SYNTHESIS template MACv2.0 - Paper - PSP - Special Topic.dotx



Photoredox Synthesis of Aryl-Hydroxylamines from Carboxylic Acids and NitrosoarenesJacob Daviesa Lucrezia AngeliniaMohammed A. AlkhalifahbLaia Malet SanzcNadeem S. Sheikh*bDaniele Leonori*aa School of Chemistry, University of Manchester, Oxford Road, Manchester M13 9PL, UK.b Department of Chemistry, Faculty of Science, King Faisal University, P.O. Box 380, Al-Ahsa 3192, Saudi Arabia.c Eli Lilly and Company Limited, Erl Wood Manor, Windlesham, Surrey GU20 6PH, UK.* nsheikh@kfu.edu.sa * daniele.leonori@manchester.ac.ukClick here to insert a dedication.Received: Accepted: Published online: DOI: Abstract Hydroxylamines are found in biologically active compounds and serve as building blocks for the preparation of nitrogen-containing molecules. Here, we demonstrate the direct conversion of carboxylic acids into the corresponding alkyl hydroxylamines using organo-photoredox catalysis. The process relies in the generation of alkyl radicals via photo-induced 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, photoredoxHydroxylamines 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 1A).PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SYWNlPC9BdXRob3I+PFllYXI+MjAxNzwvWWVhcj48UmVj

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ADDIN EN.CITE.DATA 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.Visible-light photoredox catalysis is now an established and powerful technique to perform single-electron transfer (SET) ADDIN EN.CITE <EndNote><Cite><Author>Studer</Author><Year>2015</Year><RecNum>1430</RecNum><DisplayText><style face="superscript">2</style></DisplayText><record><rec-number>1430</rec-number><foreign-keys><key app="EN" db-id="f9arva0tlwwezbewzd8prsrtvefxvzesw2w2" timestamp="1462470692">1430</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>A. Studer</author><author>D. P. Curran</author></authors></contributors><titles><title>Catalysis of Radical Reactions: A Radical Chemistry Perspective</title><secondary-title>Angew. Chem. Int. Ed.</secondary-title></titles><periodical><full-title>Angew. Chem. Int. Ed.</full-title></periodical><pages>58-102</pages><volume>55</volume><dates><year>2015</year></dates><urls></urls></record></Cite></EndNote>2 reactions under mild conditions.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QcmllcjwvQXV0aG9yPjxZZWFyPjIwMTM8L1llYXI+PFJl

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ADDIN EN.CITE.DATA 3 In particular, the ability of harvesting carboxylic acids for the generation of sp3 C-radical by oxidative decarboxylation has enabled the development of many C–C and C–X (X = F, N3, S…) bond-forming processes. ADDIN EN.CITE <EndNote><Cite><Author>Xuan</Author><Year>2015</Year><RecNum>1489</RecNum><DisplayText><style face="superscript">4</style></DisplayText><record><rec-number>1489</rec-number><foreign-keys><key app="EN" db-id="f9arva0tlwwezbewzd8prsrtvefxvzesw2w2" timestamp="1467012482">1489</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>J. Xuan</author><author>Z.-G. Zhang</author><author>W.-J. Xiao</author></authors></contributors><titles><title>Visible-Light-Induced Decarboxylative Functionalization of Carboxylic Acids and Their Derivatives</title><secondary-title>Angew. Chem. Int. Ed.</secondary-title></titles><periodical><full-title>Angew. Chem. Int. Ed.</full-title></periodical><pages>15632</pages><volume>54</volume><dates><year>2015</year></dates><urls></urls></record></Cite></EndNote>4Owing to our ongoing interest in the preparation of hydroxylamine derivatives as nitrogen-radical precursors,PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SZWluYTwvQXV0aG9yPjxZZWFyPjIwMTc8L1llYXI+PFJl

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ADDIN EN.CITE.DATA 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. ADDIN EN.CITE <EndNote><Cite><Author>Yamamoto</Author><Year>2007</Year><RecNum>1873</RecNum><DisplayText><style face="superscript">6</style></DisplayText><record><rec-number>1873</rec-number><foreign-keys><key app="EN" db-id="f9arva0tlwwezbewzd8prsrtvefxvzesw2w2" timestamp="1509446017">1873</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>H. Yamamoto</author><author>M. Kawasaki</author></authors></contributors><titles><secondary-title>Bull. Chem. Soc. Jpn.</secondary-title></titles><periodical><full-title>Bull. Chem. Soc. Jpn.</full-title></periodical><pages>595</pages><volume>80</volume><dates><year>2007</year></dates><urls></urls></record></Cite><Cite><Author>Yamamoto</Author><Year>2005</Year><RecNum>1874</RecNum><record><rec-number>1874</rec-number><foreign-keys><key app="EN" db-id="f9arva0tlwwezbewzd8prsrtvefxvzesw2w2" timestamp="1509446063">1874</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>H. Yamamoto</author><author>N. Momiyama</author></authors></contributors><titles><secondary-title>Chem. Commun.</secondary-title></titles><periodical><full-title>Chem. Commun.</full-title></periodical><pages>3514</pages><volume>7</volume><dates><year>2005</year></dates><urls></urls></record></Cite><Cite><Author>Zuman</Author><Year>1994</Year><RecNum>1875</RecNum><record><rec-number>1875</rec-number><foreign-keys><key app="EN" db-id="f9arva0tlwwezbewzd8prsrtvefxvzesw2w2" timestamp="1509446113">1875</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>P. Zuman</author><author>B. Shah</author></authors></contributors><titles><secondary-title>Chem. Rev.</secondary-title></titles><periodical><full-title>Chem. Rev.</full-title></periodical><pages>1621</pages><volume>94</volume><dates><year>1994</year></dates><urls></urls></record></Cite></EndNote>6 Such an approach would be complementary to the more established ionic pathways where nitrosoarenes are used as electrophiles in conjunction with organometallic reagents,PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LYW5lZ2F3YTwvQXV0aG9yPjxZZWFyPjIwMDg8L1llYXI+

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ADDIN EN.CITE.DATA 9/NHC ADDIN EN.CITE <EndNote><Cite><Author>Wong</Author><Year>2008</Year><RecNum>1859</RecNum><DisplayText><style face="superscript">10</style></DisplayText><record><rec-number>1859</rec-number><foreign-keys><key app="EN" db-id="f9arva0tlwwezbewzd8prsrtvefxvzesw2w2" timestamp="1509445035">1859</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>F. T. Wong</author><author>P. K. Patra</author><author>J. Seayad</author><author>Y. Zhang</author><author>J. Y. Ying</author></authors></contributors><titles><secondary-title>Org. Lett.</secondary-title></titles><periodical><full-title>Org. Lett.</full-title></periodical><pages>2333</pages><volume>10</volume><dates><year>2008</year></dates><urls></urls></record></Cite></EndNote>10-based catalytic systems (Scheme 1B). ADDIN EN.CITE <EndNote><Cite><Author>Ayhan</Author><Year>2011</Year><RecNum>1860</RecNum><DisplayText><style face="superscript">11</style></DisplayText><record><rec-number>1860</rec-number><foreign-keys><key app="EN" db-id="f9arva0tlwwezbewzd8prsrtvefxvzesw2w2" timestamp="1509445101">1860</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>P. Ayhan</author><author>A. S. Demir</author></authors></contributors><titles><secondary-title>Adv. Synth. Catal.</secondary-title></titles><periodical><full-title>Adv. Synth. Catal.</full-title></periodical><pages>624</pages><volume>353</volume><dates><year>2011</year></dates><urls></urls></record></Cite></EndNote>11 Furthermore, the preparation of hydroxylamines via radical addition onto nitrosoarenes has been considerably overlooked and only few protocols are available.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HaW5ncmFzPC9BdXRob3I+PFllYXI+MTk1NDwvWWVhcj48

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ADDIN EN.CITE.DATA 12 Most notably, de Alaniz ADDIN EN.CITE <EndNote><Cite><Author>Fisher</Author><Year>2016</Year><RecNum>1871</RecNum><DisplayText><style face="superscript">13</style></DisplayText><record><rec-number>1871</rec-number><foreign-keys><key app="EN" db-id="f9arva0tlwwezbewzd8prsrtvefxvzesw2w2" timestamp="1509445915">1871</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>D. J. Fisher</author><author>J. B. Shaum</author><author>C. L. Mills</author><author>J. R. de Alaniz</author></authors></contributors><titles><secondary-title>Org. Lett.</secondary-title></titles><periodical><full-title>Org. Lett.</full-title></periodical><pages>5074</pages><volume>18</volume><dates><year>2016</year></dates><urls></urls></record></Cite><Cite><Author>Fisher</Author><Year>2015</Year><RecNum>1872</RecNum><record><rec-number>1872</rec-number><foreign-keys><key app="EN" db-id="f9arva0tlwwezbewzd8prsrtvefxvzesw2w2" timestamp="1509445965">1872</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>D. J. Fisher</author><author>G. L. Burnett</author><author>R. Velasco</author><author>J. R. de Alaniz</author></authors></contributors><titles><secondary-title>J. Am. Chem. Soc.</secondary-title></titles><periodical><full-title>J. Am. Chem. Soc.</full-title></periodical><pages>11614</pages><volume>137</volume><dates><year>2015</year></dates><urls></urls></record></Cite></EndNote>13 and Selander ADDIN EN.CITE <EndNote><Cite><Author>Werf</Author><Year>2017</Year><RecNum>1870</RecNum><DisplayText><style face="superscript">14</style></DisplayText><record><rec-number>1870</rec-number><foreign-keys><key app="EN" db-id="f9arva0tlwwezbewzd8prsrtvefxvzesw2w2" timestamp="1509445834">1870</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>A. van der Werf</author><author>M. Hribersek</author><author>N. Selander</author></authors></contributors><titles><secondary-title>Org. Lett.</secondary-title></titles><periodical><full-title>Org. Lett.</full-title></periodical><pages>2374</pages><volume>19</volume><dates><year>2017</year></dates><urls></urls></record></Cite></EndNote>14 have recently developed Cu(II)-catalyzed protocols for the coupling of nitrosoarenes with radical deriving from -Br-carbonyls and sodium triflinate, respectively (Scheme 1C).Scheme 1 Relevance of hydroxylamines, previous ionic and radical approaches using nitrosoarenes and this work.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 1D).At the outset, we envisioned a catalytic cycle starting with the visible-light-promoted excitation of a photocalyst and the following oxidative SET decarboxylation of acid A upon in situ deprotonation (A?B) (Scheme 2A). ADDIN EN.CITE <EndNote><Cite><Author>Xuan</Author><Year>2015</Year><RecNum>1489</RecNum><DisplayText><style face="superscript">4</style></DisplayText><record><rec-number>1489</rec-number><foreign-keys><key app="EN" db-id="f9arva0tlwwezbewzd8prsrtvefxvzesw2w2" timestamp="1467012482">1489</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>J. Xuan</author><author>Z.-G. Zhang</author><author>W.-J. Xiao</author></authors></contributors><titles><title>Visible-Light-Induced Decarboxylative Functionalization of Carboxylic Acids and Their Derivatives</title><secondary-title>Angew. Chem. Int. Ed.</secondary-title></titles><periodical><full-title>Angew. Chem. Int. Ed.</full-title></periodical><pages>15632</pages><volume>54</volume><dates><year>2015</year></dates><urls></urls></record></Cite></EndNote>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. ADDIN EN.CITE <EndNote><Cite><Author>Studer</Author><Year>2001</Year><RecNum>1252</RecNum><DisplayText><style face="superscript">15</style></DisplayText><record><rec-number>1252</rec-number><foreign-keys><key app="EN" db-id="f9arva0tlwwezbewzd8prsrtvefxvzesw2w2" timestamp="1438077691">1252</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>A. Studer</author></authors></contributors><titles><secondary-title>Chem. Eur. J.</secondary-title></titles><periodical><full-title>Chem. Eur. J.</full-title></periodical><pages>1159</pages><volume>7</volume><dates><year>2001</year></dates><urls></urls></record></Cite></EndNote>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 we conducted preliminary DFT studies (Scheme 2B). 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. ADDIN EN.CITE <EndNote><Cite><Author>Kanegawa</Author><Year>2008</Year><RecNum>1861</RecNum><DisplayText><style face="superscript">7a, 8c</style></DisplayText><record><rec-number>1861</rec-number><foreign-keys><key app="EN" db-id="f9arva0tlwwezbewzd8prsrtvefxvzesw2w2" timestamp="1509445288">1861</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>S. Kanegawa</author><author>S. Karasawa</author><author>M. Maeyama</author><author>M. Nakano</author><author>N. Koga</author></authors></contributors><titles><secondary-title>J. Am. Chem. Soc.</secondary-title></titles><periodical><full-title>J. Am. Chem. Soc.</full-title></periodical><pages>3079</pages><volume>130</volume><dates><year>2008</year></dates><urls></urls></record></Cite><Cite><Author>Payette</Author><Year>2008</Year><RecNum>1867</RecNum><record><rec-number>1867</rec-number><foreign-keys><key app="EN" db-id="f9arva0tlwwezbewzd8prsrtvefxvzesw2w2" timestamp="1509445687">1867</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>J. N. Payette</author><author>H. Yamamoto</author></authors></contributors><titles><secondary-title>J. Am. Chem. Soc.</secondary-title></titles><periodical><full-title>J. Am. Chem. Soc.</full-title></periodical><pages>12276</pages><volume>130</volume><dates><year>2008</year></dates><urls></urls></record></Cite></EndNote>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 (?DB). ADDIN EN.CITE <EndNote><Cite><RecNum>1404</RecNum><DisplayText><style face="superscript">16</style></DisplayText><record><rec-number>1404</rec-number><foreign-keys><key app="EN" db-id="f9arva0tlwwezbewzd8prsrtvefxvzesw2w2" timestamp="1460717634">1404</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors></contributors><titles></titles><pages>See SI for more information.</pages><dates></dates><urls></urls></record></Cite></EndNote>16 These values are in line with I being a competent radical acceptor. We then assessed the preferred site of radical attack by calculating the N and O atom Mulliken spin densities (MSDs) in the triplet state (??*). ADDIN EN.CITE <EndNote><Cite><RecNum>1404</RecNum><DisplayText><style face="superscript">16</style></DisplayText><record><rec-number>1404</rec-number><foreign-keys><key app="EN" db-id="f9arva0tlwwezbewzd8prsrtvefxvzesw2w2" timestamp="1460717634">1404</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors></contributors><titles></titles><pages>See SI for more information.</pages><dates></dates><urls></urls></record></Cite></EndNote>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; ?+rc = 0.34). ADDIN EN.CITE <EndNote><Cite><Author>Vleeschouwer</Author><Year>2007</Year><RecNum>1303</RecNum><DisplayText><style face="superscript">17</style></DisplayText><record><rec-number>1303</rec-number><foreign-keys><key app="EN" db-id="f9arva0tlwwezbewzd8prsrtvefxvzesw2w2" timestamp="1459616042">1303</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>F. D. Vleeschouwer</author><author>V. V. Speybroeck</author><author>M. Waroquier</author><author>P. Geerlings</author><author>F. D. Proft</author></authors></contributors><titles><secondary-title>Org. Lett.</secondary-title></titles><periodical><full-title>Org. Lett.</full-title></periodical><volume>9</volume><number>2721</number><dates><year>2007</year></dates><urls></urls></record></Cite></EndNote>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. ADDIN EN.CITE <EndNote><Cite><RecNum>1404</RecNum><DisplayText><style face="superscript">16</style></DisplayText><record><rec-number>1404</rec-number><foreign-keys><key app="EN" db-id="f9arva0tlwwezbewzd8prsrtvefxvzesw2w2" timestamp="1460717634">1404</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors></contributors><titles></titles><pages>See SI for more information.</pages><dates></dates><urls></urls></record></Cite></EndNote>16 The very low |TS| values also indicate that these radical additions are not very influenced by polar effects in the transition state and should be predominantly enthalpy controlled. ADDIN EN.CITE <EndNote><Cite><Author>Weber</Author><Year>1998</Year><RecNum>1590</RecNum><DisplayText><style face="superscript">18</style></DisplayText><record><rec-number>1590</rec-number><foreign-keys><key app="EN" db-id="f9arva0tlwwezbewzd8prsrtvefxvzesw2w2" timestamp="1489563613">1590</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>M. Weber</author><author>H. Fischer</author></authors></contributors><titles><secondary-title>Helv. Chim. Acta</secondary-title></titles><periodical><full-title>Helv. Chim. Acta</full-title></periodical><pages>770</pages><volume>81</volume><dates><year>1998</year></dates><urls></urls></record></Cite><Cite><Author>Wong</Author><Year>1994</Year><RecNum>1603</RecNum><record><rec-number>1603</rec-number><foreign-keys><key app="EN" db-id="f9arva0tlwwezbewzd8prsrtvefxvzesw2w2" timestamp="1489574276">1603</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>M. W. Wong</author><author>A. Pross</author><author>L. Radom</author></authors></contributors><titles><secondary-title>J. Am. Chem. Soc.</secondary-title></titles><periodical><full-title>J. Am. Chem. Soc.</full-title></periodical><pages>6284</pages><volume>116</volume><dates><year>1994</year></dates><urls></urls></record></Cite></EndNote>18To assess our working hypothesis, we investigated the reaction of adamantane carboxylic acid 1a and nitrosobenzene using various photoredox catalysts 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)PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5OaWNld2ljejwvQXV0aG9yPjxZZWFyPjIwMTQ8L1llYXI+

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ADDIN EN.CITE.DATA 19 as the photoredox catalyst, Cs2CO3 as the base under blue LEDs irradiation, the product 3a was obtained in good yield (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 were screened (2b–d) 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). Table 1 Optimization of the visible-light-mediated synthesis of hydroxylamine 3a from carboxylic acid 1a.EntryPC1a:PhNOBase[M]Yield (%)12a1:1Cs2CO30.055822a1:1.1Cs2CO30.057232a1:2Cs2CO30.059042a2:1Cs2CO30.057052a1:2K2CO30.056262a1:22,6-lutidine0.05–72a1:2Cs2CO30.15082a1:2Cs2CO30.23692b1:2Cs2CO30.0575102c1:2Cs2CO30.05–112d1:2Cs2CO30.05–122a1:2Cs2CO30.05–13a2a1:2Cs2CO30.05–14–1:2Cs2CO30.05–a The reaction was run in the dark.With the optimized reaction conditions in hand we evaluated the scope of the process using nitrosobenzene and a series of structurally different carboxylic acids (Scheme 3). In general, tertiary carboxylic acids worked well and provided the desired hydroxylamines in good yields (3b–g). This approach tolerated several functional groups like alkyl halides, terminal olefins, carbamates and was effective for accessing C-3 and C-4 amino piperidines 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 could also be employed albeit in lower yield (3l). Scheme 3 Scope of the process.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 4, we successfully used this approach to modify the blockbuster drug gemfibrozil (1i?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 (1j?3n) and the antiulcer drug enoxolone (1k?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) ADDIN EN.CITE <EndNote><Cite><Author>Bume</Author><Year>2017</Year><RecNum>1795</RecNum><DisplayText><style face="superscript">20</style></DisplayText><record><rec-number>1795</rec-number><foreign-keys><key app="EN" db-id="f9arva0tlwwezbewzd8prsrtvefxvzesw2w2" timestamp="1507713505">1795</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>D. D. Bume</author><author>C. R. Pitts</author><author>F. Ghorbani</author><author>S. A. Harry</author><author>J. N. Capilato</author><author>M. A. Siegler</author><author>T. Lectka</author></authors></contributors><titles><secondary-title>Chem. Sci.</secondary-title></titles><periodical><full-title>Chem. Sci.</full-title></periodical><pages>6918</pages><volume>8</volume><dates><year>2017</year></dates><urls></urls></record></Cite><Cite><Author>Pitts</Author><Year>2017</Year><RecNum>1767</RecNum><record><rec-number>1767</rec-number><foreign-keys><key app="EN" db-id="f9arva0tlwwezbewzd8prsrtvefxvzesw2w2" timestamp="1503069378">1767</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>C. R. Pitts</author><author>D. D. Bume</author><author>S. A. Harry</author><author>M. A. Siegler</author><author>T. Lectka</author></authors></contributors><titles><secondary-title>J. Am. Chem. Soc.</secondary-title></titles><periodical><full-title>J. Am. Chem. Soc.</full-title></periodical><pages>2208</pages><volume>139</volume><dates><year>2017</year></dates><urls></urls></record></Cite></EndNote>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. ADDIN EN.CITE <EndNote><Cite><Author>Davies</Author><Year>2017</Year><RecNum>1825</RecNum><DisplayText><style face="superscript">5b</style></DisplayText><record><rec-number>1825</rec-number><foreign-keys><key app="EN" db-id="f9arva0tlwwezbewzd8prsrtvefxvzesw2w2" timestamp="1507791204">1825</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>J. Davies</author><author>N. S. Sheikh</author><author>D. Leonori</author></authors></contributors><titles><secondary-title>Angew. Chem. Int. Ed.</secondary-title></titles><periodical><full-title>Angew. Chem. Int. Ed.</full-title></periodical><pages>13361</pages><volume>56</volume><dates><year>2017</year></dates><urls></urls></record></Cite></EndNote>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 persisten 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-di-methyl substituted C-radical S (to give T) by DFT and found it feasible. ADDIN EN.CITE <EndNote><Cite><RecNum>1404</RecNum><DisplayText><style face="superscript">16</style></DisplayText><record><rec-number>1404</rec-number><foreign-keys><key app="EN" db-id="f9arva0tlwwezbewzd8prsrtvefxvzesw2w2" timestamp="1460717634">1404</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors></contributors><titles></titles><pages>See SI for more information.</pages><dates></dates><urls></urls></record></Cite></EndNote>16Scheme 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% (entry 1). In this case however, increasing the amount of nitrosobenzene with respect to 4a was detrimental (entries 2 and 3) and eventually we identified a ratio of 1:1.1 (entry 4) and a reaction concentration of 0.05 M to be optimum for this transformation (entry 5). Also in this case control experiments confirmed the requirement for base, 2a and blue LEDs irradiation (entries 6–8).Table 2 Optimization of the imino-hydroxylamination cascade using oxime 6a.Entry4a:PhNO[M]Yield (%)11:20.14821:30.12631:40.11641:20.055351:1.10.056061:1.10.05677a1:1.10.05–8b1:1.10.05–9c1:1.10.05–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 we tested other iminyl radical precursors (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 prolinol analogues. Interestingly, in this case we were able to engage a secondary -ester radical (7d) in the cascade cyclization-functionalization reaction.Scheme 6 Scope of the process.Other nitrosoarenes were compatible with the process as shown by the formation of products 7–h in good to moderate yields. Also in this case, the use of highly electron poor nitrosoarenes (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.The experimental section has no title; please leave this line here.All required fine chemicals were used directly without purification unless stated otherwise. All air and moisture sensitive reactions were carried out under nitrogen atmosphere using standard Schlenk manifold technique. 1H and 13C Nuclear Magnetic Resonance (NMR) spectra 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). Infra-red spectra were recorded using a JASCO FT/IR 410 spectrometer 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.ProceduresGeneral Procedure for the Preparation of 3a–o – 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 ?mol, 5 mol%), Cs2CO3 (66 mg, 0.1 mmol, 1.0 equiv.) and the nitrosoarene (0.4 mmol, 2.0 equiv.). The tube was capped with a Supelco aluminium crimp seal with septum (PTFE/butyl) and it was evacuated and refilled with N2 (x 3). CH2Cl2 (dry and degassed by bubbling through with N2 for 20 min) (4.0 mL) was added. The nitrogen inlet was then removed and the cap sealed with para-film. The mixture was stirred at room temperature 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 x 5 mL). The combined organic layers were dried (MgSO4), filtered and evaporated. Purification by column chromatography on silica gel gave 3a–p.N-((3s,5s,7s)-Adamantan-1-yl)-N-phenylhydroxylamine (3a)Following GP1, 1-Adamantanecarboxylic acid (36 mg, 0.2 mmol) gave 3a (25 mg, 51%) as a brown solid, purified by column chromatography (CH2Cl2). IR (film): 2905, 2850, 1595, 1486, 1451, 1357, 1306, 1209, 1209, 1103, 1074. 1H NMR (CDCl3, 400 MHz): ? = 7.21 (4H, dt, J = 15.4, 7.7 Hz), 7.10 (1H, t, J = 7.0 Hz), 6.58 (1H, s, br), 2.04 (2H, s, br), 1.77 – 1.71 (6H, d, J = 2.0 Hz), 1.57 (6H, q, J = 12.0 Hz).13C NMR (CDCl3, 101 MHz): ? = 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 [MH]+ calcd for C16H22ON: 244.1696; found: 244.1691.N-(1-Methylcyclohexyl)-N-phenylhydroxylamine (3b)Following GP1, 1-Methyl-1-cyclohexanecarboxylic acid (28 mg, 0.2 mmol) gave 3b (19 mg, 46%) as a brown solid, purified by column chromatography (pentane:CH2Cl2 1:1).IR (film): 2925, 2857, 2361, 1596, 1487, 1449, 1372, 1120, 1028.1H NMR (CDCl3, 400 MHz): ? = 7.33 (2H, br d, J = 7.8 Hz), 7.28 (2H, t, J = 7.8 Hz), 7.17 (1Ht, J = 7.1 Hz), 1.73 – 1.65 (3H, m), 1.58 – 1.51 (3H, m), 1.42 – 1.27 (4H, m), 1.09 (3H, s).13C NMR (CDCl3, 126 MHz): ? 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 [MH]+ calcd for C13H20ON: 206.1539; found: 206.1540.N-Phenyl-N-(1-phenylcyclohexyl)hydroxylamine (3c)Following GP1, 1-phenylcyclohexane-1-carboxylic acid (41 mg, 0.2 mmol) gave 3c (33 mg, 62%) as an orange solid, purified by column chromatography (pentane:CH2Cl2 1:1).IR (film): 2929, 2861, 1593, 1484, 1456, 1447, 1204, 1152, 1037.1H NMR (CDCl3, 400 MHz): δ 7.32 – 7.11 (5H, m), 7.15 – 6.99 (3H, m), 6.71 (2H, d, J = 7.6 Hz), 5.98 (1H, br s), 2.41 (2H, d, J = 12.6 Hz), 1.90 (2H, t, J = 11.7 Hz), 1.66 (2H, d, J = 9.5 Hz), 1.49 (1H, d, J = 4.7 Hz), 1.39 – 1.12 (3H, 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 [MH]+ calcd for C18H22ON: 268.1696; found: 268.1699.N-((1r,3s,5R,7S)-3-Chloroadamantan-1-yl)-N-phenylhydroxylamine (3d)Following GP1, 3-chloroadamantane-1-carboxylic acid (43 mg, 0.2 mmol) gave 3d (34 mg, 61%) as a brown solid, purified by column chromatography (pentane:CH2Cl2 1:1).IR (film): 2913, 2859, 1595, 1487, 1450, 1349, 1328, 1303, 1204, 1154, 1074.1H NMR (CDCl3, 400 MHz): ? = 7.25 (2H, t, J = 7.5 Hz), 7.17 (2H, d, J = 7.7 Hz), 7.13 (1H, t, J = 7.2 Hz), 6.93 (1H, br s), 2.21 (1H, br s), 1.97 (4H, q, J = 12.0 Hz), 1.72 (2H, d, J = 11.7 Hz, 1H), 1.68 (2H, q, J = 11.7 Hz), 1.58 – 1.37 (2H, 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(-Cl), 204, 170, 133.HRMS (HESI): m/z [MH]+ calcd for C16H21ON: 278.1306; found: 278.1304.N-(2-Methylbut-3-en-2-yl)-N-phenylhydroxylamine (3e)Following GP1, 2,2-dimethylpent-4-enoic acid (26 mg, 0.2 mmol) gave 3e (9 mg, 24%) 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, 1027.1H NMR (CDCl3, 400 MHz): ? = 7.31 – 7.23 (4H, m), 7.19 – 7.08 (1H, m), 5.93 (1H ddt, J = 15.8, 10.9, 7.4 Hz), 5.79 (1H, br s), 5.08 (1H, d, J = 1.4 Hz), 5.07 – 4.99 (1H, m), 2.34 (2H, d, J = 7.3 Hz), 1.08 (6H, s).13C NMR (CDCl3, 101 MHz): ? = 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 [MNa]+ calcd for C12H16ONNa: 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 (49 mg, 0.2 mmol) gave 3f (30 mg, 49%) as a brown solid, purified by column chromatography (CH2Cl2).IR (film): 3350, 2975, 2359, 1692, 1661, 1597, 1488, 1453, 1425, 1392, 1365, 1284, 1161, 1087.1H NMR (CDCl3, 400 MHz, rotamers): ? = 7.26 (4H, m), 7.15 (1H s), 7.12 – 7.07 (1H, m), 4.35 (0.8H, d, J = 13.8 Hz), 4.02 (0.8H d, J = 12.9 Hz), 3.78 – 3.70 (0.2H, m), 3.57 (0.2H, br s), 3.32 – 3.17 (0.4H, m), 2.88 (0.8H, t, J = 12.2 Hz), 2.65 (0.8H, d, J = 13.9 Hz), 2.15 (0.8H, q, J = 12.2 Hz), 1.93 (0.2H, br s), 1.68 (1.2H, d, J = 13.3 Hz), 1.47 (9H, s), 1.43 – 1.28 (2H, m), 0.94 (3H, m).13C NMR (CDCl3, 101 MHz, rotamers): ? = 157.2M, 154.9m, 149.3M, 148.8m, 127.8M&m, 125.4m, 125.0M, 124.5m, 124.4M, 80.2M&m, 61.6m, 61.1M, 53.1M&m, 46.3M, 44.3m, 34.9M, 34.4m, 28.6M&m, 21.7M, 21.6m, 17.3M, 16.7m.MS (EI): m/z = 290 [MH-OH], 217, 190, 160, 132. HRMS (HESI): m/z [MH]+ calcd for C17H27O3N2: 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 (49 mg, 0.2 mmol) gave 3g (50 mg, 81%) 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, 1026.1H NMR (CDCl3, 400 MHz, rotamers): ? = 7.31–7.21 (4H, m), 7.19 – 7.11 (1H, m), 3.78 (2H, br s), 3.18–3.04 (2H, m), 1.94–1.74 (2H, m,), 1.57–1.37 (11H, m), 1.09 (3H, s).13C NMR (CDCl3, 101 MHz, 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 [MH]+ calcd for C17H27O3N2: 307.2016; found: 307.2018.N-((3s,5s,7s)-Adamantan-1-yl)-N-(4-methoxyphenyl)hydroxylamine (3j)Following GP1, 1-Adamantanecarboxylic acid (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, 1034.1H NMR (CDCl3, 400 MHz): ? = 7.11 (2H, d, J = 8.2 Hz), 6.78 (2H, d, J = 8.2 Hz), 3.82 (3H, s), 2.05 (3H, s), 1.74 (6H, s), 1.59 (6H, q, J = 12.1 Hz).13C NMR (CDCl3, 101 MHz): ? = 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 (–OMe), 214, 200, 163, 135. HRMS (ASAP): m/z [M]+ calcd for C17H23O2N: 273.1723; found: 273.1726.N-((3s,5s,7s)-Adamantan-1-yl)-N-(o-tolyl)hydroxylamine (3k)Following GP1, 1-Adamantanecarboxylic acid (36 mg, 0.2 mmol) gave 3k (29 mg, 56%) as a red solid, purified by column chromatography (pentane:CH2Cl2 3:1?1:1).IR (film): 2905, 2850, 1487, 1452, 1356, 1307, 1103, 1080.1H NMR (CDCl3, 400 MHz): ? = 7.48 (1H, d, J = 8.0 Hz), 7.18 (1H, t, J = 7.5 Hz), 7.14 (1H, d, J = 7.3 Hz), 7.08 (1H, t, J = 7.3 Hz), 5.11 (1H, s, br), 2.32 (3H, s), 2.06 (3H, s, br), 1.83 (6H, s, br).13C NMR (CDCl3, 101 MHz): ? = 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 [MH]+ calcd for C17H24ON: 258.1852; found: 258.1845. N-((3s,5s,7s)-Adamantan-1-yl)-N-(3-(trifluoromethyl)phenyl)hydroxylamine (3l)Following GP1, 1-Adamantanecarboxylic acid (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, 1068.1H NMR (CDCl3, 400 MHz): ? = 7.41 (1H, s), 7.30 (4H, m), 6.55 (1H, br s), 2.08 (3H, br s), 1.75 (6H, s), 1.63 (3H, d, J = 11.6 Hz), 1.55 (3H, d, J = 11.5 Hz).13C NMR (CDCl3, 101 MHz): ? = 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): ? = –62.5.MS (EI): m/z = 311 [M]+, 295, 275, 238, 135.HRMS (ASAP): m/z [MH]+ calcd for C17H21ONF3 : 312.1570; found: 312.1566.N-(5-(2,5-Dimethylphenoxy)-2-methylpentan-2-yl)-N-phenylhydroxylamine (3m)Following GP1, gemfibrozil (50 mg, 0.2 mmol) gave 3m (14 mg, 22%) 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, 1002.1H NMR (CDCl3, 400 MHz): ? = 7.26–7.21 (4H, m), 7.15–7.07 (1H, m), 7.00 (1H, d, J = 7.4 Hz), 6.66 (1H, d, J = 7.4 Hz), 6.60 (1H, br s), 3.86 (2H, t, J = 6.3 Hz), 2.32 (3H, s), 2.16 (3H, s), 1.95–1.77 (2H, m), 1.78–1.62 (2H, m), 1.08 (6H, s).13C NMR (CDCl3, 101 MHz): ? = 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 = [M–OH] 296, 282, 204, 160, 135.HRMS (HESI): m/z [MNa]+ calcd for C20H26O2NNa : 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 (91 mg, 0.2 mmol) gave 3n (29 mg, 28%) as a red solid, purified by column chromatography (CH2Cl2). IR (film): 2945, 1486, 1463, 1386, 1364, 1263, 1028.1H NMR (CDCl3, 400 MHz): ? = 7.42 – 7.33 (2H, d, j = 7.7 Hz), 7.26 (2H, t, J = 7.7 Hz), 7.08 (1H, t, J = 7.3 Hz), 5.21 (1H, t, J = 3.4 Hz), 4.76 (1H, br s), 3.32 - 3.13 (1H, m), 2.49 (1H, d, J = 13.0 Hz), 2.26 – 2.15 (1H, m), 2.16 – 2.04 (1H, m), 2.05 – 1.88 (2H, m), 1.82 – 1.69 (2H, m), 1.68 – 1.54 (7H, m), 1.53 – 1.46 (2H, m), 1.45 – 1.40 (2H, m), 1.39 – 1.29 (2H, m), 1.28 – 1.24 (2H, m), 1.21 (3H, s), 1.17 – 1.09 (2H, m), 1.05 (3H, s), 1.02 (3H, s), 0.96 (3H, s), 0.83 (3H, s), 0.81 (3H, s), 0.62 (3H, s).13C NMR (CDCl3, 101 MHz): ? = 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 [MH]+ calcd for C35H54O2N : 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, glycyrrhetinic acid (91 mg, 0.2 mmol) gave 3o (83 mg, 78%) 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, 1037.1H NMR (CDCl3, 400 MHz, diastereomers): δ = 7.24 (4H, m), 7.13 (1H, t, J = 6.9 Hz), 5.63 (0.2H, d), 5.55 (0.8H, s), 3.23 (1H, dd, J = 10.6, 5.6 Hz), 2.79 (1H, dt, J = 13.5, 3.5 Hz), 2.16–1.98 (2H, m), 1.86–1.72 (2H, m), 1.74–1.55 (8H, m), 1.49–1.32 (5H, m), 1.33 (3H, s), 1.12 (7H, m), 1.09 (3H, s), 1.01 (3H, s), 0.95 (2H, m), 0.86–0.68 (6H, m).13C NMR (CDCl3, 126 MHz, diastereomers): δ = 199.8m, 199.7M, 169.8m, 168.8M, 149.4m, 147.7M, 127.8M, 127.7m, 127.3m, 127.1M, 125.0M, 124.4M&m, 123.5m, 78.3m, 78.2M, 63.3M, 61.8m, 61.6m, 61.2M, 54.5m, 54.4M, 47.4M, 45.8m, 44.8M&m, 42.9m, 42.7M, 41.4m, 39.3M 38.7M&m, 38.6M&m, 36.6M&m, 36.3M, 35.4m, 32.5m, 32.3M, 32.2M&m, 31.7M, 31.2m, 29.1M, 28.1m, 27.8M&m, 27.7M&m, 27.6M&m, 26.8M, 26.4m, 26.0m, 25.8M, 22.9M, 22.8m, 18.2M, 17.0M&m, 16.4m, 15.8M&m, 15.1M&m.MS (EI): m/z = 515 (M–OH2), 424 (–NOHPh), 257, 216, 175, 135, 91. HRMS (ASAP): m/z [MH]+ calcd for C35H52O3N: 534.3942; found: 534.3949.General Procedure for the Preparation of 7a–h – 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 ?mol, 5 mol%), Cs2CO3 (33 mg, 0.1 mmol, 1.0 equiv.) and the nitrosoarene (0.11 mmol, 1.1 equiv.). The tube was capped with a Supelco aluminium crimp seal with septum (PTFE/butyl) and it was evacuated and refilled with N2 (x 3). CH2Cl2 (dry and degassed by bubbling through with N2 for 20 min) (2.0 mL) was added. The nitrogen inlet was then removed and the cap sealed with para-film. The mixture was stirred at room temperature 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 x 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 (35 mg, 60%) 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, 1063.1H NMR (CDCl3, 101 MHz): ? = 7.89 (2H, dd, J = 8.0, 1.4 Hz), 7.49–7.39 (5H, m), 7.30 (2H, t, J = 7.9 Hz), 7.13 (1H, t, J = 7.3 Hz), 4.37 (1H, t, J = 8.2 Hz), 3.04 (1H, dddd, J = 16.8, 10.3, 3.0, 2.5 Hz), 2.83 (1H, dtd, J = 11.6, 9.5, 2.3 Hz), 2.07 (1H, dddd, J = 11.3, 9.8, 8.0, 3.3 Hz), 1.85–1.74 1H, (m), 1.27 (3H, s), 1.11 (3H, s).13C NMR (CDCl3, 101 MHz): ? = 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 [MH]+ calcd for C19H22ON2: 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, 1026.1H NMR (CDCl3, 400 MHz): ? = 9.00 (1H, d, J = 2.2 Hz), 8.70 (1H, dd, J = 4.8, 1.7 Hz), 8.25 (1H, dt, J = 7.9, 2.0 Hz), 7.41–7.35 (3H, m), 7.33–7.24 (2H, m), 7.15–7.10 (1H, m), 4.43 (1H, tt, J = 8.2, 2.4 Hz), 3.05 (1H, dddd, J = 17.3, 10.4, 3.5, 2.3 Hz), 2.93–2.79 (m, 1H), 2.11 (dddd, J = 13.2, 9.8, 8.0, 3.5 Hz, 1H), 1.87 (1H, ddt, J = 13.1, 10.3, 8.6 Hz), 1.24 (3H, s), 1.08 (3H, s).13C NMR (CDCl3, 101 MHz): ? = 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 [MH]+ calcd for C18H22ON3: 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, 1111.1H NMR (CDCl3, 400 MHz): ? = 7.29 (4H, m), 7.13 (1H, t, J = 6.7 Hz), 6.45 (1H, s, br), 4.55 (1H, tt, J = 8.2, 2.8 Hz), 3.88 (3H, s), 2.92 (1H, ddt, J = 17.7, 10.4, 3.4 Hz), 2.83–2.69 (1H, m), 2.10–2.00 (1H, m), 1.94 (1H, dq, J = 13.4, 8.6 Hz), 1.23 (3H, s), 0.96 (3H, s).13C NMR (CDCl3, 101 MHz): ? = 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 [MH]+ calcd for C15H21O3N2: 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 (11 mg, 34%) 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, 1155.1H NMR (CDCl3, 400 MHz): ? = 7.85–7.79 (2H, m), 7.48–7.36 (4H, m), 7.32–7.27 (1H, m), 7.14 (0.8H, d, J = 7.9 Hz), 7.09 (1.2H, d, J = 7.8 Hz), 7.00–6.87 (1H, m), 4.97–4.88 (1H, m), 4.48 (0.6H, d, J = 6.4 Hz), 4.33 (0.4H, d, J = 7.4 Hz), 3.72 (1.2H, s), 3.71 (1.8H, s), 3.11 (1H, dddd, J = 19.8, 10.2, 4.2, 2.2 Hz), 3.03–2.92 (1H, m), 2.40–2.31 (1H, m), 2.09–1.96 (1H, m).13C NMR (CDCl3, 101 MHz): ? = 174.7M, 174.3m, 171.8m, 171.1M, 151.2M, 150.9m, 134.0m, 133.8M, 130.9M, 130.8m, 129.0m, 128.8M, 128.5M, 128.4m, 127.9M, 127.9m, 121.8m, 121.5M, 115.3M&m, 72.9m, 72.2M, 71.6M, 70.7m, 52.1M, 52.0m, 35.4M, 35.0m, 26.7M, 26.5m.MS (EI): m/z = 308 (MH–OH), 249, 145, 104, 77.HRMS (APCI): m/z [MH]+ calcd for C19H21O3N2: 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, 1033.1H NMR (CDCl3, 400 MHz): ? = 7.91 (2H, d, J = 6.8 Hz), 7.52–7.44 (3H, m), 7.37 (2H, d, J = 8.8 Hz), 6.86 (2H, d, J = 8.8 Hz), 4.41 (1H, t, J = 8.1 Hz), 3.82 (3H, s), 3.06 (1H, ddt, J = 16.4, 10.4, 2.8 Hz), 2.92–2.79 (1H, m), 2.15–2.03 (1H, m), 1.90–1.73 (1H, m), 1.26 (3H, s), 1.08 (3H, s).13C NMR (CDCl3, 101 MHz): ? = 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 C20H24O2N2: 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, 1011.1H NMR (CDCl3, 400 MHz): ? = 9.27 (1H, s, br), 7.87 (2H, d, J = 7.4 Hz), 7.46 (3H, m), 7.33 (2H, d, J = 8.6 Hz), 7.25 (2H, d, J = 8.7 Hz), 4.33 (1H, t, J = 6.8 Hz), 3.09–2.99 (1H, m), 2.84 (1H, m), 2.12–2.03 (1H, m), 1.84 – 1.72 (1H, m), 1.22 (3H, s), 1.10 (3H, s).13C NMR (CDCl3, 101 MHz): ? = 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 [MNa]+ calcd for C19H21ON2ClNa: 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 (14 mg, 39%) as a brown oil, purified by column chromatography (CH2Cl2).IR (film): 2979, 1616, 1576, 1439, 1381, 1362, 1326, 1281, 1163, 1119, 1095, 1068.1H NMR (CDCl3, 400 MHz): ? = 7.88 (2H, d, J = 7.4 Hz, 2H), 7.65 (1H, s), 7.57 (1H, d, J = 7.4 Hz), 7.47 (3H, m), 7.39 (2H, m), 4.34 (1H, s, br), 3.11–3.01 (1H, m), 2.86 (1H, m), 2.15–2.06 (1H, m), 1.79 (1H, m), 1.23 (3H, s), 1.13 (3H, s).13C NMR (CDCl3, 101 MHz): ? = 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): ? = –63.9.MS (EI): m/z = 346 (MH-OH), 345, 327, 202, 186, 145, 91.HRMS (ASAP): m/z [MH]+ calcd for C20H22ON2F3: 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, 1027.1H NMR (CDCl3, 400 MHz): ? = 7.89 (2H, d, J = 6.9 Hz), 7.70 (1H, d, J = 7.9 Hz), 7.45 (3H, m), 7.19 (2H, d, J = 8.1 Hz), 7.10 (1H, t, J = 7.3 Hz), 4.62 (1H, t, J = 8.1 Hz), 3.06 (1H, ddt, J = 16.2, 10.2, 2.7 Hz), 2.95–2.85 (1H, m), 2.45 (3H, s), 2.20–2.06 (1H, m), 1.93–1.81 (1H, m), 1.27 (3H, s), 0.95 (3H, s).13C NMR (CDCl3, 101 MHz): ? = 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 [MH]+ calcd for C20H24ON2: 308.1883; found: 308.1887.Funding InformationD. L. thanks the European Union for a Career Integration Grant (PCIG13-GA-2013-631556) and EPSRC for a research grant (EP/P004997/1). AcknowledgmentL. A. thanks Eli Lilly for a PhD CASE Award. M. A. A. and N. S. S. thank the Department of Chemistry, King Faisal University, Saudi Arabia for the support.Supporting InformationIs there Supporting Information to be published? Click here to indicate YES or NO (text and links will be updated prior to publication).Primary DataIs there Primary Data to be associated with this manuscript? Click here to indicate YES or NO (text and links will be updated prior to publication).References[1](a) The Chemistry of Hydroxylamines, Oximes and Hydroxamic Acids 2008, Patai’s Chemistry of Functional Groups; (b) Ashani, Y.; Silman, I. 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Schmidt, N. Darvatkar, S. R. Natarajan, P. S. Baran, Science 2015, 348, 886.[13](a) D. J. Fisher, J. B. Shaum, C. L. Mills, J. R. d. Alaniz, Org. Lett. 2016, 18, 5074; (b) D. J. Fisher, G. L. Burnett, R. Velasco, J. R. d. Alaniz, J. Am. Chem. Soc. 2015, 137, 11614.[14]A. v. d. Werf, M. Hribersek, N. Selander, Org. Lett. 2017, 19, 2374.[15]A. Studer, Chem. Eur. J. 2001, 7, 1159.[16]See SI for more information.[17]F. D. Vleeschouwer, V. V. Speybroeck, M. Waroquier, P. Geerlings, F. D. Proft, Org. Lett. 2007, 9.[18](a) M. Weber, H. Fischer, Helv. Chim. Acta 1998, 81, 770; (b) M. W. Wong, A. Pross, L. Radom, J. Am. Chem. Soc. 1994, 116, 6284.[19](a) D. A. Nicewicz, T. M. Nguyen, ACS Catal. 2014, 4, 355; (b) K. A. Margrey, D. A. Nicewicz, Acc. Chem. Res. 2016, 49, 1997; (c) S. Fukuzumi, K. Ohkubo, Org. Biomol. Chem. 2014, 12, 6059.Checklist (have these on hand for manuscript submission in ScholarOne):cover letter, including a statement of the work’s significancefull mailing address, telephone and fax numbers, and e-mail address of the corresponding authoremail address for each authororiginal Word fileoriginal graphics files zipped into one zip fileeye-catching graphical abstract as an individual file5–8 key wordsseparate Supporting Information file ADDIN EN.REFLIST 1.aRace, N. J.; Hazelden, I. R.; Faulkner, A.; Bower, J. F., Chem. Sci. 2017, 8, 5248; bGao, H.; Zhou, Z.; Kwon, D.-H.; Coombs, J.; Jones, S.; Behnke, N. E.; Ess, D. H.; Kürti, L., Nat. Chem. 2017, 9, 681; c, The Chemistry of Hydroxylamines, Oximes and Hydroxamic Acids; d, Hydroxylamines and Oximes: Biological Properties and Potential Uses as Therapeutic Agents.2.Studer, A.; Curran, D. P., Angew. Chem. Int. Ed. 2015, 55, 58-102.3.aPrier, C. K.; Rankic, D. A.; MacMillan, D. W. C., Chem. Rev. 2013, 113, 5322-5363; bSkubi, K. L.; Blum, T. R.; Yoon, T. P., Chem. Rev. 2016, 116, 10035; cRomero, N. A.; Nicewicz, D. A., Chem. Rev. 2016, 116, 10075; dHopkinson, M. N.; 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, 15632.5.aReina, D. F.; Duncey, E. M.; Morcillo, S. P.; Svejstrup, T. D.; Popescu, M. V.; Douglas, J. J.; Sheikh, N. S.; Leonori, D., Eur. J. Org. Chem. 2017, 2108; bDavies, J.; Sheikh, N. S.; Leonori, D., Angew. Chem. Int. Ed. 2017, 56, 13361; cJ. Davies; Svejstrup, T. D.; Reina, D. F.; Sheikh, N. S.; Leonori, D., J. Am. Chem. Soc. 2016, 138, 8092; dDavies, J.; Booth, S. G.; Essafi, S.; Dryfe, R. W. A.; Leonori, D., Angew. Chem. Int. Ed. 2015, 54, 14017.6.aYamamoto, H.; Kawasaki, M., Bull. Chem. Soc. Jpn. 2007, 80, 595; bYamamoto, H.; Momiyama, N., Chem. Commun. 2005, 7, 3514; cZuman, P.; Shah, B., Chem. Rev. 1994, 94, 1621.7.aKanegawa, S.; Karasawa, S.; Maeyama, M.; Nakano, M.; Koga, N., J. Am. Chem. Soc. 2008, 130, 3079; bForrester, A. R.; Fullerton, J. D.; McConnachie, G., J. Chem. Soc., Perkin Trans. 1 1983, 1759; cDhayalan, V.; S?mann, C.; Knochel, P., Chem. Commun. 2015, 51, 3239; dLi, Y.; Chakrabarty, S.; Studer, A., Angew. Chem. Int. Ed. 2015, 54, 3587.8.aMomiyama, N.; Yamamoto, H., Org. Lett. 2002, 4, 3579; bMomiyama, N.; Yamamoto, H., J. Am. Chem. Soc. 2003, 125, 6038; cPayette, J. N.; Yamamoto, H., J. Am. Chem. Soc. 2008, 130, 12276; dYanagisawa, A.; Izumib, Y.; Takeshita, S., Synlett 2009, 716; eYanagisawa, A.; Takeshita, S.; Izumi, Y.; Yoshida, K., J. Am. Chem. Soc. 2010, 132, 5328.9.aB?gevig, A.; Sundén, H.; Córdova, A., Angew. Chem. Int. Ed. 2004, 43, 1109; bKano, T.; Ueda, M.; Takai, J.; Maruoka, K., J. Am. Chem. Soc. 2006, 128, 6046; cPalomo, C.; Vera, S.; Velilla, I.; Mielgo, A.; Gómez-Bengoa, E., Angew. Chem. Int. Ed. 2007, 46, 8054; dShen, K.; Liu, X.; Wang, G.; Lin, L.; Feng, X., Angew. Chem. Int. Ed. 2011, 50, 4684.10.Wong, F. T.; Patra, P. K.; Seayad, J.; Zhang, Y.; Ying, J. Y., Org. Lett. 2008, 10, 2333.11.Ayhan, P.; Demir, A. S., Adv. Synth. Catal. 2011, 353, 624.12.aGingras, B. A.; Water, W. A., J. Chem. Soc. 1954, 1920; bInamoto, N.; Simamura, O., J. Org. Chem. 1958, 23, 408; cHosogai, T.; Inamoto, N.; Okazaki, R., J. Chem. Soc. Chem. Commun. 1971, 3399; dCorey, E. J.; Gross, A. W., J. Org. Chem. 1985, 50, 5391; eGui, J.; Pan, C.-M.; Jin, Y.; Qin, T.; Lo, J. C.; Lee, B. J.; Spergel, S. H.; Mertzman, M. E.; Pitts, W. J.; Cruz, T. E. L.; Schmidt, M. A.; Darvatkar, N.; Natarajan, S. R.; Baran, P. S., Science 2015, 348, 886.13.aFisher, D. J.; Shaum, J. B.; Mills, C. L.; Alaniz, J. R. d., Org. Lett. 2016, 18, 5074; bFisher, D. J.; Burnett, G. L.; Velasco, R.; Alaniz, J. R. d., J. Am. Chem. Soc. 2015, 137, 11614.14.Werf, A. v. d.; 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, F. D.; Speybroeck, V. V.; Waroquier, M.; Geerlings, P.; Proft, F. D., Org. Lett. 2007, 9 (2721).18.aWeber, M.; Fischer, H., Helv. Chim. Acta 1998, 81, 770; bWong, M. W.; Pross, A.; Radom, L., J. Am. Chem. Soc. 1994, 116, 6284.19.aNicewicz, D. A.; Nguyen, T. M., ACS Catal. 2014, 4, 355; bMargrey, K. A.; Nicewicz, D. A., Acc. Chem. Res. 2016, 49, 1997; cFukuzumi, S.; Ohkubo, K., Org. Biomol. Chem. 2014, 12, 6059.20.aBume, D. D.; Pitts, C. R.; Ghorbani, F.; Harry, S. A.; Capilato, J. N.; Siegler, M. A.; Lectka, T., Chem. Sci. 2017, 8, 6918; bPitts, C. R.; Bume, D. D.; Harry, S. A.; Siegler, M. A.; Lectka, T., J. Am. Chem. Soc. 2017, 139, 2208. ................
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