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. 2020 Apr 28;59(30):12376–12380. doi: 10.1002/anie.202003079

Photochemical Transformations with Iodine Azide after Release from an Ion‐Exchange Resin

Teresa Kösel 1,†, Göran Schulz 1,†, Gerald Dräger 1, Andreas Kirschning 1,✉
PMCID: PMC7384096  PMID: 32208548

Abstract

This report discloses the photochemical homolytic cleavage of iodine azide after its formation following release from polymer‐bound bisazido iodate(I) anions. A series of radical reactions are reported including the 1,2‐functionlization of alkenes and the unprecedented chemoselective oxidation of secondary alcohols in the presence of primary alcohols.

Keywords: azide radicals, C−H activation, iodine azide, photochemistry, polymer-bound reagents

Give me azide radicals! Stable and storable polymer‐bound bisazido‐iodate(I) anions are a source of azide radicals upon photochemical activation. These promote azidooxygenations of alkenes and C−H abstraction of alcohols. The latter reactivity initiates the chemoselective oxidation of secondary alcohols and C−H abstraction of aldehydes.

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The pioneering work of Hassner1 introduced iodine azide (IN3) to the reagent portfolio of preparative organic chemists. However, its explosive character hampered broader synthetic studies. Due to this property, iodine azide is commonly prepared in situ from sodium azide and iodine chloride in polar solvents.1, 2

Many years ago we reported on a new class of electrophilic halonium reagents that are obtained by iodine(III)‐mediated oxidation of ammonium bromide or iodide (1; Scheme 1).3 The resulting acylated haloate(I) complexes 2 4 can be further diversified by ligand exchange using silylated nucleophiles that yields ate(I) anions in 3 a–d. These reagents have been employed in various transformations with alkenes and alkynes5 for the activation of thioglycosides6 as well as dithioacetals7 and as cooxidants for TEMPO‐mediated oxidations.8 Chemically, the haloate(I) anions in 3 a–d behave like Br‐OAc, I‐OAc, I‐OTfa, and I‐N3. It can be assumed that these species are liberated from 3 a–d prior to the reaction with different nucleophiles.9, 10

Scheme 1.

Scheme 1

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Preparation of haloate(I) complexes. Ac=acetyl, Nu=nucleophile, Tfa=trifluoroacetyl; R1=alkyl or polystyrene; the ammonium counterion can be replaced by phosphonium PR4 +[3].

With these results in mind we initiated a program for extending the scope of these compounds to photochemical reactions, and the highly useful functionalized ion‐exchange resin 3 d was our reagent of choice. This orange‐colored polymer is a non‐explosive source of iodine azide (5) and can be for stored in the dark for several months under an argon atmosphere at −15 °C without loss of activity. Reactions are commonly terminated by filtration through a piece of cotton that is positioned at the opening of the vial. The polymeric byproduct 4 generated during transformations with 3 d is removed by simple filtration (Scheme 2)11 and its regeneration is achieved by exchange of azide with iodide, PhI(OAc)2‐promoted oxidation to 3 b, and ligand exchange with TMSN3. Principally, polymer‐bound iodine azide 3 d resolves the problems arising from the explosive character of iodine azide (5). So far photocatalytic reactions with iodine azide (5) have not been reported.12 Since 3 d is a source of Hal‐X species, we assumed that it is ideally suited to generate and study the chemical versatility of the azide radical (6) (Scheme 2).13

Scheme 2.

Scheme 2

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Polymer‐bound bisazidoiodate(I) 3 d, release of iodine azide (5), proposed photochemical generation of the azide radical 6, and resin regeneration.

Huang and Groves determined the bond dissociation energy (BDE) for H‐N3 (12) to be 92.7 kcal mol−1,14 which indicates that the azide radical (6) is a much stronger hydrogen‐atom abstractor than iodine or bromine radicals (BDE(H‐I)=71.3 kcal mol−1, BDE(H‐Br)=86.5 kcal mol−1).15 Azidoiodinanes 8–10 show similar I‐N3 BDE values to iodine azide (5) in the range of 29–35 kcal mol−1 (Figure 1).14

Figure 1.

Figure 1

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X–N3 bond dissociation energies (BDE) of common organic halogen azides (5, 8–11) and of HN3 (12).14

To prove that polymer‐bound reagent 3 d can serve as a source of azide radicals (6) we exposed it to blue LED light (445–510 nm) in the presence of indene (13). Under these conditions the syn‐bisazido adduct 14 formed (Scheme 3). The anti‐azido‐iodination product 15 is commonly formed under nonradical conditions and was only detected in trace amounts. The syn stereochemistry in 14 was determined by comparison with literature values.16

Scheme 3.

Scheme 3

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Radical bisazidation of indene (13) by photochemical activation of polymer‐bound reagent 3 d.

Noteworthy, thiosulfate ion exchange resin was added for reductive workup of all reactions and removal of byproducts such as iodine and IN3. Thus, the need for hydrolytic workup is bypassed. Further evidence for the presence of a radical process was collected using 2,2,6,6‐tetramethylpiperidinyloxyl (TEMPO) as a radical‐scavenging agent. Consequently, the anti 1,2‐adduct 17 was formed (Scheme 4).

Scheme 4.

Scheme 4

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Radical 1,2‐addition of azide and TEMPO to alkenes and formation of 17–24 by photochemical activation of polymer‐bound reagent 3 d; structure of TEMPO azide 16 (16 was also described to be a salt19).

A brief solvent check demonstrated that besides acetonitrile also DMF, CH2Cl2, and THF can be employed. However, in THF oxidized furan 18 was also detected in trace amounts. In the absence of indene (13) the radically formed THF adduct 18 was isolated in 91 % yield.17 There is precedence for radical H abstractions from tetrahydrofurans and other heterocycles when iodide salts are mixed with t‐butyl hydroperoxide.18a Alternatively, the azide radical (6) can be generated from PhI(OAc)2 and sodium azide which also leads to H radical abstraction from the solvent THF.18b As suggested for bulky TEMPO derivatives, TEMPO–azide adducts can form, serving as an azide radical in a “resting state”.19 A sample taken from a reaction mixture consisting of polymer 3 d and TEMPO in acetonitrile was analyzed by HPLC‐MS after 2 h and a signal at m/z=199.2 (M++1) was detected which could be TEMPO‐N3 16.

Next, the scope of this radical process was extended to several other alkenes. These yielded the corresponding 1,2‐addition products 17–23. 1,2‐Disubstituted alkenes commonly reacted with complete diastereocontrol. Under these conditions, 3‐(acetoxy)‐androst‐5‐en‐17‐one yielded the anti‐1,2‐bisazido adduct 24 in 50 % yield and not the azido oxygenation product. The structure of 24 was determined by X‐ray crystallographic analysis (see the Supporting Information).20 This result is consistent with the observations of Lin and co‐workers, who found that aminoxyl radicals are able to catalyze the anti‐diazidation of alkenes, likely with 16 serving as an azide radical reservoir.19 This alternative outcome of the reaction is fostered by increasing steric hindrance around the alkene moiety and the aminoxyl radical.

A radical clock experiment was conducted under the established conditions using vinyl cyclopropane 25 as starting material (Scheme 5). The ring‐opened allyl azide 26 was obtained besides the iodoazidated product formed by ionic 1,2‐addition to the terminal alkene. The formation of 26 clearly proved the presence of the azide radical (6).

Scheme 5.

Scheme 5

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Radical clock experiment with vinyl cyclopropane 25.

It has to be noted that azidooxygenations of alkenes were reported before by Studer et al., who employed azido benziodoxolone (Zhdankin's reagent21) in combination with highly reactive TEMPONa as a reducing agent and precursor for TEMPO.22 A second approach relied on the electrochemical reduction of TEMPO to TEMPO+. The resulting metastable charge‐transfer complex with azide 16 (TEMPO+/N3 −) decomposes to TEMPO and the azide radical (6).23 Recently, Kashya and co‐workers published the first photocatalyzed azidooxygenation that relied on trimethylsulfonium [bis(azido)iodate(I)] species, which are generated in situ from trimethylsilyl azide and sulfonium bis(acetoxy)iodate(I).24

During our studies we also observed an unexpected property of iodine azide (5) under photolytic conditions. We found that secondary alcohols are smoothly oxidized to the corresponding ketones while primary alcohols reacted very sluggishly (Schemes 6–8). This unexpected difference of reactivity was substantiated for the diols 34–36 (Scheme 7).25 In all cases the secondary hydroxyl group was oxidized with remarkable chemoselectivity, forming hydroxyketones 37–39. The selective oxidation of the 2,3‐deoxyglycoside 36 26 to the corresponding uloside 39 is particularly noteworthy and synthetically useful as protecting group chemistry, a typical feature in carbohydrate synthesis, is circumvented.

Scheme 6.

Scheme 6

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Oxidation of secondary alcohols with functionalized polymer 3 d and formation of ketones 27–33 (gray mark refers to site of oxidation).

Scheme 7.

Scheme 7

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Chemoselective oxidation of diols 34–36 with functionalized polymer 3 d.

We found that primary alcohols are also oxidized by the azide radical (6). Compared to fenchol (44), which was quantitatively oxidized to fenchone (32) within seven hours at room temperature, heptanol 40 reacted much more sluggishly. After 20 h hexylcarbamoyl azide (41) formed under the typical photolytic conditions in the presence of polymer 3 d (Scheme 8, top). Mechanistically, one can assume that heptanal (42) is formed first followed by H abstraction and generation of an acyl radical. When this is trapped by the azide radical (6) the acyl azide 43 would form. Next a Curtius rearrangement would yield the corresponding isocyanate, which finally reacts with HN3. Evidence for this series of events was collected when heptanal (42) was exposed to polymer 3 d under the typical photolytic conditions in the presence of polymer 3 d. Acyl azide 43 was isolated in 90 % yield. Obviously the Curtius rearrangement did not take place. The number of equivalents HX formed (X=I or N3) is larger when starting from heptanol (40) than from heptanal (42). These promote formation of carbamoylazide 41 from acyl azide 43. This chemoselectivity was unequivocally proven in a competition experiment between (+)‐fenchol(44) and heptanol (40) in the presence of different amounts of 3 d (Scheme 8, bottom). Finally, C−H activation similar to that described here was encountered for cyclic and acyclic ethers using strongly oxidizing reagents or transition metal catalysts.27, 28, 29

Scheme 8.

Scheme 8

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Oxidation of heptanol (40) and heptanal (42), competition experiments between (+)‐fenchol (44) and heptanol (40) (ratios determined by 1H NMR spectroscopic analysis; workup by addition of thiosulfate ion exchange resin and filtration).

To collect evidence that alcohol oxidations proceed via ketyl radicals, we carried out three experiments. First, we employed 1‐cyclopropylethan‐1‐ol (45), which was expected to undergo a rapid ring opening after radical formation (Scheme 9, example A). Treatment of 45 under the established conditions yielded bisazide 46, a clear indication that a ketyl radical 47 must have formed as an intermediate and subsequent reactions via intermediates 48 and 49 furnished bisazide 46. Secondly, methyl ether 50 was exposed to the established conditions and the corresponding ketone 51 was isolated as the main product (Scheme 9, example B). Finally, we carried out detailed mass spectrometric studies (LC‐ESI‐MS) on the crude mixture collected from the oxidation of isopropanol 52 in the presence of TEMPO. These displayed a signal at m/z=216.2 (M++1) indicative for TEMPO adduct 53, which, however, could not be isolated (Scheme 9, example C).

Scheme 9.

Scheme 9

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Three experiments (A–C) that provide evidence for C−H activation and ketyl radical formation during alcohol oxidation.

With reference to the BDE of IN3, and the H‐abstraction capability of both radicals, a mechanistic scheme can be summarized (Scheme 10). Polymer‐bound iodate(I) complex 3 d provides iodine azide (5), which under photocatalytic conditions undergoes homolytic cleavage to yield the azide 6 and iodine radical (7). While 7 is able to recombine to form I2, the corresponding dimerization of the azide radical (6) to form N6 is not reported. The azide radical (6) is able to add to alkenes and the newly formed radical I can be trapped by the iodine or the azide radicals 6 and 7 or by TEMPO. The azide radical (6) also enforces C−H abstraction next to a C−O bond such as in tetrahydrofuran or alcohols. In the former example this was proven by isolation of the TEMPO adduct, while in the second case the corresponding ketones formed from secondary alcohols via the ketyl radicals II. Primary alcohols also form intermediate II but the resulting aldehyde undergoes a second C−H abstraction to yield an acyl radical III. This is trapped by 6 to yield acyl azides, which may undergo the Curtius rearrangement with final addition of HN3 to the intermediate isocyanate.

Scheme 10.

Scheme 10

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Proposed mechanistic considerations for radical processes reported here.

In essence, we have showed that the polymer‐bound bisazido(iodate(I)) anion 3 d is the most versatile source of the azide radical (6) in photocatalytic reactions.30 It performs azidooxygenations of alkenes and C−H abstractions of ethers and alcohols.

Conflict of interest

The authors declare no conflict of interest.

Supporting information

As a service to our authors and readers, this journal provides supporting information supplied by the authors. Such materials are peer reviewed and may be re‐organized for online delivery, but are not copy‐edited or typeset. Technical support issues arising from supporting information (other than missing files) should be addressed to the authors.

Supplementary

Click here for additional data file. (4.2MB, pdf)

Acknowledgements

This work was funded in part by the BMBF (project: SILVIR, grant no. 16GW0202). Dr. J. Fohrer (Leibniz University Hannover) is thanked for support in NMR analyses. We thank Alexey Stepanyuk (Leibniz University Hannover) for expert technical assistance.

T. Kösel, G. Schulz, G. Dräger, A. Kirschning, Angew. Chem. Int. Ed. 2020, 59, 12376.

In memory of Prof. Rolf Huisgen

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

As a service to our authors and readers, this journal provides supporting information supplied by the authors. Such materials are peer reviewed and may be re‐organized for online delivery, but are not copy‐edited or typeset. Technical support issues arising from supporting information (other than missing files) should be addressed to the authors.

Supplementary

Click here for additional data file. (4.2MB, pdf)

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