Direct Synthesis of Unprotected 2-Azidoamines from Alkenes via an Iron-Catalyzed Difunctionalization Reaction

Szabolcs Makai, Eric Falk, and Bill Morandi*

Abstract

Unprotected, primary 2-azidoamines are versatile precursors to vicinal diamines, which are among the most common motifs in biologically active compounds. Herein, we report their operationally simple synthesis through an iron-catalyzed difunctionalization of alkenes. A wide array of alkene substrates are tolerated, including complex drug-like molecules and a tripeptide. Facile derivatizations of the azidoamine group demonstrate the versatility of this masked diamine motif in chemoselective, orthogonal transformations. Applications of the methodology in the concise synthesis of RO 20-1724 as well as in the formal total syntheses of both (±)-hamacanthin B and (±)-quinagolide further demonstrate the broad synthetic potential of this highly functional-group-tolerant reaction.

Summary

Most notably, Lin and Xu have described elegant electrochemical and iron-catalyzed processes, respectively, for the direct synthesis of diazides starting from a wide variety of alkenes (Scheme 2a). Whereas these reactions are powerful tools for accessing symmetrical vicinal diamines in two steps, an azido group and a protected amino group. However, these reactions are synthetically limited because they either introduce the amino group in a form which is difficult to deprotect (e.g., N(SO2Ph)2, Scheme 2b)10 or they rely on a
they are less suitable in cases where two chemically distinct amino groups need to be orthogonally synthesized (e.g., through amide coupling), a scenario which is common in target-oriented synthesis.7 Indeed, diazides suffer from poor regioselectivity upon monoreduction, making the direct synthesis of 2-azidoamines from alkenes highly challenging.8 Alternatively, some progress has been made in installing both suitably positioned directing group (Guan/Bi/Fu’s work, Scheme 2c).11
Thus, a simple, catalytic aminoazidation reaction exhibiting a broad substrate scope and allowing for the installation of, ideally, an unprotected amino group would certainly allow for the step-economical and orthogonal synthesis of nearly any 1,2-diamine derivative, thereby accelerating the synthesis and discovery of bioactive molecules (Scheme 2d).12−16
Herein, we report an iron-catalyzed difunctionalization reaction of unactivated alkenes to directly access unprotected primary 2-azidoamines. This process tolerates a broad substrate scope including unactivated mono-, di-, and trisubstituted alkenes bearing unprotected polar functional groups commonly found in drug-like molecules.

■ RESULTS AND DISCUSSION

On the basis of our recent research interest in accessing amino alcohols and 2-chloroamines under iron catalysis,17 we set out to develop conditions for the aminoazidation of alkenes using a traditionally more challenging substrate, 1-dodecene (Table 1, with further details in the SI). The evaluation of different azide salts in combination with different transition-metal catalysts and hydroxylamine derivatives led us to identify suitable reaction conditions for the aminoazidation of 1-dodecene. Iron(II) acetate and triflate efficiently catalyzed the desired reaction in good yields using this usually unreactive substrate (entries 1, 3, and 4). The possible catalytic effect of impurities from the iron source was ruled out by a control experiment with a trace-metals-based source which delivered the same outcome, confirming that the iron species plays a key role.18 Evaluating different O-acylhydroxylamine reagents suggested that steric encumbrance around the carbonyl functionality was essential for efficient reactivity (entry 6 and SI Table S2). Covalent azide sources failed to afford any product, while ionic azides were most suitable (entry 8). Interestingly, this reaction can be performed open to air in technical grade methanol, a critical issue in the possible rapid adoption of this new reaction by synthetic practitioners. During our optimization, we found that excess anhydrous lithium azide gave an increase in yield (75% NMR yield); however, sodium azide was chosen for further experiments due to its commercial availability (entry 12).
With the optimized conditions in hand, we then investigated the scope of the aminoazidation reaction (Scheme 3). Looking into aryl-substituted alkenes, electron-poor (2b−e, 2g, 2h) and electron-rich (2k) systems were efficiently transformed into their corresponding azidoamines. Aryl-substituted internal alkenes indene and trans-β-methylstyrene afforded syn addition products 2l and 2m in excellent diastereoselectivity (dr > 19:1).
With regard to unactivated alkenes, mono-, di-, and trisubstituted alkenes performed well (2n−s). This is especially important since the products bearing a tertiary azide offer the possibility to be transformed into an α-tertiary amine functionality, a common motif in natural products with only limited accessibility.19 Remarkably, a triene derived from αionol reacted exclusively at the monosubstituted alkene, demonstrating a high sterically controlled site selectivity (2r). In all cases, only one regioisomer was observed, making the reaction fully regioselective.
Aside from various carbon scaffolds, several functional groups were found to be tolerated under the reaction conditions, such as aryl (pseudo)halides (2b, 2e), multiple aryl substituents (2b−l), nitriles (2c, 2u), protected amines (2k, 2v, 2ak), free alcohols (2w, 2x, 2aa), and phosphonates (2y, 2z). Remarkably, even alkynes in close proximity remained untouched (2aa). Acid-labile functionalities were also tolerated (e.g., free tertiary alcohols (2x), silyl ethers (2ab), and N-Boc protecting groups (2k, Boc = tertbutyloxycarbonyl)). Furthermore, heterocycles (indole in 2k, oxetane in 2ac) further expanded the wide scope of this transformation. Synthetically relevant carboxylic acid derivatives, such as amides (2ad−ag), formamides (2f), and esters (2ah), performed well under the reaction conditions. Interestingly, esters with a shorter alkenyl chain cyclized in the process to afford lactams 2ad and 2ae in a single step.
This excellent functional group tolerance encouraged us to tackle even more challenging substrates. An artemether-derived substrate (2ai) was converted in moderate yield to the desired product, leaving the highly oxidized cage structure and the sensitive peroxo group intact. Excitingly, an allyl glycine-based tripeptide reacted cleanly to form the corresponding azidoamine product, 2ak, in an unoptimized 21% yield along with 78% of unreacted alkene starting material isolated, demonstrating the excellent chemoselectivity of this reaction. Another aspect worth mentioning here is the scalability of the presented methodology. On a gram scale, azidoamine 2t was obtained in comparable yield and purity. To our delight, the product could be isolated in clean form through precipitation of the ammonium salt followed by liberation of the amine upon basic workup, avoiding purification by column chromatography completely. (See the SI for further details.) Collectively, these results clearly highlight the synthetic potential of this new methodology for early- and late-stage introduction of an azidoamine functionality.
Because of the high demand for the synthesis of isotopically labeled compounds, we synthesized a [15N]-labeled version of the reagent, starting from [15N]-hydroxylamine.20 This new reagent was used to generate the corresponding labeled product, [15N]-2n, with excellent isotopic purity and in good yields, highlighting its potential for the rapid synthesis of [15N] compounds. (See the SI for detailed information.)
We next investigated the potential of azidoamines in subsequent synthetic transformations. Azides have found broad synthetic utility in copper-catalyzed azide−alkyne cycloaddition (CuAAC)21 and Staudinger bioconjugation.22 Using azidoamine 2t as a starting material, a click-type CuAAC reaction proceeded selectively at the azido group, leaving the unprotected amine untouched. The synthetic utility of the formed 2-azidoamines was further demonstrated through several orthogonal derivatization reactions (Scheme 4).
Subjecting 2t to a phosphine-mediated Staudinger reduction afforded diamine 3b in good yield. Conventional reductive amination or amide coupling delivered secondary amine 3f and amide 3d. The azide moiety of the latter could be further reduced in a subsequent step to obtain primary amine 3e. This sequence clearly showcases the orthogonality of this simple masked diamine motif. Making combined use of both nitrogen moieties, a Staudinger/aza-Wittig (SAW) cyclization directly afforded imidazolidinone 3c in one step.23
We next applied our methodology to the concise synthesis of biologically relevant molecules. RO 20-1724 (4c, Scheme 5) is a highly specific inhibitor of cAMP-specific phosphodiesterase type IV (PDE 4, IC50 = 2 μM) commonly used in pharmaceutical research.24 Starting from allyl aryl 4a, we could access key intermediate 4b on a 1.45 g scale with an unoptimized yield of 30% through a direct iron-catalyzed aminoazidation reaction. Subjecting this intermediate to the adapted SAW conditions next afforded RO 20−1724 in 63% Scheme 4. Conditions for the Derivatization of Azidoamine 2ta yield. This new route does not only decrease the step count significantly (previously reported: 7 steps), but, according to the report by the Audisio lab,23 also bears the potential to introduce short-lived isotopes through the use of labeled CO2 in the last step.25
Furthermore, we utilized our methodology in the formal total synthesis of antibacterial marine natural product hamacanthin B 4g.26 A previously reported synthesis relied on an azidoamine intermediate for a key SAW-cyclization step to construct the diaza heterocycle of the final product. Remarkably, our new aminoazidation reaction enabled us to access key intermediate 4f in a single catalytic step, providing a new and rapid formal synthesis of the racemic form of this natural product. Yields are of isolated products. dr was determined by NMR analysis. See the Supporting Information for detailed experimental details.
We next turned our attention toward applying our reaction to the synthesis of 3-azidopiperidines, which are important precursors for a wide range of pharmaceutically active 3aminopiperidines.13f A representative thereof is the specific D2 receptor agonist quinagolide, a drug prescribed for hyperprolactinemia and commercialized as its racemate.27a−c Recently, Chavan and co-workers have shown alternative routes to constructing the molecule, with one featuring a 3azidopiperidine intermediate (4n).27d−f In this synthesis, the azido intermediate could be easily transformed into the desired sulfamide; however, the preparation of the masked diamine required a lengthy synthesis. We therefore targeted the synthesis of this 3-azidopiperidine core using our methodology. Starting from literature-known allyl β-tetralone 4i, diastereoselective reduction gave rise to desired cis-alcohol 4k, which was subsequently mesylated (with further information in the SI; Ms = mesyl). Having set an appropriate leaving group, we applied our methodology to obtain azidoamine 4m with a dr of 1:1 in 39% yield. Cyclization to form the piperidine ring followed by alkylation led to desired key intermediate 4n in eight steps from commercially available starting materials.
Collectively, these applications clearly show the method’s potential in the synthesis of bioactive compounds.
Intrigued by the features of the presented methodology, we next conducted some control experiments to shed light on the reaction mechanism (Scheme 6). We first compared the behavior of two radical clocks with different rates of opening. Cyclopropyl substrate 5a, which has a relatively slow rate of opening, did not open, whereas rapidly opening cyclopropyl substrate 5d readily underwent ring opening (Scheme 6a).28 Correlating it with the rates reported in literature, the lifetime of the putatively formed radical can be tentatively stated as short-lived [(5a•) kr = 4 × 105 s−1, (5d•) kr = 7 × 1010 s−1].28 Subjecting radical clock 5a to the standard conditions also gave methoxylated side product 5c, the formation of which could indicate the intermediacy of a benzylic cation which is then trapped by the methanol solvent. However, nonbenzylic positions do not lead to any detectable formation of methoxylated product, suggesting the absence of a carbocation intermediate in these cases. Despite its short-lived nature, we next attempted to trap the radical intermediate. When (2,2,6,6tetramethylpiperidin-1-yl)oxyl (TEMPO) was added to the reaction, no adduct could be detected, albeit the yield of azidoamine 5g decreased significantly. Additional support for a stepwise mechanism is provided by the lack of stereoretention when using either (E)- or (Z)-oct-4-ene 5h, which both led to a similar ratio of (R*,R*)- and (R*,S*)-product 5i.
Interestingly, a closer look into this experiment revealed that isomerized alkene (E)-5h was detected in small amounts under standard reaction conditions. A similar observation was reported in a previously disclosed aminohalogenation reaction and was explained by a possible reversible addition of an amino radical to a double bond.29,30
To delve deeper into the electronic dependence of the aminoazidation reaction, a Hammett study was next performed using intermolecular competition experiments. We obtained a slope of ρ = −0.51 (Scheme 6d), which suggests only minor positive charge buildup in the transition state of the product selective step of the reaction. Assuming that this step is the C− N bond-forming event, the relatively small ρ value correlates better with radical-based amination mechanisms than with carbocationic ones.31
Collectively, these results are consistent with the results previously obtained for our aminochlorination reaction.17a However, the complete lack of stereoretention may indicate that the putative carbon-centered radical intermediate is slightly more long-lived in the aminoazidation case. On the basis of these experiments, we propose a mechanism in which the hydroxylamine-derived reagent is first reductively cleaved by an iron catalyst. The resulting putative N-centered radical32 or iron nitrenoid33 could then add to an alkene. The resulting C-centered radical is then trapped by an iron-coordinated azido ligand to release the product.

■ CONCLUSIONS

We have reported the direct synthesis of unprotected primary 2-azidoamines from a wide range of different alkenes. This mild and highly selective transformation provides operationally simple and robust access to versatile 2-azidoamines using a benign and inexpensive iron catalyst. The products obtained can further engage in various derivatizations where the azidoamine motif functions as an ideal masked 1,2-diamine, enabling a fast and orthogonal transformation to many useful building blocks. In a broader context, these features emphasize the value of the presented methodology for the versatile synthesis of diamine derivatives which are ubiquitously found in bioactive molecules.

■ REFERENCES

(1) (a) Lucet, D.; Le Gall, T.; Mioskowski, C. The Chemistry of Vicinal Diamines. Angew. Chem., Int. Ed. 1998, 37, 2580−2627. (b) Kizirian, J.-C. Chiral Tertiary Diamines in Asymmetric Synthesis. Chem. Rev. 2008, 108, 140−205.
(2) (a) de Figueiredo, R. M. Transition-Metal-Catalyzed Diamination of Olefins. Angew. Chem., Int. Ed. 2009, 48, 1190−1193. (b) Cardona, F.; Goti, A. Metal-catalysed 1,2-diamination reactions. Nat. Chem. 2009, 1, 269−275. (c) Müller, T. E.; Beller, M. MetalInitiated Amination of Alkenes and Alkynes. Chem. Rev. 4067−4105.
(3) For selected reviews on the dihydroxylation of alkenes, see (a) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Catalytic Asymmetric Dihydroxylation. Chem. Rev. 1994, 94, 2483−2547. (b) Bataille, C. J. R.; Donohoe, T. J. Osmium-free direct syndihydroxylation of alkenes. Chem. Soc. Rev. 2011, 40, 114−128. (c) Noe, M. C.; Letavic, M. A.; Snow, S. L. Asymmetric Dihydroxylation of Alkenes. In Organic Reactions; McCombie, S. W., Ed.; John Wiley & Sons, Inc.: Hoboken, NJ, 2005; pp 109−625.
(4) For further selected examples of catalytic diazidation, see (a) Wu, D.; Cui, S.-S.; Lin, Y.; Li, L.; Yu, W. Visible Light-Driven Azidation/Difunctionalization of Vinyl Arenes with Azidobenziodoxole under Copper Catalysis. J. Org. Chem. 2019, 84, 10978−10989. (b) Kamble, D. A.; Karabal, P. U.; Chouthaiwale, P. V.; Kashyap, S. Visible-light activated metal catalyst-free vicinal diazidation of olefins with sulfonium iodate(I) species. Chem. Commun. 2019, 55, 2833−2836. (e) Zhou, H.; Jian, W.; Qian, B.; Ye, C.; Li, D.; Zhou, J.; Bao, H.
Copper-Catalyzed Ligand-Free Diazidation of Olefins with TMSN3 in CH3CN or in H2O. Org. Lett. 2017, 19, 6120−6123.
(5) For selected examples and reviews, see (a) Fu, N.; Sauer, G. S.; Saha, A.; Loo, A.; Lin, S. Metal-catalyzed electrochemical diazidation of alkenes. Science 2017, 357, 575−579. (b) Siu, J. C.; Parry, J. B.; Lin, S. Aminoxyl-Catalyzed Electrochemical Diazidation of Alkenes Mediated by a Metastable Charge-Transfer Complex. J. Am. Chem. Soc. 2019, 141, 2825−2831. For selected reviews, see (c) Parry, J. B.; Fu, N.; Lin, S. Electrocatalytic Difunctionalization of Olefins as a
General Approach to the Synthesis of Vicinal Diamines. Synlett 2018, 29, 257−265. (d) Sauer, G. S.; Lin, S. An Electrocatalytic Approach to the Radical Difunctionalization of Alkenes. ACS Catal. 2018, 8, 5175−5187.
(6) (a) Yuan, Y.-A.; Lu, D.-F.; Chen, Y.-R.; Xu, H. Iron-Catalyzed Direct Diazidation for a Broad Range of Olefins. Angew. Chem., Int. Ed. 2016, 55, 534−538. (b) Zhu, H.-T.; Arosio, L.; Villa, R.; Nebuloni, M.; Xu, H. Process Safety Assessment of the Iron-Catalyzed Direct Olefin Diazidation for the Expedient Synthesis of Vicinal Primary Diamines. Org. Process Res. Dev. 2017, 21, 2068−2072. (c) Shen, S.-J.; Zhu, C.-L.; Lu, D.-F.; Xu, H. Iron-Catalyzed Direct Olefin Diazidation via Peroxyester Activation Promoted by NitrogenBased Ligands. ACS Catal. 2018, 8, 4473−4482.
(7) For an example of the two-step synthesis of mono-N-Bocprotected vicinal diamines from alkenes, see Olson, D. E.; Su, J. Y.; Roberts, D. A.; Du Bois, J. Vicinal Diamination of Alkenes under RhCatalysis. J. Am. Chem. Soc. 2014, 136, 13506−13509.
(8) For an example of a regioselective azide reduction, see Nyffeler, P. T.; Liang, C.-H.; Koeller, K. M.; Wong, C.-H. The Chemistry of Amine-Azide Interconversion: Catalytic Diazotransfer and Regioselective Azide Reduction. J. Am. Chem. Soc. 2002, 124, 10773−10778. For a chemoselective azide reduction, see Udumula, V.; Nazari, S. H.; Burt, S. R.; Alfindee, M. N.; Michaelis, D. J. Chemo- and SiteSelective Alkyl and Aryl Azide Reductions with Heterogeneous Nanoparticle Catalysts. ACS Catal. 2016, 6, 4423−4427.
(9) McGrath, N. A.; Brichacek, M.; Njardarson, J. T. A Graphical Journey of Innovative Organic Architectures That Have Improved Our Lives. J. Chem. Educ. 2010, 87, 1348−1349. Top 200 Small Molecule Pharmaceuticals by Retail sales in 2018, available from njardarson.lab.arizona.edu.
(10) For sulfonamide-protected aminoazidation, see (a) Zhang, B.; Studer, A. Copper-Catalyzed Intermolecular Aminoazidation of Alkenes Org. Org. Lett. 2014, 16, 1790−1793. (b) Lei, B.; Wang, X.; Ma, L.; Li, Y.; Li, Z. NFSI-paricipated intermolecular aminoazidation of alkenes through iron catalysis. Org. Biomol. Chem. 2018, 16, 3109−3113. (c) Kawauchi, D.; Ueda, H.; Tokuyama, H. Double Functionalization of Styrenes by Cu-Mediated Assisted Tandem Catalysis. Eur. J. Org. Chem. 2019, 2019, 2056−2060.
(11) Li, Y.; Liang, Y.; Dong, J.; Deng, Y.; Zhao, C.; Su, Z.; Guan, W.; Bi, X.; Liu, Q.; Fu, Junkai Directed Copper-Catalyzed Intermolecular Aminative Difunctionalization of Unactivated Alkenes. J. Am. Chem. Soc. 2019, 141, 18475−18485.
(12) For an example of a superstoichiometric aminoazidation of styrene, see (a) Minisci, F.; Galli, R.; Cecere, M. Amminazione radicalica di olefin con acido idrossilamminsolfonico e idrossilammina. Sterochimica dell’ammino-clorurazione. Chim, Ind. (Milan) 1966, 48, 132−136. (b) Minisci, F. Free-Radical Additions to Olefins in the Presence of Redox Systems. Acc. Chem. Res. 1975, 8, 165−171.
(13) For examples of intramolecular aminoazidation, see (a) Foschi, F.; Loro, C.; Sala, R.; Oble, J.; Lo Presti, L.; Beccalli, E. M.; Poli, G.; Broggini, G. Intramolecular Aminoazidation of Unactivated Terminal Alkenes by Palladium-Catalyzed Reactions with Hydrogen Peroxide as the Oxidant. Org. Lett. 2020, 22,Unsaturated Amines. J. Org. Chem. 2014, 79, 571−581.
(14) For recent perspectives of the importance of protecting-groupfree transformations, see (a) Young, I. S.; Baran, P. S. Protectinggroup-free synthesis as an opportunity for invention. Nat. Chem. 2009, 1, 193−205. (b) Blakemore, D. C.; Castro, L.; Churcher, I.; Rees, D. C.; Thomas, A. W.; Wilson, D. M.; Wood, A. Organic synthesis provides opportunities to transform drug discovery. Nat. Chem. 2018, 10, 383−394. (c) Fernandes, R. A. Protecting-Group-Free Organic Synthesis; John Wiley & Sons, Ltd: Chichester, U.K., 2018; pp 1−9.
(15) For selected recent examples for the synthesis of unprotected amines from unsaturated compounds, see (a) Cheng, Q.-Q.; Zhou, Z.; Jiang, H.; Siitonen, J. H.; Ess, D. H.; Zhang, X.; Kürti, L. Yoon, T. P. Iron Catalyzed Asymmetric Oxyamination of Olefins. J. Am. Chem. Soc. 2012, 134, 12370−12373. (p) Ruffoni, A.; Julia, F.; Svejstrup, T. D.; McMillan,́ A. J.; Douglas, J. J.; Leonori, D. Practical and regioselective amination of arenes using alkyl amines. Nat. Chem. 2019, 11, 426−433.
(16) During the revision of this manuscript, a photochemical synthesis of 2-chloroamines which can be further one-pot transformed into unsymmetrical vicinal diamines was published by Leonori and coworkers: Govaerts, S.; Angelini, L.; Hampton, C.; Malet-Sanz, L.; Ruffoni, A.; Leonori, D. Photoinduced Olefin Diamination with Alkylamines. Angew. Chem., Int. Ed. 2020, 59, 15021−15028.
(17) (a) Legnani, L.; Prina-Cerai, G.; Delcaillau, T.; Willems, S.; Morandi, B. Efficient access to unprotected primary amines by ironcatalyzed aminochlorination of alkenes. Science 2018, 362, 434−439. (b) Legnani, L.; Morandi, B. Direct Catalytic Synthesis of Unprotected 2-Amino-1-Phenylethanols from Alkenes by Using Iron(II) Phthalocyanine. Angew. Chem., Int. Ed. 2016, 55, 2248− 2251. (c) Legnani, L.; Bhawal, B. N.; Morandi, B. Recent Developments in the Direct Synthesis of Unprotected Primary Amines. Synthesis 2017, 49, 776−789.
(18) Thome, I.; Nijs, A.; Bolm, Ć . Trace metal impurities in catalysis. Chem. Soc. Rev. 2012, 41, 979−987.
(19) For reviews of α-tertiary amines, see (a) Hager, A.; Vrielink, N.; Hager, D.; Lefranc, J.; Trauner, D. Synthetic approaches towards alkaloids bearing α-tertiary amines. Nat. Prod. Rep. 2016, 33, 491− 522. (b) Clayden, J.; Donnard, M.; Lefranc, J.; Tetlow, D. J. Quaternary centers bearing nitrogen (α-tertiary Tetrahedron Lett. 2013, 54, 545−548. (b) Hanson, J. R. The Organic Chemistry of Isotopic Labelling; Royal Society Chemistry: Cambridge, 2011.
(21) (a) Moses, J. E.; Moorhouse, A. D. The growing applications of click chemistry. Chem. Soc. Rev. 2007, 36, 1249−1262. (b) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Click Chemistry: Diverse Chemical Function from a Few Good Reactions. Angew. Chem., Int. Ed. 2001, 40, 2004−2021.
(22) (a) Schilling, C. I.; Jung, N.; Biskup, M.; Schepers, U.; Brase, S.̈ Bioconjugation via azide-Staudinger ligation: an overview. Chem. Soc. Rev. 2011, 40, 4840−4871. (b) van Berkel, S. S.; van Eldijk, M. B.; van Hest, J. C. M. Staudinger Ligation as a Method for Bioconjugation. Angew. Chem., Int. Ed. 2011, 50, 8806−8827.
(23) Del Vecchio, A.; Caille, F.; Chevalier, A.; Loreau, O.; Horkka,́ K.; Halldin, C.; Schou, M.; Camus, N.; Kessler, P.; Kuhnast, B.; Taran, F.; Audisio, D. Late-Stage Isotopic Carbon Labeling of Pharmaceutically Relevant Cyclic Ureas Directly from CO2. Angew. Chem., Int. Ed. 2018, 57, 9744−9748.
(24) (a) Brackeen, M. F.; Stafford, J. A.; Cowan, D. J.; Brown, P. J.; Domanico, P. L.; Feldman, P. L. Design and Synthesis of Conformationally Constrained Analogs of 4-(3-Butoxy-4methoxybenzyl)imidazolidin-2-one (RO 20−1724) as Potent Inhibitors of cAMP-Specific Phosphodiesterase. J. Med. Chem. 1995, 38, 4848−4854. (b) Gruenman, V.; Hoffer, M. Hoffmann-La Roche Inc., US 3,923,833, 1975. (c) Number of references including RO 20-1724 in biological studies: 459; Data obtained from SciFindern, accessed 10/02/2020.
(25) For the use of a 11C-labelled version, see (a) DaSilva, J. N.; Lourenco, C. M.; Wilson, A. A.; Houle, S. Syntheses of the Phosphodiesterase-4 Inhibitors [11C]Ro 20−1724, R-, R/S- and S[11C]Rolipram. J. Labelled Compd. Radiopharm. 2001, 44, 373−384. (b) Lourenco, C. M.; DaSilva, J. N.; Warsh, J. J.; Wilson, A. A.; Houle, S. Imaging of cAMP-Specific Phosphodiesterase-IV: Comparison of [11C]Rolipram and [11C]Ro 20−1724 in Rats. Synapse 1999, 31, 41−50.
(26) (a) Gunasekera, S. P.; McCarthy, P. J.; Kelly-Borges, M. Hamacanthins A and B, New Antifungal Bis Indole Alkaloids from the Deep-Water Marine Sponge, Hamacantha Sp. J. Nat. Prod. 1994, 57, 1437−1441. (b) Jiang, B.; Yang, C.-G.; Wang, J. Enantioselective Synthesis of Marine Indole Alkaloid Hamacanthin B. J. Org. Chem. 2002, 67, 1396−1398. (c) Bao, B.; Sun, Q.; Yao, X.; Hong, J.; Lee, C.O.; Cho, H. Y.; Jung, J. H. Bisindole Alkaloids of the Topsentin and Hamacanthin Classes from a Marine Sponge Spongosorites sp. J. Nat. Prod. 2007, 70, 2−8.
(27) (a) Barlier, A.; Jaquet, P. Quinagolide – a valuable treatment option for hyperprolactinaemia. Eur. J. Endocrinol. 2006, 154, 187− 195. For synthesis approaches to quinagolide, see (b) Nordmann, R.; Petcher, T. J. Octahydrobenzo[g]quinolines: Potent Dopamine Agonists Which Show the Relationship between Kadam, A. L.; Kawale, S. A. Total Synthesis of (±)-Quinagolide: A Potent D2 Receptor Agonist for the Treatment of Hyperprolactinemia. ACS Omega 2019, 4, 8231−8238. (f) Chavan, S. P.; Kadam, A. L.; Gonnade, R. G. Enantioselective Formal Total Synthesis of (−)-Quinagolide. Org. Lett. 2019, 21, 9089−9093.
(28) For a general overview of the use of radical clocks, see (a) Newcomb, M. Radical Kinetics and Clocks. In Encyclopedia of Radicals Chemistry Biology and Materials; John Wiley & Sons, 2012; pp 1−18. For recent examples for the applications of radical clocks, see (b) Budai, B.; Leclair, A.; Wang, Q.; Zhu, J. J. Org. Chem. 1998, 63, 8609−8613.
(29) Kirsch, A. Radical Addition of N-Chlorophthalimide and NBromophthalimide to Alkenes. J. Prakt. Chem. 1998, 340, 129−134.
(30) On the basis of the data on hand, we propose a mechanism involving direct aminoazidation through a radical mechanism. However, we cannot fully exclude, for all substrates involved, an alternative mechanism proceeding through an initial aziridination followed by ring opening through a nucleophilic Chem., Int. Ed. 2013, 52, 5309−5313.
(31) (a) Musacchio, A. J.; Nguyen, L. Q.; Beard, G. H.; Knowles, R. R. Catalytic Olefin Hydroamination with Aminium Radical Cations: A Photoredox Method for Direct C−N Bond Formation. J. Am. Chem. Soc. 2014, 136, 12217−12220. (b) Mojelsky, T.; Chow, Y. L. McDonald, R. S.; Shapiro, S. A. Kinetics and Mechanism of Electrophilic Addition. I. A Comparison of Second- and Third-Order Brominations. J. Org. Chem. 1973, 38, 2460−2464.
(32) (a) Chow, Y. L.; Danen, W. C.; Nelsen, S. F.; Rosenblatt, D. H. Nonaromatic aminium radicals. Chem. Rev. 1978, 78, 243−274. (b) Neale, R. S. Nitrogen Radicals as Synthesis Intermediates. NHalamide Rearrangements and Additions to Unsaturated Hydrocarbons. Synthesis 1971, 1971, 1−15. (c) Hioe, J.; Šakic, D.; Vrć ek, V.;̌ Zipse, H. The stability of nitrogen-centered radicals. Org. Biomol. Chem. 2015, 13, 157−169. (d) Foo, K.; Sella, E.; Thome, I.; Eastgate,́ M. D.; Baran, P. S. A Mild, Ferrocene-Catalyzed C-H Imidation of (Hetero)Arenes. J. Am. Chem. Soc. 2014, 136, 5279−5282.
(33) (a) Lu, D.-F.; Zhu, C.-L.; Sears, J. D.; Xu, H. Iron(II)Catalyzed Intermolecular Aminofluorination of Unfunctionalized Olefins Using Fluoride Ion. J. Am. Chem. Soc. 2016, 138, 11360− 11367. (b) Lu, D.-F.; Zhu, C.-L.; Jia, Z.-X.; Xu, H. Iron(II)-Catalyzed Intermolecualr Amino-Oxygenation of Olefins through the N-O amination strategies based on nitrogen-centered radical chemistry. Chem. Soc. Rev. 2016, 45, 3069−3087. (e) Murakami, K.; Perry, G. J. P.; Itami, K. Aromatic CH amination: a radical approach for adding new functions into biology- and materials-oriented aromatics. Org. Biomol. Chem. 2017, 15, 6071−6075.