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Direct Intermolecular Anti-Markovnikov Hydroazidation of Unactivated Olefins Hongze Li, Shou-Jie Shen, Cheng-Liang Zhu, and Hao Xu J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 09 May 2019 Downloaded from http://pubs.acs.org on May 9, 2019
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Journal of the American Chemical Society
Direct Intermolecular Anti-Markovnikov Hydroazidation of Unactivated Olefins Hongze Li, Shou-Jie Shen, Cheng-Liang Zhu, and Hao Xu* Department of Chemistry, Georgia State University, 100 Piedmont Avenue SE, Atlanta Georgia 30303, United States. ABSTRACT: We herein report a direct intermolecular anti-Markovnikov hydroazidation method for unactivated olefins, which is promoted by a catalytic amount of bench-stable benziodoxole at ambient temperature. This method facilitates previously difficult, direct addition of hydrazoic acid across a wide variety of unactivated olefins in both complex molecules and unfunctionalized commodity chemicals. It conveniently fills a gap of existing olefin hydroazidation procedures and thereby provides a valuable tool for azido-group labeling in organic synthesis and chemical biology studies.
INTRODUCTION Olefin hydroazidation, the nitrogen atom transfer process that involves direct or formal addition of hydrazoic acid (HN3) across an unactivated alkene, is valuable for synthetic chemistry. Not only does this reaction introduce the azido-group to a variety of complex molecules for organic synthesis1 and chemical biology studies,2 it can also complement olefin hydroamination methods3,4 that rapidly convert unfunctionalized olefins to high-value nitrogencontaining building blocks. The direct acid-catalyzed Markovnikov addition of HN3 across a list of activated or strained olefins is known,5 presumably through the intermediacy of stabilized tertiary and benzylic carbocations.5 Markovnikov hydroazidation of unactivated olefins has also been developed. Carreira6 and Boger7 independently reported metal hydride-catalyzed or mediated Markovnikov olefin hydroazidation methods (Scheme 1a). Scheme 1. Existing and currently reported hydroazidation methods for unactivated olefins a) Markovnikov olefin hydroazidation mediated by metal hydrides R2
R1 R3
+
MH
N3 R1
R4SO2N3 R
R2
3
M: Co, Fe, et al
H
b) existing methods for indirect anti-Markovnikov olefin hydroazidation
1
R H R
3
R2
1) hydroboration 2) oxidation 3) mesylation 4) azidation R1
N3
1) catecholborane, MeCONMe2 (cat.) 2) benzenesulfonyl azide, R2 radical initiator (cat.), 80 °C
R1 H R3
R2
N3
R3
c) this research: direct anti-Markovnikov hydroazidation of unactivated olefins
R1 R3
R2 +
TMSN3
benziodoxole (0.10.2 equiv) H2O or a proton donor (1.0 equiv) 22 °C, 24 h
H R1 R2
R3 N3
However, the direct anti-Markovnikov hydroazidation methods for unactivated olefins have been underdeveloped and the direct addition of HN3 across an unactivated alkene remains difficult. As a result, a hydroboration–oxidation–mesylation–azidation procedure is often used for indirect anti-Markovnikov olefin hydroazidation (Scheme 1b).1c As a significant advance, Renaud8a reported a two-step hydroazidation procedure that involves anti-Markovnikov olefin hydroboration using a stoichiometric amount of catecholborane and the subsequent azidation with benzenesulfonyl azide (Scheme 1b). A stereoselective variant tailored for an array of trisubstituted olefins was recently developed by the same group through asymmetric olefin hydroboration using (+)-IpcBH2.8b As a specific tandem reaction, metal-catalyzed formal hydroazidation of homoallylic benzyl ethers was also achieved through the olefin azidation–intramolecular 1,5H atom transfer–oxidative debenzylation cascade.9 These multi-step, indirect methods are synthetically enabling; however, a stoichiometric amount of both oxidants and reductants are often used in these formal HN3 addition reactions. Therefore, a general method of direct anti-Markovnikov addition of HN3 across a wide variety of unactivated olefins is yet to be developed that will fill the gap of existing hydroazidation approaches and thereby minimize the generation of a stoichiometric amount of byproducts. Herein, we report the direct antiMarkovnikov olefin hydroazidation that is promoted by a catalytic amount of benziodoxole (Scheme 1c). This roomtemperature reaction directly adds HN3 across a broad range of unactivated olefins in both unfunctionalized and complex molecules, many of which are incompatible with the existing anti-Markovnikov hydroazidation procedures. Our preliminary mechanistic studies suggest a unique reaction pathway that is distinct from the known olefin hydroazidation reactions.
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RESULTS AND DISCUSSION We selected 1-dodecene 1, a prototypical unactivated olefin, as a model substrate for reaction discovery (Table 1). Through numerous explorations, we discovered that a catalytic amount of benziodoxole 2a, a bench-stable oxidant as the precursor for an array of hyper-valent iodine reagents,10,11 effectively promotes dodecene hydroazidation in the presence of TMSN3 and H2O at ambient temperature, affording terminal azide 3 with excellent anti-Markovnikov selectivity (Table 1, 90% yield). Since 2a is almost insoluble in CH2Cl2,11 the reaction mixture is initially heterogeneous and it does become homogenous upon reaction completion. Notably, 2a is converted to TMS o-iodobenzoate at end of the reaction. Table 1. Reaction discovery of the Markovnikov dodecene hydroazidation
direct
develop a more efficient hydroazidation procedure with lower promoter loading, we evaluated an array of Brønsted acid additives (entries 7–8). Surprisingly, a catalytic amount of CF3CO2H (0.2 equiv) proves uniquely effective and it cooperatively promotes high-yielding dodecene hydroazidation with 2a (entry 8, 0.07 equiv).12 Table 2. Substrate scope of the direct anti-Markovnikov olefin hydroazidation
anti-
O
+
C10H21 1 entrya
TMSN3 1.8 equiv
O (0.1 equiv) I 2a OH H2O (1.0 equiv) CH2Cl2, 22 °C, 2 h
variation from the standard conditions
H N3
C10H21
3 90% yield
conversion (%)
yield (%)b
1
in the absence of 2a
