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. 2023 Oct 9;145(41):22347–22353. doi: 10.1021/jacs.3c09122

Iron-Mediated Photochemical Anti-Markovnikov Hydroazidation of Unactivated Olefins

Henry Lindner 1, Willi M Amberg 1, Erick M Carreira 1,*
PMCID: PMC10591317  PMID: 37811819

Abstract

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Unactivated olefins are converted to alkyl azides with bench-stable NaN3 in the presence of FeCl3·6H2O under blue-light irradiation. The products are obtained with anti-Markovnikov selectivity, and the reaction can be performed under mild ambient conditions in the presence of air and moisture. The transformation displays broad functional group tolerance, which renders it suitable for functionalization of complex molecules. Mechanistic investigations are conducted to provide insight into the hydroazidation reaction and reveal the role of water from the iron hydrate as the H atom source.

Organic azides are an integral part of an array of drug molecules, energetic materials, and chemical probes.1 They also are valuable building blocks in the synthesis of natural products, pharmaceuticals, and agrochemicals.2 As synthetic handles, azides have found widespread application in classic methods such as Staudinger reduction and ligation,3 Huisgen cycloaddition4 and click chemistry,5 as well as Schmidt6 and aza-Wittig reactions.7 More recently, azides have been utilized as nitrene precursors in transition-metal-catalyzed C–H bond aminations.8 Especially in the context of multistep synthesis, R–N3 can serve as a protected amine.9 Herein, we report the first iron- and light-mediated anti-Markovnikov hydroazidation of unactivated olefins (Figure 1). The transformation employs NaN3 as a bench-stable10 azide source, tolerates air and moisture, and proceeds under mild conditions allowing for a wide functional group compatibility.

Figure 1.

Figure 1

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Iron-mediated photochemical anti-Markovnikov hydroazidation of unactivated olefins.

The widespread application of organic azides in synthetic chemistry and biology necessitates methodologies to access them directly from readily available starting materials. Traditionally, organic azides have been synthesized via nucleophilic substitution as well as diazo- and azido-transfer reactions.11 In a complementary approach, direct transformations of olefins to alkyl azides have been explored. Early studies by Hassner and Kropp focused on the addition of HN3 to alkenes, affording the corresponding Markovnikov products (Figure 2A).12

Figure 2.

Figure 2

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Approaches toward (A) Markovnikov and (B) anti-Markovnikov hydroazidation of unactivated olefins and (C) desired transformation.

Milder and more broadly applicable conditions for the Markovnikov hydroazidation of unactivated olefins were developed in our group which employ a cobalt catalyst, silane, and TsN3.13 Boger later disclosed a Markovnikov hydroazidation that is presumed to proceed via an iron hydride species.14 To obtain anti-Markovnikov addition products, multistep sequences were required. Only recently has the direct anti-Markovnikov azidation of double bonds been reported (Figure 2B). Chiba and Gagosz have investigated a hypervalent iodine reagent (azidobenziodoxolone, ABX) for the hydroazidation of homoallylic benzyl ethers with the latter serving as intramolecular H atom donor in the reaction.15 Yu and co-workers have documented a hydroazidation reaction of unsaturated aryl amides using an Ir photocatalyst and TMSN3.16 Most recently, Xu and Liu independently generated the active hypervalent iodine reagent ABX in situ from TMSN3 and a benziodoxolone to achieve anti-Markovnikov hydroazidation.17 Despite these important advances, convenient procedures using NaN3 as an off-the-shelf, inexpensive azide source are lacking.

Our interest in metal-mediated olefin hydroazidation reactions and, more recently, alkene functionalization and photochemical methods has led us to examine approaches to alkyl azides.13,18 Applications of transition-metal salts (e.g., CuII, TiIV, and FeIII) under visible-light irradiation caught our attention.19 The excitation of these salts with visible light induces ligand-to-metal charge transfer (LMCT), resulting in, for example, dichlorination, diazidation, or Giese reaction.19c−19g,20 We focused on the most abundant transition metal and hypothesized that the use of radicals generated from an iron complex under blue-light irradiation may be suitable to effect hydroazidation in a mild and selective manner. To this end, 4-phenylbutene (1a) was subjected to NaN3 (3.0 equiv) and Fe(NO3)3·9H2O (1.0 equiv) in dichloromethane (0.2 M) and irradiated (λmax = 446 nm, 350 W blue LED photoreactor; for technical details see the Supporting Information) for 16 h at room temperature. In this experiment, primary azide 2a was observed in 36% yield (Table 1, entry 1). Further studies revealed that FeCl3·6H2O in CH2Cl2 afforded the highest yield among all investigated iron salts (for details see the Supporting Information). As azides are known to displace the chlorides in CH2Cl2, subsequently generating highly explosive intermediates,21 solvent alternatives were investigated. The use of polar solvents such as acetone, ethyl acetate, and MeCN did not yield any hydroazidation, instead giving the diazide in a range of yields (for details see the Supporting Information).19c,19d In contrast, employing less polar solvents such as haloarenes yielded monoazide in a good yield. Of the alternatives investigated, α,α,α-trifluorotoluene (PhCF3) performed best. Under optimized conditions (1.5 equiv of FeCl3·6H2O, 3.0 equiv of NaN3, PhCF3 (0.2 M), 0 °C for 16 h, blue LEDs, entry 2), 2a was formed in 83% yield.

Table 1. Optimization of the Reaction Conditions.

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entry deviation from standard conditions 2aa (%)
1 Fe(NO3)3·9H2O (1.0 equiv), CH2Cl2, rt 36
2 none 83
3 TMSN3 instead of NaN3 17
4 no iron salt 0
5 no light 0
6 FeCl3 instead of FeCl3·6H2O <5
7 40 W blue LED Kessil light, rt 80
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a

Yield obtained by 1H NMR with mesitylene as internal standard.

Control experiments were performed to gain further insights into the transformation (for details including oxygen sensitivity, see the Supporting Information). When the reaction was conducted with TMSN3 under otherwise identical conditions, 2a was produced in 17% yield (entry 3). The reaction did not provide the product in the absence of iron salt or light, and 1a was fully recovered (entries 4 and 5). If anhydrous FeCl3 was used in oven-dried glassware under otherwise identical conditions, merely traces of the product were formed, indicating the necessity of water (entry 6). When using a 40 W blue LED Kessil light at 25% intensity, the best results were obtained at room temperature (entry 7; for details see the Supporting Information).

With the optimized conditions in hand, we set out to investigate the functional group tolerance of the hydroazidation reaction (Figure 3). To this end, a variety of alkyl azides were accessed in moderate to high yields from the corresponding alkenes.22 When vinyl silane 1b was subjected to the reaction conditions, β-silyl azide 2b was obtained in 80% yield. Alkyl azides 2c and 2d were isolated in yields of 73 and 80% from primary haloalkenes 1c and 1d. Notably, no substitution of either chloride or bromide was observed under the reaction conditions. 1-Dodecene yielded 2e in 86% yield. A variety of electron-poor and -rich arenes were tolerated, furnishing 2f–2h in 81–90% yield. Substrates containing protic groups, such as alcohol 1i, tosyl amide 1j, carbamate 1k, and N-tosyl imide 1l, were converted to the corresponding azides in 65–82% yield. Acid-labile t-BuMe2Si-protected alcohol 1m afforded 2m in 61% yield. Methyl carbonate 1n and thioether 1o were competent under reaction conditions, resulting in 2n and 2o in 85 and 43% yield, respectively. Azides 2p–2s were accessed in 62–75% yield. Markedly, alkenes bearing a heterocycle, such as thiophene, furan, phthalimide, oxetane, and pyridine, were also well tolerated and gave rise to products 2t–2x in 44–86% yield. The practical aspects of the method were demonstrated by the synthesis of 2a on a larger scale (2.0 mmol) in 75% yield. All terminal olefins underwent anti-Markovnikov hydroazidation in excellent selectivity (rr =12:1 to >20:1; for details see the Supporting Information).

Figure 3.

Figure 3

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Substrate scope. Reaction conditions: olefin (0.20 mmol), NaN3 (0.60 mmol), FeCl3·6H2O (0.30 mmol) in PhCF3 (1.0 mL), irradiation in 350 W photoreactor at 0 °C for 16 h. dr determined by 1H NMR of the unpurified reaction mixture. aCarried out on 2.0 mmol scale with a 40 W blue LED Kessil light at rt. bYield obtained by 1H NMR with mesitylene as internal standard. c8 h reaction time.

Next, the effects of the alkene substitution patterns were examined. The reaction was amenable to di-, tri-, and tetrasubstituted olefins. 1,1-Disubstituted olefins 1y to 1aa afforded primary azides in 73–78% yield. Substrates bearing a tosylate, malonate, acetal, or carbamate were successfully converted to products 2ab–2ae in 40–75% yield. β-Adamantyl azide 2af was accessed in 77% yield. Acyclic and cyclic 1,2-disubstituted alkenes were subjected to the reaction conditions, furnishing the corresponding azides 2ag–2aj in 51–83% yield. Strained olefins, in particular norbornene and dicyclopentadiene, were hydroazidated in high yield (80 and 85%, respectively).23 Trisubstituted olefins were well tolerated, giving rise to secondary azides with 2am and 2an isolated in 63 and 52% yield. All di- and trisubstituted olefins employed underwent anti-Markovnikov azidation in good regioselectivity (for details see the Supporting Information). Finally, tetrasubstituted alkenes 1ao and 1ap yielded 2ao and 2ap in 66 and 45% yield, respectively.

Encouraged by the broad functional group tolerance of the hydroazidation reaction, we set out to explore the generality of the protocol in a more complex setting. An array of alkenes derived from active pharmaceutical ingredients and natural products was subjected to the reaction conditions (Figure 4). To our delight, these substrates led to the formation of desired azides 4a–4u in good yields (40–86%). In particular, molecules featuring diversely substituted arenes and heterocycles, such as oxazoles, indoles, thiazoles, β-lactams, and diazoles were well tolerated, indicating the potential of this method for late-stage application.

Figure 4.

Figure 4

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Substrate scope for olefins derived from natural products and drugs. dr determined by 1H NMR of the unpurified reaction mixture.

In order to deal with the volatility and inherent risk of low-molecular-weight azides, we examined several transformations subsequent to hydroazidation. One-pot procedures would avoid work-up, solvent evaporation, purification, isolation, and handling of the azide intermediates (Scheme 1). First, attempts to perform a Cu(I)-catalyzed azide–alkyne click reaction in situ were unsuccessful. We observed that the addition of NEt3 was crucial for the formation of triazole 7a in 76% yield. When cyclooctyne was employed as a reaction partner, triazole 7b was isolated in 54% yield from volatile azide 2ao. Primary amine 7c was accessed in 72% yield through Pd-catalyzed hydrogenation, and Staudinger reduction of cyclohexyl azide 2ah with subsequent Boc-protection furnished the corresponding carbamate 7d in 62% yield.

Scheme 1. Sequential One-Pot Transformations.

Scheme 1

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To gain mechanistic insights into the hydroazidation, a series of experiments was conducted (Figure 5). Initial investigations focused on determining whether radical species are involved in the reaction. The addition of 2.0 equiv TEMPO as radical scavenger24 under standard conditions suppressed the reaction, and no hydroazidation product could be detected by either 1H NMR or HRMS. Instead, alkene starting material was recovered.

Figure 5.

Figure 5

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Mechanistic investigations and the proposal of a plausible mechanistic construct. dr determined by 1H NMR of the unpurified reaction mixture. aYield obtained by 1H NMR with mesitylene as internal standard.

In the context of our examination of the substrate scope, when aldehyde 8 was subjected to the standard reaction conditions, we observed 1-azido-4-methylpentane (9) as the sole product (Figure 5B). This is consistent with the formation of a secondary carbon-centered radical from the olefin followed by a 1,5-radical hydrogen atom abstraction from the aldehyde. Decarbonylation affords the more stable tertiary radical which is quenched.25

This result prompted us to examine substrates 10a and 10b which could undergo 5-exo-trig cyclization reactions (Figure 5C). N-Tosyl diallyl amine furnished pyrrolidine 11a in 55% yield, and diethyl diallylmalonate delivered the corresponding cyclopentyl product 11b in 79% yield. For both substrates, only cyclization products were isolated, suggesting that quenching is slower than cyclization for 10a and 10b.26

It has been proposed in the literature that under visible-light irradiation Fe(III) azides generate Fe(II) salts along with azidyl radicals.19c,19d Based on these reports, in the system we describe the azidyl radical can then add (anti-Markovnikov) to the olefin to provide a reactive carbon-centered radical.27 This intermediate is ultimately quenched by an H atom donor. Accordingly, we set out to identify the origin of the hydrogen atom involved in the quenching.

It has previously been observed that hydrates of boron (Me3B·OH2) and titanium (Cp2ClTi·OH2) serve as H atom donors in radical reactions.28 Consequently, we hypothesized that the iron-bound water in FeCl3·6H2O might be involved as an H atom source. In an experiment in oven-dried glassware under a nitrogen atmosphere, D2O was added to anhydrous FeCl3 followed by addition of PhCF3/NaN3/4-phenylbutene (Figure 5D). After being stirred for 16 h under blue-light irradiation, azidodeuterated product 2a-D1 was isolated in 18% yield. In parallel experiments using H2O under otherwise identical conditions, product 2a was obtained in 77% yield. The difference in yield between the two experiments suggests a strong primary kinetic isotope effect (kH/kD ≫ 1; for details see the Supporting Information). These data support water as the terminal H atom source and indicate that the H atom transfer to the secondary carbon-centered radical likely is the rate-limiting step of the transformation.17a,29 Although free water is not known to be an H atom source (HBDE(HO–H) = 118 kcal/mol), its coordination to iron dramatically decreases the bond-dissociation energy (HBDE(FeII(H2O)5(HO–H)) = 77 kcal/mol).30,31 Our observation of solvent effects described in the optimization reactions suggests that the nature of the solvent affects speciation of Fe(III) complexes in the presence of azide and chloride counterions as well as water. Further mechanistic studies to understand the nature of Fe complexes formed, including μ2-bridged dimers, are clearly necessary as they may provide additional avenues for the development of new transformations.32

In conclusion, we have developed a photochemical anti-Markovnikov hydroazidation of unactivated alkenes with FeCl3·6H2O. The transformation shows broad functional group tolerance and was amenable to terminal as well as highly substituted olefins. Salient features of the reaction are its tolerance to air and moisture and the successful use of NaN3 as a bench-stable, low-cost, and easy-to-handle azide source. We demonstrated that the simplicity and generality of this method make it ideally positioned for late-stage applications, allowing for the efficient and versatile synthesis of diverse organic azides featuring biologically active motifs.

Acknowledgments

This work was funded by the European Research Council (OLECAT, Grant ID 833540). We are grateful to Dr. M.-O. Ebert, R. Frankenstein, S. Burkhardt, and R. Arnold for support with NMR experiments, Dr. N. Trapp and M. Solar for X-ray crystallographic analysis, and C. A. Bärtschi, C. Marro, and H. Benz for the maintenance and construction of the photoreactor (all ETH Zürich). W.M.A. is grateful for partial support with funding from the SSCI (Scholarship Fund of the Swiss Chemical Industry).

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacs.3c09122.

  • Experimental procedures and characterization data (PDF)

The authors declare no competing financial interest.

Supplementary Material

ja3c09122_si_001.pdf (18.2MB, pdf)

References

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