Skip to main content
NCBI home page
ACS Organic & Inorganic Au logoLink to ACS Organic & Inorganic Au
. 2022 May 9;2(5):392–395. doi: 10.1021/acsorginorgau.2c00017

Radical-Mediated Functionalization of Internal Alkenes: Synthesis of Multisubstituted Allylic and Homoallylic Azides

Yasu Chen †, Jie Wang †, Xinxin Wu †, Chen Zhu †,‡,*
PMCID: PMC9955241  PMID: 36855664

Abstract

graphic file with name gg2c00017_0006.jpg

Radical-mediated functionalization of alkenes provides a powerful tool for transformation of simple alkenes into numerous value-added products. The precedent radical functionalization of alkenes is mainly restricted to terminal alkenes, while the conversion of internal alkenes generally remains challenging, as the increased steric congestion on alkenes significantly conflicts with the intermolecular addition of radicals. Herein, we describe an efficient photoredox catalytic functionalization of internal trisubstituted alkenes, leading to a plethora of valuable multifunctionalized allylic and homoallylic azides, which are otherwise difficult to obtain. The azide products serve as versatile feedstock for construction of useful heterocycles. Allylic or homoallylic azides are selectively generated in the transformation, regulated by the regioselective deprotonation process. This method also features mild reaction conditions and high product diversity.

Keywords: radical reaction, azide, internal alkene, photoredox catalysis, fluoroalkyl, N-heterocycle

Organic azides are versatile synthetic intermediates that provide access to a diversity of nitrogenous compounds.1−3 Their synthetic utility is extensively illustrated by participating in many useful organic and bio-orthogonal transformations, such as the “click” reaction (Huisgen cycloaddition),4−6 Staudinger ligation,7,8 Curtius rearrangement,9 and the Schmidt reaction.10 Therefore, the preparation of organic azides is of considerable importance in interdisciplinary fields crossing synthetic chemistry, chemical biology, and materials sciences. Allylic azides are a unique azide subclass and heavily suffer from the Winstein rearrangement that can occur at room temperature or even lower temperatures.11,12 Consequently, they often exist as the form of regioisomeric mixtures. Development of practical approaches to access allylic azides, in particular, multifunctionalized allylic azides, as single regioisomers, is in high demand.

Radical-mediated functionalization of alkenes supplies a powerful tool for conversion of simple alkenes to numerous value-added products.13−18 We apply this strategy for the formation of structurally complex multisubstituted allylic and homoallylic azides that are otherwise difficult to obtain.19−22 In our hypothesis, oxidative quenching of the excited photocatalyst (PC*) by alkyl bromide 2 generates an alkyl radical, which then adds to 1,1-disubstituted allylic azide 1 (or 4). The resulting radical intermediate a can be single-electron oxidized by PC•+, leading to the cation species b. Deprotonation of b gives rise to allylic azide 3 (or homoallylic azide 5).23 However, the precedent radical functionalization of alkenes is mainly restricted to terminal alkenes, whereas the conversion of internal alkenes usually remains challenging,24 as the increased steric congestion on alkenes significantly conflicts with the intermolecular addition of radicals (Scheme 1A).

Scheme 1. Synthesis of Multisubstituted Allylic and Homoallylic Azides.

Scheme 1

Open in a new tab

Herein, we provide a proof-of-principle experimental study for the hypothesis (Scheme 1B). An efficient radical-mediated functionalization of internal alkenes is disclosed, selectively generating allylic and homoallylic azides dependent on the substitution of substrates. The product diversity and complexity can be improved by simply altering external radicals. The transformation features mild photoredox catalytic conditions and unique regioselectivity. The azide products serve as versatile feedstock for construction of useful heterocycles.

At the outset, the easily accessed 1,1-diphenyl allylic azide 1a was harnessed as the starting material and reacted with bromodifluoroacetate 2a to survey the reaction parameters (Table 1). Under photochemical conditions,25−29 evaluation of photosensitizers indicated that fac-Ir(ppy)3 delivered the best catalytic efficiency (entries 1–6). A series of inorganic and organic bases was then investigated (entries 7–12). The use of K2HPO4 significantly improved the reaction outcome, which might neutralize the HBr generated in situ during the reaction. Among the common solvents examined, 1,2-dichloroethane (DCE) further improved the yield to 74% (entries 13–18).

Table 1. Reaction Parameter Surveya.

graphic file with name gg2c00017_0005.jpg

entry PC base solvent yield (%)b
1 4CzIPN K2CO3 DMF 12
2 Ru(bpy)3(PF6)2 K2CO3 DMF 15
3 PTH K2CO3 DMF 0
4 cat. 1c K2CO3 DMF 16
5 cat. 2d K2CO3 DMF 8
6 fac-Ir(ppy)3 K2CO3 DMF 41
7 fac-Ir(ppy)3 K3PO4 DMF 42
8 fac-Ir(ppy)3 K2HPO4 DMF 62
9 fac-Ir(ppy)3 KH2PO4 DMF 52
10 fac-Ir(ppy)3 Na2HPO4 DMF 52
11 fac-Ir(ppy)3 NaOH DMF 51
12 fac-Ir(ppy)3 Et3N DMF 38
13 fac-Ir(ppy)3 K2HPO4 THF 31
14 fac-Ir(ppy)3 K2HPO4 CH3CN 60
15 fac-Ir(ppy)3 K2HPO4 DMSO 19
16 fac-Ir(ppy)3 K2HPO4 DCM 68
17 fac-Ir(ppy)3 K2HPO4 DCE 74
18 fac-Ir(ppy)3 K2HPO4 EtOAc 46
Open in a new tab
a

Reaction conditions: 1a (0.2 mmol, 1.0 equiv), 2a (0.4 mmol, 2.0 equiv), photocatalyst (2 mol %), and base (0.2 mmol, 1.0 equiv) in solvent (2.0 mL) under N2, irradiated with 15 W blue LEDs at rt.

b

Isolated yield.

c

Cat. 1 = Ir[dF(CF3)ppy]2(dtbbpy)(PF6).

d

Cat. 2 = Ir(ppy)2(dtbbpy)(PF6). 4CzIPN = 1,2,3,5-tetrakis(carbazol-9-yl)-4,6-dicyanobenzene. PTH = 10-phenylphenothiazine.

With the optimized reaction conditions in hand, we assessed the generality of the protocol (Figure 1). A set of symmetric 1,1-diaryl allylic azides 1b–1e was first examined in the reaction with 2a. The substrates bearing either electron-donating (e.g., methoxy) or electron-withdrawing (e.g., halides) groups were compatible with the reaction, leading to the desired products 3b–3e in comparable yields. Unsymmetric 1,1-diaryl substrates also readily afforded the corresponding products 3f–3q in useful yields, but the products were obtained, in general, as a mixture of Z/E isomers. Positional change (from para to meta or ortho) on the aryl substitution to phenyl, naphthyl, and heteroaryl, such as benzofuryl, was also tolerated in the transformation (3p and 3q). The reaction using the congeners bromodifluoromethyl sulfone 2b, bromomonofluoroacetate 2c, bromoacetate 2d, and bromopropanoate 2e instead of 2a consistently gave rise to the desired products in synthetically useful yields (3r–3u). This approach demonstrated a high product diversity in which the tetrasubstituted allylic azides can be easily modified by variation of external radicals and substrates. It should be noted that monoaryl substrates, such as (3-azidoprop-1-en-1-yl)benzene, were not amenable to the reaction, as the reaction proceeded via an alternative atom transfer radical addition (ATRA) process and gave the corresponding bromide product.

Figure 1.

Figure 1

Open in a new tab

Reaction scope. aReaction conditions: 1 (0.2 mmol, 1.0 equiv), 2 (0.4 mmol, 2.0 equiv), fac-Ir(ppy)3 (2 mol %), and K2HPO4 (0.2 mmol, 1.0 equiv) in DCE (2.0 mL) under N2, irradiated with 15 W blue LEDs at rt. The yields of isolated products are given. bZ/E = 1/1. cZ/E = 2/1. dZ/E = 1.4/1. eZ/E = 1.5:1.

The protocol could be extended to the synthesis of homoallylic azides starting from alkyl-substituted materials. Some representative examples are illustrated in Figure 2. Under the same conditions, the use of 1-methyl-1-phenyl allylic azide 4a furnished homoallylic azide 5a via the regioselective deprotonation to generate terminal alkene instead of internal alkene. It might be attributed to base-promoted deprotonation which generally prefers a less hindered site. Changing the electronic property of phenyl by installation of functionalities might impact the outcome of the reaction (5b). The consumption of 4a and 4b should be carefully monitored in the reaction, as the over-reaction involving the generated 5a and 5b significantly decreased the yields. Altering methyl to other alkyl (e.g., ethyl and butyl) groups resulted in the corresponding products (5c and 5d), of which (Z)-alkenes are the major isomers. The configuration of 5c was determined by the NOE NMR analysis, where the allylic CH3 group has a correlation with the phenyl C–H bonds, and the alkenyl C–H bond shows the correlation with the CH2 moiety adjacent to azide. It could be anticipated that more homoallylic azide products could be afforded by varying either the aryl or the alkyl substituents. Surprisingly, the reaction with the substrate bearing a benzyl group was messy, and only a trace amount of corresponding product 5e was detected by the mass spectrum.

Figure 2.

Figure 2

Open in a new tab

Representative examples for synthesis of allylic azides. aReaction conditions: 4 (0.2 mmol, 1.0 equiv), 2a (0.4 mmol, 2.0 equiv), fac-Ir(ppy)3 (2 mol %), and K2HPO4 (0.2 mmol, 1.0 equiv) in DCE (2.0 mL) under N2, irradiated with 15 W blue LEDs at rt. The yields of isolated products are given.

The practicality of the method could be illustrated by the gram-scale preparation, leading to a synthetically useful yield of 3a (Figure 3A). Allylic azide 3a serves as a versatile intermediate to construct various nitrogenous heteroarenes (Figure 3B). For instance, irradiation of the reaction of 3a with NBS under compact fluorescent light resulted in the difluoroalkyl-substituted quinoline 6.30 Treatment of 3a with PPh3 delivered the α,α-difluorobutyrolactam 7 via the Staudinger reduction of azide to amine followed by intramolecular cyclization. Furthermore, the existence of azide provides a platform of “click” reaction to attach the tetrasubstituted alkene to bioactive molecules (8), such as ethynyl estradiol 3-methyl ether.

Figure 3.

Figure 3

Open in a new tab

Gram-scale synthesis and product transformations.

In summary, we have disclosed an efficient photoredox catalytic approach for elusive radical-mediated functionalization of internal trisubstituted alkenes. A portfolio of valuable multifunctionalized allylic and homoallylic azides are obtained in synthetically useful yields. The regioselective deprotonation leading to different products is predominated by the substitution of substrates. The products serve as versatile feedstock for the construction of useful nitrogenous heterocycles. The protocol features mild reaction conditions and high product diversity and paves a new avenue for the synthesis of complex azides.

Acknowledgments

We are grateful for the financial support from the National Natural Science Foundation of China (Grant Nos. 21971173, 22001185, and 22171201), the Project of Scientific and Technologic Infrastructure of Suzhou (SZS201905), and the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD).

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsorginorgau.2c00017.

  • All experimental details including further optimization studies; detailed procedures; proper characterization of all products; and copies of 1H, 19F, 13C NMR, and NOE spectra (PDF)

Author Contributions

Y.C. and J.W. contributed equally. Y.C. and J.W. performed all experiments. Y.C., J.W., X.W., and C.Z. conceived the project and analyzed the results. C.Z. wrote the manuscript with the input of all the authors.

The authors declare no competing financial interest.

Supplementary Material

gg2c00017_si_001.pdf (11.3MB, pdf)

References

  1. Brase S.; Gil C.; Knepper K.; Zimmermann V. Organic Azides: An Exploding Diversity of a Unique Class of Compounds. Angew. Chem., Int. Ed. 2005, 44, 5188–5240. 10.1002/anie.200400657. [DOI] [PubMed] [Google Scholar]
  2. Evano G.Organic Azides: Syntheses and Applications; John Wiley & Sons, Ltd.: Chichester, U.K., 2010. [Google Scholar]
  3. Lapointe G.; Kapat A.; Weidner K.; Renaud P. Radical Azidation Reactions and Their Application in the Synthesis of Alkaloids. Pure. Appl. Chem. 2012, 84, 1633–1641. 10.1351/PAC-CON-11-11-21. [DOI] [Google Scholar]
  4. Kolb H. C.; Finn M. G.; Sharpless K. B. Click Chemistry: Diverse Chemical Function from a Few Good Reaction. Angew. Chem., Int. Ed. 2001, 40, 2004–2021. 10.1002/1521-3773(20010601)40:11<2004::AID-ANIE2004>3.0.CO;2-5. [DOI] [PubMed] [Google Scholar]
  5. Kolb H. C.; Sharpless K. B. The Growing Impact of Click Chemistry on Drug Discovery. Drug Discovery Today. 2003, 8, 1128–1137. 10.1016/S1359-6446(03)02933-7. [DOI] [PubMed] [Google Scholar]
  6. Meldal M.; Tornøe C. W. Cu-Catalyzed Azide–Alkyne Cycloaddition. Chem. Rev. 2008, 108, 2952–3015. 10.1021/cr0783479. [DOI] [PubMed] [Google Scholar]
  7. Kohn M.; Breinbauer R. The Staudinger Ligation-A Gift to Chemical Biology. Angew. Chem., Int. Ed. 2004, 43, 3106–3116. 10.1002/anie.200401744. [DOI] [PubMed] [Google Scholar]
  8. Sletten E. M.; Bertozzi C. R. From Mechanism to Mouse: A Tale of Two Bioorthogonal Reactions. Acc. Chem. Res. 2011, 44, 666–676. 10.1021/ar200148z. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Lebel H.; Leogane O.; Huard K.; Lectard S. Catalytic Activation of Nitrogen Derivatives with Transition-metal Complexes. Pure Appl. Chem. 2006, 78, 363–375. 10.1351/pac200678020363. [DOI] [Google Scholar]
  10. Lang S.; Murphy J. A. Azide Rearrangements in Electron-Deficient Systems. Chem. Soc. Rev. 2006, 35, 146–156. 10.1039/B505080D. [DOI] [PubMed] [Google Scholar]
  11. Gagneux A.; Winstein S.; Young W. G. Rearrangement of Allylic Azides. J. Am. Chem. Soc. 1960, 82, 5956–5957. 10.1021/ja01507a045. [DOI] [Google Scholar]
  12. Carlson A. S.; Topczewski J. J. Allylic Azides: Synthesis, Reactivity, and the Winstein Rearrangement. Org. Biomol. Chem. 2019, 17, 4406–4429. 10.1039/C8OB03178A. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Pintauer T.; Matyjaszewski K. Atom Transfer Radical Addition and Polymerization Reactions Catalyzed by ppm Amounts of Copper Complexes. Chem. Soc. Rev. 2008, 37, 1087–1097. 10.1039/b714578k. [DOI] [PubMed] [Google Scholar]
  14. Eckenhoff W. T.; Pintauer T. Copper Catalyzed Atom Transfer Radical Addition (ATRA) and Cyclization (ATRC) Reactions in the Presence of Reducing Agents. Catal. Rev. 2010, 52, 1–59. 10.1080/01614940903238759. [DOI] [PubMed] [Google Scholar]
  15. Wu X.; Wu S.; Zhu C. Radical-mediated Difunctionalization of Unactivated Alkenes through Distal Migration of Functional Groups. Tetrahedron Lett. 2018, 59, 1328–1336. 10.1016/j.tetlet.2018.02.053. [DOI] [Google Scholar]
  16. Wu X.; Zhu C. Radical-Mediated Remote Functional Group Migration. Acc. Chem. Res. 2020, 53, 1620–1636. 10.1021/acs.accounts.0c00306. [DOI] [PubMed] [Google Scholar]
  17. Li Z. L.; Fang G. C.; Gu Q. S.; Liu X. Y. Recent Advances in Copper-catalysed Radical-involved Asymmetric 1,2-Difunctionalization of Alkenes. Chem. Soc. Rev. 2020, 49, 32–48. 10.1039/C9CS00681H. [DOI] [PubMed] [Google Scholar]
  18. Jiang H.; Studer A. Intermolecular Radical Carboamination of Alkenes. Chem. Soc. Rev. 2020, 49, 1790–1811. 10.1039/C9CS00692C. [DOI] [PubMed] [Google Scholar]
  19. Rueping M.; Vila C.; Uria U. Direct Catalytic Azidation of Allylic Alcohols. Org. Lett. 2012, 14, 768–771. 10.1021/ol203310h. [DOI] [PubMed] [Google Scholar]
  20. Sawama Y.; Shibata K.; Sawama Y.; Takubo M.; Monguchi Y.; Krause N.; Sajiki H. Iron-Catalyzed Ring-Opening Azidation and Allylation of O-Heterocycles. Org. Lett. 2013, 15, 5282–5285. 10.1021/ol402511r. [DOI] [PubMed] [Google Scholar]
  21. Pramanik S.; Ghorai P. Chemoselective Three-component Synthesis of Homoallylic Azides Using an FeCl3 Catalyst. RSC Adv. 2013, 3, 23157–23165. 10.1039/c3ra42821d. [DOI] [Google Scholar]
  22. Vita M. V.; Caramenti P.; Waser J. Enantioselective Synthesis of Homoallylic Azides and Nitriles via Palladium-Catalyzed Decarboxylative Allylation. Org. Lett. 2015, 17, 5832–5835. 10.1021/acs.orglett.5b03002. [DOI] [PubMed] [Google Scholar]
  23. Tang S.; Liu K.; Liu C.; Lei A. Olefinic C–H Functionalization through Radical Alkenylation. Chem. Soc. Rev. 2015, 44, 1070–1082. 10.1039/C4CS00347K. [DOI] [PubMed] [Google Scholar]
  24. Xiong T.; Zhang Q. Recent Advances in the Direct Construction of Enantioenriched Stereocenters through Addition of Radicals to Internal Alkenes. Chem. Soc. Rev. 2021, 50, 8857–8873. 10.1039/D1CS00208B. [DOI] [PubMed] [Google Scholar]
  25. Zhang H. H.; Chen H.; Zhu C.; Yu S. A Review of Enantioselective Dual Transition Metal/Photoredox Catalysis. Sci. China Chem. 2020, 63, 637–647. 10.1007/s11426-019-9701-5. [DOI] [Google Scholar]
  26. Yoon T. P.; Ischay M. V.; Du J. Visible Light Photocatalysis as a Greener Approach to Photochemical Synthesis. Nat. Chem. 2010, 2, 527–532. 10.1038/nchem.687. [DOI] [PubMed] [Google Scholar]
  27. Narayanam J. M. R.; Stephenson C. R. G. Visible Light Photoredox Catalysis: Applications in Organic Synthesis. Chem. Soc. Rev. 2011, 40, 102–113. 10.1039/B913880N. [DOI] [PubMed] [Google Scholar]
  28. Xuan J.; Xiao W. J. Visible-Light Photoredox Catalysis. Angew. Chem., Int. Ed. 2012, 51, 6828–6838. 10.1002/anie.201200223. [DOI] [PubMed] [Google Scholar]
  29. Prier C. J.; Rankic D. A.; MacMillan D. W. C. Visible Light Photoredox Catalysis with Transition Metal Complexes: Applications in Organic Synthesis. Chem. Rev. 2013, 113, 5322–5363. 10.1021/cr300503r. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Wang W. X.; Zhang Q. Z.; Zhang T. Q.; Li Z. S.; Zhang W.; Yu W. N-Bromosuccinimide-Mediated Radical Cyclization of 3-Arylallyl Azides: Synthesis of 3-Substituted Quinolines. Adv. Synth. Catal. 2015, 357, 221–226. 10.1002/adsc.201400637. [DOI] [Google Scholar]

Associated Data

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

Supplementary Materials

gg2c00017_si_001.pdf (11.3MB, pdf)

Articles from ACS Organic & Inorganic Au are provided here courtesy of American Chemical Society

RESOURCES