Hz), 4.33 (1 H, t, J = 6.8 Hz), 3.09–2.99 (1 H, m), 2.84 (1 H, m), 2.12–2.03 (1 H, m), 1.84–1.72 (1 H, m), 1.22 (3 H, s), 1.10 (3 H, s).

¹³C NMR (CDCl₃, 101 MHz): δ = 173.7, 147.9, 133.4, 131.4, 130.2, 128.8, 128.1, 127.9, 126.5, 78.7 (br), 65.3, 34.2 (br), 25.4, 25.0, 18.0.

MS (EI): m/z = 312 (MH – OH), 269, 169, 145, 91.

HRMS (HESI): m/z [M + Na]⁺ calcd for C₁₉H₂₁ClN₂ONa: 351.1235; found: 351.1241.

N-[2-(5-Phenyl-3,4-dihydro-2H-pyrrol-2-yl)propan-2-yl]-N-[3-(trifluoromethyl)phenyl]hydroxylamine (7g)

Following GP2, 6a (29 mg, 0.1 mmol) gave 7g (13 mg, 36%) as a brown oil, purified by column chromatography (CH₂Cl₂).

IR (film): 2979, 1616, 1576, 1439, 1381, 1362, 1326, 1281, 1163, 1119, 1095, 1068 cm^–1.

¹H NMR (CDCl₃, 400 MHz): δ = 7.88 (2 H, d, J = 7.4 Hz), 7.65 (1 H, s), 7.57 (1 H, d, J = 7.4 Hz), 7.47 (3 H, m), 7.39 (2 H, m), 4.34 (1 H, br s), 3.11–3.01 (1 H, m), 2.86 (1 H, m), 2.15–2.06 (1 H, m), 1.79 (1 H, m), 1.23 (3 H, s), 1.13 (3 H, s).

¹³C NMR (CDCl₃, 101 MHz): δ = 173.9, 145.0, 133.3, 131.5, 130.3 (q, J = 32.1 Hz), 128.8, 128.4, 128.2, 128.1, 124.3 (q, J = 272.7 Hz), 121.8 (q, J = 3.8 Hz), 121.6 (q, J = 3.7 Hz), 79.0, 65.6, 34.3, 25.3, 24.8, 17.8.

¹⁹F NMR (CDCl₃, 376 MHz): δ = –63.9.

MS (EI): m/z = 346 (MH – OH), 345, 327, 202, 186, 145, 91.

HRMS (ASAP): m/z [M + H]⁺ calcd for C₂₀H₂₂F₃N₂O: 363.1679; found: 363.1679.

N-[2-(5-Phenyl-3,4-dihydro-2H-pyrrol-2-yl)propan-2-yl]-N- (o-tolyl)hydroxylamine (7h)

Following GP2, 6a (29 mg, 0.1 mmol) gave 7h (17 mg, 55%) as a brown solid, purified by column chromatography (CH₂Cl₂ → CH₂Cl₂/MeOH 99.5:0.5).

IR (film): 2979, 1616, 1576, 1487, 1447, 1376, 1342, 1168, 1063, 1027 cm^–1.

¹H NMR (CDCl₃, 400 MHz): δ = 7.89 (2 H, d, J = 6.9 Hz), 7.70 (1 H, d, J = 7.9 Hz), 7.45 (3 H, m), 7.19 (2 H, d, J = 8.1 Hz), 7.10 (1 H, t, J = 7.3 Hz), 4.62 (1 H, t, J = 8.1 Hz), 3.06 (1 H, ddt, J = 16.2, 10.2, 2.7 Hz), 2.95–2.85 (1 H, m), 2.45 (3 H, s), 2.20–2.06 (1 H, m), 1.93–1.81 (1 H, m), 1.27 (3 H, s), 0.95 (3 H, s).

¹³C NMR (CDCl₃, 101 MHz): δ = 173.2, 147.9, 135.7, 133.7, 131.0, 130.3, 128.6, 128.0, 126.7, 125.7, 80.1 (br), 66.2, 34.4, 25.2, 22.4, 19.2, 17.1 (br).

MS (EI): m/z = 292 (MH – OH), 186, 148, 115, 91.

HRMS (ASAP): m/z [M + H]⁺ calcd for C₂₀H₂₄N₂O: 308.1883; found: 308.1887.

Acknowledgment

L. A. thanks Eli Lilly for a Ph.D. CASE Award. M. A. A. and N. S. S. thank the Department of Chemistry, King Faisal University, Saudi Arabia for the support.

• References

• 1a The Chemistry of Hydroxylamines, Oximes and Hydroxamic Acids. Rappoport Z. Liebman JF. Wiley; Chichester: 2008
• 1b Ashani Y. Silman I. Hydroxylamines and Oximes: Biological Properties and Potential Uses as Therapeutic Agents. In The Chemistry of Hydroxylamines, Oximes and Hydroxamic Acids. Rappoport Z. Liebman JF. Wiley; Chichester: 2008. Chap. 13
• 1c Race NJ. Hazelden IR. Faulkner A. Bower JF. Chem. Sci. 2017; 8: 5248
• 1d Gao H. Zhou Z. Kwon D.-H. Coombs J. Jones S. Behnke NE. Ess DH. Kürti L. Nat. Chem. 2017; 9: 681
• 2 Studer A. Curran DP. Angew. Chem. Int. Ed. 2015; 55: 58
• 3a Prier CK. Rankic DA. MacMillan DW. C. Chem. Rev. 2013; 113: 5322
• 3b Skubi KL. Blum TR. Yoon TP. Chem. Rev. 2016; 116: 10035
• 3c Romero NA. Nicewicz DA. Chem. Rev. 2016; 116: 10075
• 3d Hopkinson MN. Sahoo B. Li J.-L. Glorius F. Chem. Eur. J. 2014; 20: 3874
• 4 Xuan J. Zhang Z.-G. Xiao W.-J. Angew. Chem. Int. Ed. 2015; 54: 15632
• 5a Reina DF. Duncey EM. Morcillo SP. Svejstrup TD. Popescu MV. Douglas JJ. Sheikh NS. Leonori D. Eur. J. Org. Chem. 2017; 2108
• 5b Davies J. Sheikh NS. Leonori D. Angew. Chem. Int. Ed. 2017; 56: 13361
• 5c Davies J. Svejstrup TD. Reina DF. Sheikh NS. Leonori D. J. Am. Chem. Soc. 2016; 138: 8092
• 5d Davies J. Booth SG. Essafi S. Dryfe RW. A. Leonori D. Angew. Chem. Int. Ed. 2015; 54: 14017
• 6a Yamamoto H. Kawasaki M. Bull. Chem. Soc. Jpn. 2007; 80: 595
• 6b Yamamoto H. Momiyama N. Chem. Commun. 2005; 7 3514
• 6c Zuman P. Shah B. Chem. Rev. 1994; 94: 1621
• 7a Kanegawa S. Karasawa S. Maeyama M. Nakano M. Koga N. J. Am. Chem. Soc. 2008; 130: 3079
• 7b Forrester AR. Fullerton JD. McConnachie G. J. Chem. Soc., Perkin Trans. 1 1983; 1759
• 7c Dhayalan V. Sämann C. Knochel P. Chem. Commun 2015; 51: 3239
• 7d Li Y. Chakrabarty S. Studer A. Angew. Chem. Int. Ed. 2015; 54: 3587
• 8a Momiyama N. Yamamoto H. Org. Lett. 2002; 4: 3579
• 8b Momiyama N. Yamamoto H. J. Am. Chem. Soc. 2003; 125: 6038
• 8c Payette JN. Yamamoto H. J. Am. Chem. Soc. 2008; 130: 12276
• 8d Yanagisawa A. Izumib Y. Takeshita S. Synlett 2009; 716
• 8e Yanagisawa A. Takeshita S. Izumi Y. Yoshida K. J. Am. Chem. Soc. 2010; 132: 5328
• 9a Bøgevig A. Sundén H. Córdova A. Angew. Chem. Int. Ed. 2004; 43: 1109
• 9b Kano T. Ueda M. Takai J. Maruoka K. J. Am. Chem. Soc. 2006; 128: 6046
• 9c Palomo C. Vera S. Velilla I. Mielgo A. Gómez-Bengoa E. Angew. Chem. Int. Ed. 2007; 46: 8054
• 9d Shen K. Liu X. Wang G. Lin L. Feng X. Angew. Chem. Int. Ed. 2011; 50: 4684
• 10 Wong FT. Patra PK. Seayad J. Zhang Y. Ying JY. Org. Lett. 2008; 10: 2333
• 11 Ayhan P. Demir AS. Adv. Synth. Catal. 2011; 353: 624
• 12a Gingras BA. Water WA. J. Chem. Soc. 1954; 1920
• 12b Inamoto N. Simamura O. J. Org. Chem. 1958; 23: 408
• 12c Hosogai T. Inamoto N. Okazaki R. J. Chem. Soc., Chem. Commun. 1971; 3399
• 12d Corey EJ. Gross AW. J. Org. Chem. 1985; 50: 5391
• 12e Gui J. Pan C.-M. Jin Y. Qin T. Lo JC. Lee BJ. Spergel SH. Mertzman ME. Pitts WJ. Cruz TE. L. Schmidt MA. Darvatkar N. Natarajan SR. Baran PS. Science 2015; 348: 886
• 13a Fisher DJ. Shaum JB. Mills CL. Read de Alaniz J. Org. Lett. 2016; 18: 5074
• 13b Fisher DJ. Burnett GL. Velasco R. Read de Alaniz J. J. Am. Chem. Soc. 2015; 137: 11614
• 14 van der Werf A. Hribersek M. Selander N. Org. Lett. 2017; 19: 2374
• 15 Studer A. Chem. Eur. J. 2001; 7: 1159
• 16 See SI for more information.
• 17 Vleeschouwer FD. Speybroeck VV. Waroquier M. Geerlings P. Proft FD. Org. Lett. 2007; 9: 2721
• 18a Weber M. Fischer H. Helv. Chim. Acta 1998; 81: 770
• 18b Wong MW. Pross A. Radom L. J. Am. Chem. Soc. 1994; 116: 6284
• 19a Nicewicz DA. Nguyen TM. ACS Catal. 2014; 4: 355
• 19b Margrey KA. Nicewicz DA. Acc. Chem. Res. 2016; 49: 1997
• 19c Fukuzumi S. Ohkubo K. Org. Biomol. Chem. 2014; 12: 6059
• 20a Pitts DD. Ghorbani CR. Harry SA. Capilato JN. Siegler MA. Lectka T. Chem. Sci. 2017; 8: 6918
• 20b Pitts CR. Bume DD. Harry SA. Siegler MA. Lectka T. J. Am. Chem. Soc. 2017; 139: 2208