Recent advances in radical azidation using sulfonyl azides are presented. For instance, radical carboazidation using α-iodoketones, desulfitative carboazidation, and anti-Markovnikov hydroazidation of alkenes are described. These novel methods tolerate a large number of functional groups and allow the synthesis of organic azides that would be difficult to synthesize otherwise. The transformation of the azides using reductive processes as well as a Schmidt reaction under nonacidic conditions were used to synthesize alkaloids including indolizidine 167B, monomorine I, cylindricine C, and lepadiformine 

Kapat, Ajoy

Lapointe, Guillaume

Renaud, Philippe

Weidner, Karin

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1633Pure Appl. Chem., Vol. 84, No. 7, pp. 1633–1641, 2012.http://dx.doi.org/10.1351/PAC-CON-11-11-21© 2012 IUPAC, Publication date (Web): 27 May 2012Radical azidation reactions and their applicationin the synthesis of alkaloids*Guillaume Lapointe, Ajoy Kapat, Karin Weidner, andPhilippe Renaud‡Department of Chemistry and Biochemistry, University of Bern, Freiestrasse 3,CH-3012 Bern, SwitzerlandAbstract: Recent advances in radical azidation using sulfonyl azides are presented. Forinstance, radical carboazidation using α-iodoketones, desulfitative carboazidation, and anti-Markovnikov hydroazidation of alkenes are described. These novel methods tolerate a largenumber of functional groups and allow the synthesis of organic azides that would be difficultto synthesize otherwise. The transformation of the azides using reductive processes as wellas a Schmidt reaction under nonacidic conditions were used to synthesize alkaloids includ-ing indolizidine 167B, monomorine I, cylindricine C, and lepadiformine C.Keywords: alkaloid synthesis; azides; radicals; C–C bond formation; hydroboration; Schmidtreaction.INTRODUCTIONSince the preparation of the first organic azide by Peter Grieß in 1864 [1,2], numerous syntheses andapplications of these energy-rich molecules have been developed. Azido-containing compounds arehighly energetic and yet paradoxically locked up, and this high energy unfolds a huge synthetic versa-tility ranging from the simple introduction of amino group, to the generation of nitrenes, up to the trig-ger of rearrangement and cycloaddition reactions [3,4].The main approach to the synthesis of organic azides involves a classical substitution reactionusing an inorganic azide as nucleophile [5]. Tertiary alkyl azides are often difficult to generate via sub-stitution reactions, and free radical processes proved to be particularly efficient for their synthesis [6].Free radical reactions not only allow the mild introduction of azides, but are also compatible with alarge number of functional groups and offer unique possibilities to perform sequential transformations. Previously, we disclosed an intermolecular radical azidation process that allowed the efficient azi-dation of secondary and tertiary alkyl radicals using arenesulfonyl azide reagents (Scheme 1) [7–10]. Inthis reaction, the alkyl radical adds to the N-terminal position of the azide moiety to give a 1,3-triazenylradical [11], which fragments to liberate the corresponding alkyl azide and arenesulfonyl radical. Polareffects are believed to play an important role in this addition. Arylsulfonyl azides are electrophilic rad-ical traps, and only nucleophilic radicals (such as tertiary and secondary carbon-centered radicals) reactefficiently with them. The α-fragmentation of the arenesulfonyl radical liberating an aryl radical andSO2 is hampered because of the instability of the aryl radical. Therefore, the arenesulfonyl radical canfurther react and propagate the chain process.*Pure Appl. Chem. 84, 1543–1667 (2012). A collection of invited papers based on presentations at the 23rd InternationalConference on Heterocyclic Chemistry (ICHC-23), Glasgow, UK, 31 July–4 August 2011.‡Corresponding authorFrom the standpoint that sulfonylazides are reactive only toward nucleophilic radicals, the radi-cal azidation could be integrated in an intermolecular process that encompasses the addition of anelectro philic ethoxycarbonylmethyl radical to unactivated alkenes, followed by azidation. This three-component sequence represents a formal carboazidation of alkenes (Scheme 2) [12,13]. When followedby a reduction/lactamization sequence, this reaction gives direct access to pyrrolizidinones andindolizidinones. While the first set of conditions developed used hexabutylditin as chain transferreagent, later on it was found that the use of triethylborane in ethanol/water was equally efficient inachieving this transformation [14]. Alternatively, 3-pyridinesulfonyl azide could be used instead ofbenzene sulfonyl azide to facilitate the purification of the products [15]. This radical carboazidation wasfurther showcased in the synthesis of lepadiformine A [16] and (+)-hyacinthacine A1 [17].Our recent efforts to address the limitation and expand the scope of the radical azidation andcarbo azidation are described here. For instance, radical carbozidation with α-iodoketone, desulfitativecarboazidation, and anti-Markovnikov hydroazidation of alkenes will be presented. The synthesis ofseveral alkaloids achieved using the radical carboazidation as well as a unique intramolecular Schmidtreaction will be described.RADICAL CARBOAZIDATION OF -IODOKETONESIn our first lepadiformine synthesis [16], the late-stage transformation of a lactam to the correspondinghydroxymethyl substituted pyrrolidine required five steps that included the addition of organometallicspecies and harsh reduction conditions. Recently, we reported a simple way to shorten this sequence byrunning the radical carboazidation with α-iodoketones. This extension allows, after reduction, directaccess to the desired substituted pyrrolidines (Scheme 3) [18]. It is possible, by the careful choice ofthe reaction partners, to install functionalized side chains having protected hydroxyl group and esters.G. LAPOINTE et al.© 2012, IUPAC Pure Appl. Chem., Vol. 84, No. 7, pp. 1633–1641, 20121634Scheme 1 Addition of carbon-centered radical onto arylsulfonyl azide.Scheme 2 Radical carboazidation and its application in synthesis.DESULFITATIVE CARBOAZIDATIONDespite the fact that radical carboazidation is a very efficient process, the need for a 3-fold excess ofthe arylsulfonyl azide and the use of organotin reagents limits its potential. While the triethylborane-mediated reaction addressed the problem associated with the use of tin reagents [14], a more atom eco-nomical system that would reduce the amount of sulfonyl azide involved was highly desired. Zard andKim used the α-scission alkanesulfonyl radicals to develop an effective radical chain reaction [19–21].Following the same principle, we envisioned that a single reagent could deliver the electrophilic ethoxy-carbonylmethyl radical and act as the azidating agent for the C–N bond formation [22]. The reactionwith this reagent worked best when di-tert-butyldiazene (t-BuN=Nt-Bu), the alkene, and the sulfonylazide are irradiated by light generated from a simple sun lamp. In general, the yields are superior tothose obtained under the tin-mediated conditions (Scheme 4). The proposed mechanism is depicted inScheme 5. Upon irradiation, t-BuN=Nt-Bu decomposes to a tert-butyl radical which then adds to thesulfonyl azide. Fragmentation and SO2 elimination afford the carbon-centered electrophilic radical thatreacts with the alkene. Finally, trapping of the resulting radical by the sulfonyl azide gives the alkylazide and the starting sulfonyl radical that sustains the chain process.© 2012, IUPAC Pure Appl. Chem., Vol. 84, No. 7, pp. 1633–1641, 2012Radical azidation reactions 1635Scheme 3 Radical carboazidation using α-iodoketones.Scheme 4 The desulfitative carboazidation.ANTI-MARKOVNIKOV HYDROAZIDATION OF ALKENESThe addition of hydrazoic acid to an alkene, notwithstanding its apparent simplicity, still remains a chal-lenging transformation. A notable exception is the recent works of Carreira et al. who described theMarkovnikov hydroazidation of alkenes using a cobalt catalyst and arenesulfonylazide [23–25]. In linewith our recent reports that B-alkylcatecholboranes are useful radical precursors that participate in effi-cient chain reactions with arenesulfonyl radicals [26–32], we developed an efficient hydroboration/rad-ical azidation sequence, hereby achieving a formal anti-Markovnikov addition of hydrazoic acid ontoalkene (Scheme 6) [33]. The scope proved to be broad, and even styrene derivatives and terminalalkenes (primary radicals) could efficiently be hydroazidated in the reaction conditions. The radicalnature of the process was further demonstrated via the cyclopropyl opening of (−)-carene and the 6-exo-G. LAPOINTE et al.© 2012, IUPAC Pure Appl. Chem., Vol. 84, No. 7, pp. 1633–1641, 20121636Scheme 5 Mechanism of the desulfitative carboazidation.Scheme 6 Anti-Markovnikov hydroazidation.trig cyclization of β-citronellene (Scheme 7). The proposed mechanism is depicted in Scheme 8. Thereaction of tert-butoxyl radicals with the B-alkylcatecholborane initiates the reaction, generating thestarting alkyl radical and a boronic ester. The alkyl radical then adds to the benzenesulfonyl azide togive the alkyl azide and a benzenesulfonyl radical that can propagate the chain by homolytic substitu-tion with the B-alkylcatecholborane.RADICAL CARBOAZIDATION IN ALKALOIDS SYNTHESISThe radical carboazidation of unactivated alkenes allows one to prepare functionalized organic azidesthat, upon reduction or rearrangement, open the door to structural skeletons that are present in naturalproducts. According to this strategy, (−)-indolizidine 167B, monomorine I, cylindricine C, and lepadi-formine C (Fig. 1) have been recently prepared, and their synthesis will be briefly discussed here.© 2012, IUPAC Pure Appl. Chem., Vol. 84, No. 7, pp. 1633–1641, 2012Radical azidation reactions 1637Scheme 7 Hydroazidation involving a radical rearrangement.Scheme 8 Hydroazidation mechanism.Fig. 1 Recently synthesized alkaloids. Synthesis of (−)-indolizidine 167B: Schmidt reaction under nonacidic conditionsIndolizidine 167B is an alkaloid isolated from the Panamanian poison frog Dendrobates speciosus [34].Despite its structural simplicity, this alkaloid has attracted the interest of the synthetic community andmany total syntheses have been achieved [35,36].A combination of the carboazidation and an intramolecular Schmidt rearrangement undernonacidic conditions gave access to (–)-indolizidine 167B as depicted in Scheme 9 [37]. The carbo -azidation on the optically active 2-substituted alkene afforded a mixture of diastereomeric azides, inwhich reduction of the ester to the alkyl chain and deprotection afforded the azidoalcohol in a 1:1 ratioof diastereoisomers. An intramolecular Schmidt rearrangement eliminated the stereochemically uncon-trolled quaternary carbon center by generating a transient iminium ion. Selective reduction of theiminium ion from the less hindered face afforded (–)-indolizidine 167B in good yield as a singlediastereoisomer.Synthesis of monomorine IMonomorine I [38,39], isolated from two species of ants [40,41] and from the dendrobateMelanophryniscus stelzneri [42] was synthesized using the α-iodoketone radical carboazidation(Scheme 10) [18]. The radical carboazidation between 2-iodohexan-2-one and hept-6-en-2-one pro-ceeded in good yield, and bis-reductive amination of the azide afforded the natural product as a singlediastereoisomer. The overall yield for the transformation of the iodoketone into monomorine I reached57 %.G. LAPOINTE et al.© 2012, IUPAC Pure Appl. Chem., Vol. 84, No. 7, pp. 1633–1641, 20121638Scheme 9 Synthesis of (–)-indolizidine 167B.Synthesis of cylindricine C and its C-13 epimerCylindricine C was isolated from the marine ascidian Clavelina cylindrica by Blackman et al. in 1994[43]. Several total syntheses of cylindricine C have been reported [44,45]. The generation of the qua-ternary amino-substituted center and the selective introduction of the hexyl side chain represent themain challenges for the synthesis of this target. These obstacles could be overcome using a α-iodo -ketone-mediated radical carboazidation followed by a bis-reductive amination to assemble thepyrrolodecahydroquinoline structure [46]. The corresponding azide was obtained in 75 % as a 7:3 ratioof diastereomers. The triethylborane-mediated conditions worked also, albeit in lower yield (59 %).While the reduced product was found to be epimeric at C-13, it was possible to obtain the 13-epicylin-dricine C and cylindricine C through an isomerization of the C-13 center (Scheme 11).© 2012, IUPAC Pure Appl. Chem., Vol. 84, No. 7, pp. 1633–1641, 2012Radical azidation reactions 1639Scheme 10 Synthesis of monomorine I.Scheme 11 Synthesis of cylindricine C.Formal synthesis of lepadiformine C Lepadiformine C was recently isolated from Clavelina moluccensis [47] and since then, two synthesesof the alkaloid have been accomplished [48,49]. In Aubé’s synthesis [48], a lactam intermediate closelyrelated to the one of our lepadiformine A intermediate [16] was prepared. As an illustration of the syn-thetic usefulness of the desulfitative carboazidation, we achieved a concise synthesis of Aubé’s inter-mediate (Scheme 12) [22]. Starting from the 2-alkylated-methylenecyclohexane, the carboazidationafforded the azide in 82 % as a 3:2 mixture of diastereomers. Reduction and lactamization directly gaveAubé’s intermediate in 39 %.CONCLUSIONMore than 10 years have passed since the discovery of the radical azidation reaction, and the followingyears have seen the simple azidation process being extended to intermolecular radical carboazidation.Recent progress in the field has allowed the development of novel alteration to the azidation, such asthe use of α-iodoketones and the desulfitative conditions in the carboazidation, up to the anti-Markovnikov hydroazidation. The potential of these reactions has been further demonstrated by thesynthesis of several alkaloids.ACKNOWLEDGMENTSWe are grateful to the Swiss National Science Foundation for financial support. We thank the BASFCorporation for the generous gift of organoboron reagents.REFERENCES1. P. Griess. Proc. R. Soc. London 13, 375 (1864).2. P. Griess. Liebigs Ann. Chem. 137, 39 (1866).3. S. Bräse, C. Gil, K. Knepper, V. Zimmermann. Angew. Chem., Int. Ed. 44, 5188 (2005).4. S. Bräse, K. 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Radical azidation reactions and their application in the synthesis of alkaloids

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