Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Iron-Catalyzed Three-Component Reaction: Synthesis of Fluoroalkylated 2H‑Azirines Nagarajan Ramkumar,† Luc Van Meervelt,‡ and Erik V. Van der Eycken*,†,§ †
Laboratory for Organic & Microwave-Assisted Chemistry (LOMAC) and ‡Biomolecular Architecture, Department of Chemistry, University of Leuven (KULeuven), Celestijnenlaan 200F, B-3001 Leuven, Belgium § Peoples’ Friendship University of Russia (RUDN University), 6 Miklukho-Maklaya Street, Moscow 117198, Russia Org. Lett. Downloaded from pubs.acs.org by KAOHSIUNG MEDICAL UNIV on 11/21/18. For personal use only.
S Supporting Information *
ABSTRACT: A convenient route for the synthesis of fluoroalkylated 2H-azirines has been developed, involving an iron-catalyzed azidoperfluoroalkylation of alkynes with perfluoroalkyl iodides and trimethylsilyl azide. This novel alkyne difunctionalization reaction produces versatile fluoroalkylated 2H-azirines, paving the way for further modifications into various heterocycles.
addition (ATRA) mechanism and the use of Togni’s reagents and Umemoto’s reagents for introducing the trifluoromethyl group (−CF3).9 Compared to these expensive trifluoromethylating reagents, perfluoroalkyl iodides are less expensive and more suitable for large-scale synthesis.10 The addition of perfluoroalkyl halides RF−X (X = Br, I) to alkynes has been improved in recent years.11 We envisioned that the simultaneous introduction of both an azide and an RF group into an alkyne could allow the efficient synthesis of fluoroalkylated 2H-azirines, thus providing a new route to fluoroalkylated heterocycles. Few methods for the synthesis of these compounds starting from alkynes are presently available.4−6 In significant individual work, Liu5 and Liang6 reported the synthesis of CF3-containing 2H-azirines, employing copper-catalyzed azidotrifluoromethylation of alkynes with Togni’s reagents and TMSN3. We here describe an iron-catalyzed12 three-component synthesis of fluoroalkylated 2H-azirines, starting from alkynes, using readily available RFI including CF3I and TMSN3 as a nitrogen source in the presence of the radical initiator tert-butyl hydroperoxide (TBHP). We commenced our investigations with a radical addition/ nitrogenation/rearrangement sequence by reaction of 1-tertbutyl-4-ethynylbenzene (1a, 0.5 mmol), C4F9I (2a, 0.7 mmol), and TMSN3 (2 mmol) using a catalytic amount of Fe(OTf)2 (10 mol %) in the presence of radical initiator TBHP (2 mmol) in THF (2 mL) at 50 °C for 3 h under N2. To our delight, 56% of target product 3a was detected by NMR analysis (Table 1, entry 1). Other azido compounds, such as NaN3 and TosN3, were not effective (Table 1, entries 2 and 3). Furthermore, catalyst screening showed that both iron(II) and iron(III) catalysts (Table 1, entries 4−6) could deliver the product, but FeCl2 gave the best yield (Table 1, entries 8 and 16). After an intense solvent screening, we found that
2H-Azirines are a class of highly reactive and strained threemembered ring compounds that have been extensively studied for their occurrence in natural products1 (Figure 1) and are also valuable for the synthesis of functionalized N-containing heterocycles.2 Fluorinated heterocyles represent key structural scaffolds in many bioactive compounds and pharmaceuticals due to their high metabolic stability, lipophilicity, and bioavailability.3 In particular, 2H-azirines containing fluoroalkyl groups are impressive synthetic intermediates for the synthesis of various substituted heterocycles.2,4 Therefore, the development of synthetic methods toward fluoroalkylated 2H-azirines are of broad interest due to the unique properties of the fluoroalkyl groups.4−6
Figure 1. Examples of azirine-containing bioactive compounds.
Fluoroalkylation methods of alkynes are an attractive tool due to the availability of the reagents and the great synthetic importance of the resulting products.7 In this regard, alkyne difunctionalization represents a straightforward pathway for the introduction of functional groups. Recently, significant progress has been made in the fluoroalkylation of alkynes by employing transition-metal and visible-light photoredox catalysis.8 These methods operate via an atom transfer radical © XXXX American Chemical Society
Received: October 17, 2018
A
DOI: 10.1021/acs.orglett.8b03324 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Table 1. Optimization of the Reaction Conditionsa
entry
catalyst
solvent
yieldb (%)
1 2c 3d 4 5 6 7 8 9 10 11 12 13 14 15 16 17e 18f 19 20g
Fe(OTf)2 Fe(OTf)2 Fe(OTf)2 Fe(OTf)3 Fe(OTs)3.6H2O FeCl3 Fe(OAc)2 FeCl2 FeCl2 FeCl2 FeCl2 FeCl2 FeCl2 FeCl2 FeCl2 FeCl2 (5 mol %) FeCl2 (5 mol %) FeCl2 (5 mol %) no catalyst FeCl2 (5 mol %)
THF THF THF THF THF THF THF THF DCE dioxane DME toluene DCM DMF CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN
56 23 trace 53 19 22 13 77 65 71 72 8 21 15 81 89 (86) 19 73 0 0
Scheme 1. Scope of Arylacetylenesa
a Reaction conditions: 1a (0.5 mmol), 2a (0.7 mmol), TMSN3 (1 mmol), TBHP (5−6 M in decane) (1 mmol), and 10 mol % catalyst in solvent (2 mL) at 50 °C for 3 h under N2. bYield by NMR analysis of crude mixture with 1,4-dimethoxybenzene as an internal standard; isolated yield in parentheses. cNaN3 was used instead of TMSN3. d TosN3 was used instead of TMSN3. eH2O2 was used instead of TBHP. fTBPB was used instead of TBHP. gNo oxidant. TBHP = tertbutyl hydroperoxide; TPBP = tert-butyl peroxybenzoate
a Reaction conditions: 1 (0.5 mmol), 2a (0.7 mmol), TMSN3 (1 mmol), TBHP (5−6 M in decane) (1 mmol), and 5 mol % FeCl2 in CH3CN (2 mL) at 70 °C for 3 h under N2. Isolated yields. b1 (0.5 mmol), 2a (1.4 mmol), TMSN3 (2 mmol) and TBHP (5−6 M in decane) (2 mmol) were used.
71% yield. The azidoperfluoroalkylation reaction was also examined using an aliphatic alkyne which produced only vinyl azide 3s, instead of the azirine. An azirine-containing estrone 3t was also obtained in 77% yield. In order to demonstrate the synthetic utility of this reaction, a gram-scale experiment was performed, which gave 3b in 62% yield. Furthermore, perfluoroalkyl iodides including CF3I were successfully transformed into the corresponding azirines (Scheme 2). A range of internal alkynes having aryl and silyl groups were also compatible and provided the desired azirines 3ab−ac in moderate to good yields. The reaction with a conjugated alkenyl acetylene also gave the desired product 3ad, albeit in a lower yield of 37%. Surprisingly, the vinyl azide 3ai was formed with high regioselectivity when ICF2CO2Et used as a fluoroalkylating reagent. The scope of RFI is an advantage of the current protocol, as the perfluoroalkyl derivatives of other fluoroalkylating reagents are quite expensive or are not commercially available. Finally, further transformations of fluoroalkylated 2H-azirine 3b were also explored. It is noteworthy that azirine 3b was successfully applied in the efficient synthesis of pyrroles13 and aziridines14 as useful building blocks with excellent diastereoselectivities (Scheme 3). Additionally, the structure of compound 4b was unambiguously confirmed by X-ray crystallography. To gain more insight into the mechanism of this reaction, we carried out some control experiments: (1) Under the standard conditions, no azirine product was formed in the presence of TEMPO (2,2,6,6-tetramethylpiperidine-1-oxyl) as
acetonitrile (Table 1, entry 15) provided higher efficiency. Further optimization of the reaction conditions revealed that the best yield was obtained with a slightly lower catalyst loading (5 mol %) as well as an increased reaction temperature of 70 °C (Table 1, entry 16). We also found that TBHP was a better radical promoter than H2O2 and TPBP (Table 1, entries 16−18). Finally, no reaction occurred in the absence of an iron catalyst or oxidant (Table 1, entries 19 and 20). Other metal catalysts CuCl2, NiCl2, PdCl2, MnCl2, CoBr2, and In(OTf)3 were found to be ineffective (see the Supporting Information). The best result was obtained when the reaction was carried out with 1-tert-butyl-4-ethynylbenzene (0.5 mmol, 1a), C4F9I (0.7 mmol, 2a), TMSN3 (1 mmol), and TBHP (1 mmol) in the presence of 5 mol % FeCl2 in CH3CN at 70 °C for 3 h, furnishing the fluoroalkylated azirine 3a in 86% yield (Table 1, entry 16). With the optimal reaction conditions in hand, we set out to investigate the scope of alkynes in the iron-catalyzed azidoperfluoroalkylation for the synthesis of fluoroalkylated 2H-azirines. Our protocol accommodated a variety of arylacetylenes, having a series of electron-donating and electron-withdrawing groups on the aromatic ring (Scheme 1). Various functional groups, such as halogens, amino, nitro, and ester, remained intact, providing the opportunity for further transformations. Ortho- and meta-substituted arylacetylenes were tolerated, leading to the products 3g and 3k,l in good yields. Multiple triple bonds present in the arylacetylene were well tolerated, leading to the corresponding dimer 3r in B
DOI: 10.1021/acs.orglett.8b03324 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Scheme 2. Scope of Perfluoroalkyl Iodides with Various Acetylenesa
Scheme 4. Control Experiments
5). A single-electron-transfer between Fe(II) and TBHP initiated the reaction by generating tert-butyloxy radical A Scheme 5. Plausible Mechanism a
Reaction conditions: 1 (0.5 mmol), 2a (0.7 mmol), TMSN3 (1 mmol), TBHP (5−6 M in decane) (1 mmol), and 5 mol % FeCl2 in CH3CN (2 mL) at 70 °C for 3 h under N2. Isolated yields. bIn case of CF3I, the reaction performed at −78 °C to rt for 1 h then 70 °C for 2 h. cTBPB was used instead of TBHP.
Scheme 3. Further Transformations of Azirine 3ba
and an Fe(III) species. A radical relay process then occurred between the tert-butyloxy radical and the perfluoroalkyl iodide, affording a new carbon-centered perfluoroalkyl radical B. This perfluoroalkyl radical added to the alkyne, generating an internal vinyl radical species C. Ligand exchange delivered Fe(III)N3, which finally reacted with radical C, leading to the formation of vinyl azide D and the regeneration of Fe(II). Finally, thermal decomposition of vinyl azide D via rearrangement afforded the fluoroalkylated 2H-azirines by liberating nitrogen gas. Rearrangement of vinyl azide D was favored only with strong electron-withdrawing perfluoroalkyl groups present in the system. TBHP served as an oxidant and an activator of both the perfluoroalkyl iodide and the nitrogen functionality. The iron catalyst was found to be irreplaceable in the whole catalytic cycle. In summary, we elaborated novel and convenient access to fluoroalkylated 2H-azirines, which can be easily converted into fluoroalkylated N-containing heterocycles. This reaction proceeds through a radical addtion/nitrogenation/rearrangement process using an environmentally friendly iron catalyst, readily available alkynes, inexpensive perfluoroalkyl iodides, and TMSN3. Further key features and synthetic transformations are underway in our laboratory.
a
All the reactions were conducted on a 0.2 mmol scale. Isolated yields. Conditions: (i) acetylacetone or dimedone, 10 mol % NiCl2· 6H2O, CH3CN, 70 °C. bConditions: (ii) NaBH4 (1.5 equiv), MeOH, 0 °C to rt. cMeMgBr (2 equiv), Et2O, −10 °C. dPyrazole (1.2 equiv), K2CO3 (2 equiv), CH3CN, rt.
a radical scavenger (Scheme 4, eq 1), and only a TEMPO-C4F9 adduct was observed in 19F NMR (see the SI). (2) A competing reaction with equal amounts of phenylacetylene 1b and styrene 6 resulted in the formation of the azidoperfluoroalkylation product 7 in 62% isolated yield (Scheme 4, eq 2). This experiment revealed that the C4F9 radical was involved in the reaction and its addition to the alkyne was much slower than to the alkene. The isolated products 3s (Scheme 1) and 3ai (Scheme 2) also confirmed that the reaction proceeds through the formation of a vinyl azide and its subsequent rearrangement under thermal conditions, leading to the fluoroalkylated 2H-azirine. A plausible radical relay-involved catalytic cycle was proposed according to the above control experiments (Scheme
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b03324. C
DOI: 10.1021/acs.orglett.8b03324 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
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Research details, experimental procedures, full characterization of products, and NMR spectra (PDF) Accession Codes
CCDC 1873105 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
[email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Erik V. Van der Eycken: 0000-0001-5172-7208 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS N.R. is thankful to SERB, India, for granting a postdoctoral fellowship. The publication was prepared with the support of the “RUDN University Program 5-100.” The Hercules Foundation is acknowledged for providing funding for an Xray diffractometer through project AKUL/09/0035.
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DOI: 10.1021/acs.orglett.8b03324 Org. Lett. XXXX, XXX, XXX−XXX
