Letter Cite This: Org. Lett. 2017, 19, 6120-6123
pubs.acs.org/OrgLett
Copper-Catalyzed Ligand-Free Diazidation of Olefins with TMSN3 in CH3CN or in H2O Huan Zhou,† Wujun Jian,† Bo Qian,† Changqing Ye,† Daliang Li,‡ Jing Zhou,† and Hongli Bao*,† †
Key Laboratory of Coal to Ethylene Glycol and Its Related Technology, State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, University of Chinese Academy of Sciences, 155 Yangqiao Road West, Fuzhou, Fujian 350002, P. R. China ‡ Biomedical Research Center of South China & College of Life Science, Fujian Normal University, 1 Keji Road, Minhou, Fuzhou, Fujian Province 350117, P. R. China S Supporting Information *
ABSTRACT: An environmentally benign, copper-catalyzed diazidation of a broad range of olefins, including vinylarenes, unactivated alkenes, allene, and dienes, under mild conditions with TMSN3 (trimethylazidosilane) as azido source, has been developed. This reaction can be carried out in organic solvent or in aqueous solution where water is the sole solvent. The functional group compatibility of this reaction is good, which is proved by late-stage functionalizations of complex substrates.
D
reactivities of a reaction taking place in water and in organic solvents. Although radical reactions are sometimes insensitive to water and many organic radical reactions have been carried out in a mixed solvent containing water, very few radical reactions can be achieved both in organic solvent and in water.11,12 In this paper, we report the copper-catalyzed, ligand-free diazidation of styrenes, unactivated alkenes, dienes, and allene with TMSN3 in organic solvent or in water (Scheme 1, eq 5) in interrupted Kharasch−Sosnovsky reaction conditions. We initiated our studies with the diazidation reaction of styrene 1a (0.5 mmol) in water with TMSN3 in the presence of TBPB. The 1,2-diazide 3 was obtained in 24% yield in 1 mL of H2O in the presence of CuI (Table 1, entry 1). The yield was improved to 50% when 2 mL of H2O was used (entry 2). An investigation of phase-transfer catalysts revealed N(Bu)4I as optimal, and product was obtained in up to 88% yield using 10 mol % of N(Bu)4I (entries 3−6). Examination of different metal catalysts revealed that Cu(OTf)2 was a better catalyst than CuI (entry 7). Other catalysts and peroxides failed to provide better results (entries 8−18). Interestingly, this reaction proceeded smoothly in CH3CN with CuI as catalysts, delivering even better results (entry 19, up to 96% yield). These versatile reaction conditions could be useful in a practical application and bioorthogonal chemistry. With the identified conditions in hand, we proceeded to study the scope of olefins in two systems (H2O and CH3CN), and the results are summarized in Table 2. Substrates with various substituents (R) such as alkyl, halogen, ester, and methyl ether on aromatic rings are compatible with this
ifunctionalization of olefins is a powerful approach for installing two functional groups on hydrocarbons.1 Among such reactions, diazidation2,3 is of particular interest because of the diverse applications of 1,2-diazides. Besides the existence of azido groups in natural products and bioactive compounds,4 1,2-diazides could serve as precursors for the synthesis of valuable 1,2-diamines,5,6 which are prevalent in bioactive compounds, drugs, and molecular ligands. Recently, Greaney and co-workers,2a as well as Loh and co-workers,2b developed the useful copper-catalyzed diazidation of styrenes separately with hypervalent iodine compounds. More recently, Xu and co-workers2c reported a powerful diazidation of general alkenes including vinylarenes and unactivated alkenes in the presence of coordinated iron catalyst, and very recently, Lin disclosed the metal-catalyzed electrochemical diazidation of general alkenes (Scheme 1, eqs 1−3).3 Notwithstanding these significant breakthroughs, the need for ligand, toxic NaN3, or azidoiodine(III) reagent attaches limitations to the state of art in diazidation of alkenes. We have developed iron-catalyzed methylation of vinylarenes using tert-butyl perbenzoate (TBPB).7 Methyl radical is generated in this reaction from TBPB. But interestingly, in the presence of a copper catalyst, we did not observe any formation of methyl radicals. This observation is consistent with the results from the classical Kharasch−Sosnovsky reaction.8 We speculate that, in the presence of a copper catalyst, diazidation might happen taking advantage of multiple functionalities of TBPB and the probability of generation of an Si−O bond (Scheme 1, eq 4), given that the bond energy of Si−O is 452 kJ/mol.9 Water is an ideal solvent for organic chemistry10 not only because of its inexpensive and environmentally benign characteristics, but also because of its well-known different © 2017 American Chemical Society
Received: September 22, 2017 Published: November 1, 2017 6120
DOI: 10.1021/acs.orglett.7b02982 Org. Lett. 2017, 19, 6120−6123
Letter
Organic Letters Table 2. Generalization of Scope of the Reactiona
Scheme 1. Diazidation of Olefins and This Work
Table 1. Reaction Condition Optimizationa
a
entry
catalyst (mol %)
solvent (mL)
1d 2d 3e 4f 5g 6 7 8 9 10 11 12 13 14 15h 16h 17h 18h 19d 20d
CuI (10) CuI (10) CuI (10) CuI (10) CuI (10) CuI (5) Cu(OTf)2 (5) Cu(CH3CN)4PF6 (5) CuCl (5) Fe(OTf)2 (5) CoCl2 (5) NiCl2(5) Mn(OAc)3 (5) Pd(OAc)2 (5) Cu(OTf)2 (5)/LPO Cu(OTf)2 (5)/TBHP Cu(OTf)2 (5)/DTBP Cu(OTf)2(5)/H2O2 CuI (10) CuI (10)
H2O (1) H2O (2) H2O (2) H2O (2) H2O (2) H2O (2) H2O (2) H2O (2) H2O (2) H2O (2) H2O (2) H2O (2) H2O (2) H2O (2) H2O (2) H2O (2) H2O (2) H2O (2) CH3CN (2) CH3CN (1), H2O (1)
b,c
yield
Results outside the parentheses were obtained in water via method A. Results in parentheses were obtained in CH3CN via method B. Method A for vinylarenes, dienes, and allene: olefin (0.5 mmol), Cu(OTf)2 (5 mol %), TBAI (10 mol %), TBPB (1.5 equiv), TMSN3 (3.5 equiv), H2O (2 mL), 50 °C; for other olefins: olefin (0.5 mmol), Cu(OTf)2 (5 mol %), TBAI (10 mol %), TBPB (1.5 equiv), TMSN3 (4.5 equiv), H2O(2 mL), 70 °C. Method B for vinylarenes, dienes and allene: olefin (0.5 mmol), CuI (10 mol %), TBPB (1.5 equiv), TMSN3 (3.5 equiv), CH3CN (2 mL), 50 °C; for other olefins: olefin (0.5 mmol), CuBr·SMe2 (5 mol %), TBPB (2 equiv), TMSN3 (4.5 equiv), CH3CN (2 mL), 70 °C. See additional details in the Supporting Information.
(%)
24 50 trace 8 80 85 88 (86) 86 70 26 24 21 trace trace trace 74 trace 20 96 (92) 88
transformation and give the desired products 4−20 in good yields. Disubstituted thiazole is compatible, delivering the corresponding product 21 in 61% yield. 1,1-Disubstituted vinylarenes and 1,2-disubstituted vinylarenes are suitable substrates for this reaction and afford the corresponding products 22 and 23 in 51−84% yield. Interestingly, the reaction in different solvent systems behaves differently with cyclized olefins and products with different diastereoisomeric ratios (dr) are obtained 24−26. Encouraged by these results, we examined the reactivity of unactivated olefins. Simple olefins with an isolated CC bond are compatible with this reaction and lead to the expected products 27−33. The products 32 and 33 containing a free hydroxyl group and a carboxylic acid are not observed in the CH3CN system but in H2O are obtained in 63−67% yield. Dienes and allene are compatible with this reaction giving products 34−38 in moderate yield. To highlight the synthetic utility of this method, late-stage functionalization of several complex molecules was investigated
1a (0.5 mmol), 2 (3.5 equiv), TBPB (1.5 equiv), N+(Bu)4I− (10 mol %) and solvent. bYields were determined by 1H NMR. cYield of isolated product. dPTC free. e18-crown-6 (100 mol %). fC11H23CO2H (100 mol %). gN+(Bu)4Br− (100 mol %). hOther peroxides were used instead of TBPB. LPO = lauroyl peroxide, TBHP = tert-butyl hydrogen peroxide, DTBP = di-tert-butyl peroxide. a
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DOI: 10.1021/acs.orglett.7b02982 Org. Lett. 2017, 19, 6120−6123
Letter
Organic Letters under the standard reaction conditions (Table 3). The natural product nootkatone, a component of grapefruit, was trans-
Scheme 2. Preliminary Mechanistic Study
Table 3. Late-Stage Functionalization of Complex Substrates and Different Chemoselectivity of Vinyl Pyridine in CH3CN and H2Oa
Scheme 3. Proposed Catalytic Cycle
a
Results outside the parentheses were obtained in water via method A. Results in parentheses were obtained in CH3CN via method B. Method A: olefin (0.25 mmol), Cu(OTf)2 (5 mol %), TBAI (10 mol %), TBPB (1.5 equiv), TMSN3 (3.5−4.5 equiv) H2O (2 mL), 50 or 70 °C. Method B: olefin (0.25 mmol), CuI (10 mol %) or CuBr·SMe2 (5 mol %), TBPB (1.5 or 2 equiv), TMSN3 (3.5−4.5 equiv), CH3CN (2 mL), 50 or 70 °C. See additional details in the Supporting Information.
generating a tert-butoxyl radical and a Cu(II) species. A radical relay process then occurs between TMSN3 and the tert-butoxyl radical to afford an azido radical that adds to the olefin, generating an internal radical. Ligand exchange delivers Cu(II)N3, and finally, this Cu(II)N3 reacts with the internal radical to deliver the desired diazidation products and regenerate Cu(I). Considering the result of 1,6-heptadiene, the formation of Cu(III) species is an alternative pathway.15 The formation of Cu(II)OH species which reacts with TMSN3 to generate azido radical, especially in aqueous solution, cannot be excluded. Similarly, the hydrolysis of TMSN3 in H2O to HN3, which participates in the following reaction, cannot be ruled out.16 In summary, we have developed a general diazidation of vinylarenes, unactivated olefins, dienes, and allene with TMSN3 as nitrogen functionality. The reaction conditions are mild, and the functional group compatibility is considerable. This reaction is operationally simple and environmentally benign, and most importantly, it can be carried out in both an organic solvent system and a water system. Such versatile reaction conditions could be useful in practical applications by offering more options.
formed to 39 in 56% yield in 1:1 diastereoisomeric ratio (dr). The drug molecules exemestane and simvastain are also compatible with the reaction conditions and deliver the diazidation products 40 and 41 as single isomers in 75% and 64% yields. Two other estrone-based complex molecules were also investigated and delivered products 42 and 43 in good yields. Amino acid derivative was examined and gave product 44 in moderate yields. Surprisingly, reaction of 2-vinylpyridine shows different chemoselectivities, producing the diazidation product 46 in CH3CN and the hydroazidation product 47 in water. The reason for this different reactivity remains unclear. We performed preliminary experiments to probe the mechanism of the reaction (Scheme 2). When a radical spin trap experiment is performed with 2,6-di-tert-butyl-4-methylphenol (BHT) as radical scavenger, no product is observed while 4-azido-2,6-ditert-butyl-4-methylcyclohexa-2,5-dienone 48 is isolated in 24% yield.13 Reactions of trans-stilbene and cis-stilbene deliver the same products in different yields but with the same dr. These results are consistent with a stepwise radical process. To further understand this reaction, reaction of 1,6heptadiene was investigated. To our surprise, a mixture of cyclized and uncyclized products 53 and 52 was obtained in 2.9:1 ratio. 5-Exo cyclization of 5-hexanyl radical is fast, and the rate constant for this step is known (about 105 s−1).14 This result implies that the second azidation step is fast or that unfree radical exists. In view of the results of these mechanistic experiments, a radical catalytic cycle is proposed (Scheme 3). A single-electron transfer between Cu(I) and TBPB initiates the reaction by
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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.7b02982. Experimental details and NMR spectra (PDF) 6122
DOI: 10.1021/acs.orglett.7b02982 Org. Lett. 2017, 19, 6120−6123
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Organic Letters
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Hongli Bao: 0000-0003-1030-5089 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We thank NSFC (Grant Nos. 21402200, 21502191, 21672213), Strategic Priority Research Program of the Chinese Academy of Sciences (Grant No. XDB20000000), The 100 Talents Program, “The 1000 Youth Talents Program”, and the Innovative Research Teams Program II of Fujian Normal University in China (IRTL1703) for financial support. We thank Professor Weiping Su from our institute for the useful suggestions.
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DOI: 10.1021/acs.orglett.7b02982 Org. Lett. 2017, 19, 6120−6123
