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Olefin Aziridination Direct and Stereospecific Synthesis of NH and NAlkyl Aziridines from Unactivated Olefins Using Hydroxylamine-O-Sulfonic Acids **
Zhiwei Ma, Zhe Zhou and László Kürti*
Aziridines are important synthetic building blocks as well as readily synthesized from the corresponding NH aziridines.[6] substructures in a number of biologically active natural and Despite alkene aziridination being a key research area for decades, unnatural products.[1] As the smallest member in the family of the direct NH/alkyl aziridination of unactivated olefins is still nitrogen-containing rings, they provide unique synthetic access to relatively underdeveloped. many important structural motifs and functionalities via ring- expansion and/or ring-opening reactions, some of which are difficult Several years ago our group reported, jointly with the Ess and to obtain without the intermediacy of aziridines.[2] Based on the Falck groups, a rhodium-catalyzed direct aziridination of olefins that electronic properties of the nitrogen atom, aziridines can be uses O-(2,4-dinitrophenyl)hydroxylamine (DPH) as the classified as activated (e.g., NTs, NNs) and non-activated (NH, stoichiometric aminating agent and 2,2,2-trifluoroethanol (TFE) as Nalkyl).[1] For more than two decades, considerable effort has been the solvent (Figure 1).[7] To the best of our knowledge, it is still the devoted by the synthetic organic chemistry community to the only reported method with a general scope that can achieve NH development of practical methods for the efficient preparation of and NMe aziridination on unactivated olefins. This transformation aziridines.[3] Although significant progress has been made, the provides good to excellent yields of the aziridines for a large variety majority of these methods are still limited to the synthesis of of olefin substrates, while tolerating a wide range of functional activated aziridines that almost invariably require the removal of the groups. However, using DPH as the stoichiometric aminating agent activating groups in order to obtain the final target compounds.[4] has led to some drawbacks: (a) while DPH can be conveniently synthesized, its commercial sources are still limited and its price is relatively high, most likely due to its relatively short shelf life and its requirement for refrigeration during storage; (b) both DPH and the byproduct 2,4-dinitrophenol have high NO2/C ratios and are toxic – these facts raised safety concerns for industrial applications and led to the reluctance towards its adoption in large scale reactions; (c) the by-product 2,4-dinitrophenol sometimes co-elutes with the aziridine product(s), thus complicating chromatographic purification and (d) the by-product 2,4-dinitrophenol causes ring- opening of some of the aziridine products this necessitates the lowering of reaction temperature especially for sensitive styrene substrates. Therefore, it has been our desire to find an alternative aminating agent to overcome the aforementioned shortcomings of this aziridination process, while retaining (and possibly improving) its operational simplicity, oxygen- and moisture-tolerance, and the Figure 1. Current methods for the Rh(II)-catalyzed N-H aziridination of overall high-efficiency. Initially, several commonly used aminating unactivated olefins. agents, such as oxaziridines and O-benzoyl hydroxylamine derivatives were tested under the original aziridination conditions The need to remove activating groups from the aziridine nitrogen used with DPH.[8] However, no aziridination products were detected. atom (e.g., SO2R or –CO2R) often causes additional synthetic After a thorough literature survey of inexpensive yet powerful challenges and loss of valuable materials due to the harsh conditions aminating agents, we noted that hydroxylamine-O-sulfonic acid necessary to cleave the strong N-sulfonyl and N-acyl bonds.[5] In (HOSA)[9] has the potential to be the optimal reagent for our comparison, the direct NH aziridination of unactivated olefins is a purposes: (a) HOSA has been widely used for the synthesis of more desirable process because: (a) removal of the activating group amines, as well as for the preparation of nitriles, oximes, amides and is circumvented and (b) virtually any N-substituted aziridine can be various nitrogen-containing heterocycles;[10] (b) HOSA does not contain a nitro group and it has robust thermal stability (decomposition temperature: 208211 °C) and is a widely available and cost-effective commercial source of electrophilic nitrogen; (c) [] Dr. Z. Ma, Dr. Z. Zhou and Prof. Dr. László Kürti Department of Chemistry the byproduct derived from HOSA is an inorganic sulfate after Rice University, BioScience Research Collaborative workup, which can be conveniently removed by simple aqueous 6500 Main Street, Rm 380, Houston, TX, 77030 (USA) extraction. Among publications focused on HOSA, several reports Fax: (+1) 713-348-5155; E-mail: [email protected] on olefin hydroamination drew our attention.[11] In 1964, Brown et. [] Financial support from Rice University, National Institutes of Health al. reported a one-pot transformation consisting of an olefin (R01 GM-114609-01), National Science Foundation hydroboration/HOSA amination sequence to provide the (CAREER:SusChEM CHE-1455335), the Robert A. Welch [11a] Foundation (Grant C-1764), ACS-PRF (Grant 51707-DNI1), Amgen corresponding primary alkylamine products. In 2013, Hartwig et. (2014 Young Investigators’ Award for LK) and Biotage (2015 Young al. reported a one-pot anti-Markovnikov olefin hydroamination Principal Investigator Award) that are greatly appreciated. We thank method via a hydrozirconation/amination sequence using various Professor Daniel H. Ess (BYU) for helpful discussions. Nalkyl HOSA derivatives as electrophilic aminating agents.[11b] More recently, the McCubbin group disclosed a transition-metal free Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/anie.201xxxxxx. 1 aryl amination method to deliver primary arylamines from aryl inorganic bases is likely detrimental to the reaction rate. To explore boronic acids using HOSA as the aminating agent.[11c] The inherent the effect of homogeneity, common organic bases soluble in HFIP advantages of HOSA encouraged us to investigate its potential were examined (Table 1, entries 1014) which led to the utilization in the direct olefin NH aziridination reaction. identification of pyridine as the optimal base (Table 1, entry 13). Compared to inorganic bases, the better solubility of pyridine in
HFIP facilitates a rapid aziridination process (within 4 h versus 16 Table 1. Optimization of conditions for the NH aziridination of h). A thorough investigation of reaction conditions found that the geranyl acetate (4). use of 1.2 equivalents of both HOSA and pyridine at 0.4 M concentration is optimal for the aziridination of geranyl acetate (Table 1, entry 15), and 2.5 hours of reaction time at ambient temperature is sufficient for the complete conversion. We found that other common Rh(II) catalysts can also facilitate the aziridination process (Table 1, entries 1619). Specifically, Rh2(OAc)4 exhibited only slight erosion of the aziridination efficiency (74% isolated yield, 1.5 mol% catalyst loading) compared to Rh2(esp)2 (85% isolated yield, 1 mol% catalyst loading), while having a wider commercial availability. The effect of excess pyridine was also examined and we found that the reaction could tolerate up to at least 10 equivalents of it without losing efficiency (Table 1, entries 20 & 21).
Table 2. Direct intermolecular NH aziridination of structurally diverse olefins using hydroxylamine-O-sulfonic acid (HOSA) as the stoichiometric aminating agent.
Monoterpenoid geranyl acetate (4) was selected as the model compound to examine the possibility of achieving direct olefin NH aziridination. When HOSA was initially tested using the original conditions,[7] no aziridine product (5) was detected after 16 h (Table 1, entry 1). Hypothesizing that the protonated nitrogen of the HOSA zwitterion prevented the formation of the presumed rhodium-NH- nitrenoid intermediate,[7] an equimolar amount of LiOH was added to the reaction mixture as a base. Gratifyingly, the reaction took place and the desired NH-aziridine (5) was obtained after 16 h with an isolated yield of 44%, along with unreacted starting material (4) (Table 1, entry 2). Since TFE is slightly acidic (pKa ~ 12.5), the acidity of the solvent was considered as a possible influential factor for the reaction. To test this hypothesis, both the more acidic 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP, pKa ~ 9.3) and the less acidic MeOH (pKa ~15.5) were tested separately as solvents. No reaction took place when the reaction was carried out in MeOH, while complete consumption of 4 was observed after 16 h and 5 was isolated with 80% yield when HFIP was used as the solvent (Table 1, entries 3 & 4). A control experiment validated that no conversion was observed in the absence of the catalyst (Table 1, entry 5), demonstrating that the dirhodium complex was essential for the aziridination process. It is also worth noting that the HOSA procedure seems to have superior regioselectivity with no detection of the 2,3-regioisomer of aziridine 5, while the DPH procedure produces about 6% of this minor regioisomer. To promote a faster and more efficient aziridination of the starting material, an array of common bases with varying basicity was With the optimized conditions in hand, we explored the scope of this screened in HFIP (Table 1, entries 714). When the base was new aziridination method using a wide range of structurally diverse absent, decomposition of alkene (4) was observed, likely caused by olefins (Table 2). Both cyclic- and acyclic-aliphatic alkenes undergo the acidic nature of HOSA (Table 1, entry 6). Among the inorganic smooth aziridination, and this new method tolerates various bases, only CsOH gave comparable yield to LiOH (Table 1, entry 4 functional groups, including esters (Table 2, entry 1), silyl ethers versus entry 9), albeit both reactions took 16 h to go to completion. (Table 2, entries 2 & 5) and alcohols (Table 2, entries 4, 8 & 13). In We propose that the heterogeneous system formed in HFIP with the case of the aziridination of an allylic acetate (Table 2, entry 9),
2 intramolecular acyl-transfer to the aziridine N, followed by an aza- Isolated olefins underwent aziridination selectively in the Payne-rearrangement took place to furnish the corresponding presence of allylic ethers, presumably due to the unfavorable epoxide 13. While this method is compatible with both allylic and inductive effect caused by the oxygen atom (Table 2, entry 1). To homoallylic alcohols (Table 2, entries 4 and 8), extra loading (2 enable a direct comparison on the reactivity and efficiency, this new equivalents) of the aminating agent and pyridine was required to aziridination method was tested on several substrates that required achieve full conversion. prolonged reaction time with the DPH protocol.[7] Gratifyingly, the Table 3. Direct intermolecular NH aziridination of structurally reaction times were reduced under HOSA conditions in all cases, diverse olefins using hydroxylamine-O-sulfonic acid (HOSA) as the while similar or higher isolated yields were obtained (Table 2, stoichiometric aminating agent. entries 1 & 1013). As a representative example, the reaction time required for the aziridination of the natural product cholesterol was reduced from 48 h to 2.5 h, and only half of the original Rh2(esp)2 catalyst loading (1 mol% vs 2 mol%) was required (Table 2, entry 13). Naturally, we decided to test a number of new, more complicated substrates in order to gauge the full capability of this new method. For a terminal alkene, higher Rh2(esp)2 loading (4 mol%) was required to enable full conversion (Table 3, entry 1). This observation is consistent with those reported for terminal olefins in our earlier work.[7] Using this differentiating property, chemoselective aziridination of the more substituted alkene was achieved when both a terminal alkene and an internal alkene were present in the same molecule (Table 3, entry 2). It is interesting to note that the presence of an aziridine moiety in the molecule seems to inhibit further aziridination, as evidenced by the failure to convert 20 to the corresponding bis-aziridine even with excess amount of the aminating agent (Table 3, entry 3). With the recent report of a Rh(II)-catalyzed C-H amination of arenes,[12] we were curious to see whether the arene amination would be a competing side reaction for the aziridination chemistry on substrates containing both arene and alkene moieties. When olefin substrates containing arenes with different electronic properties underwent aziridination, no arene C-H amination was observed, demonstrating the good chemoselectivity of this method favoring alkenes over arenes (Table 3, entries 510). Heterocycles containing electron-rich S, O and N atoms were also tolerated (Table 3, entries 1116) as well as substrates featuring cyano groups (entries 4 & 5) and alkynes (entry 9). Acid-sensitive functionalities such as Boc and acetals were also unaffected by the reaction conditions (Table 3, entries 16, 17 & 19). Complex molecules can undergo aziridination with this method and give the corresponding aziridines in good to excellent yields with superb chemoselectivity, demonstrating the potential utility of this method in natural product synthesis and medicinal chemistry (Table 1, entry 13; Table 2, entries 1720). With these exciting results for the synthesis of NH aziridines in hand, we further examined this method for the preparation of Nalkyl aziridines. The required NMe and Ni-Pr hydroxylamine- O-sulfonic acids were prepared from the corresponding hydroxylamine hydrochloride salts according to the procedure developed by Hartwig et al.[11b] The direct Nalkyl aziridination proceeded smoothly with olefins (Table 4) and the yields were good to excellent, albeit decreased slightly compared to the NH aziridination process. This reduced efficiency is possibly due to the steric hindrance originating from the larger Nalkyl groups. This new NH and Nalkyl aziridination protocol is stereospecific isomerization of double bonds was not detected. The stereoselectivity was excellent in the case of single enantiomer cyclic olefins that are conformationally restricted (e.g., cyclohexene derivative: Table 2, entry 5; cholesterol: Table 2, entry 13; carene: Table 3, entry 18), while NH aziridination of acyclic olefins with remote stereocenters and conformational flexibility proceeded in a non-stereoselective fashion (Table 3, entries 2, 13, 17 & 19). The mechanism of this new olefin aziridination process is presumably similar to the one postulated for the DPH protocol.[7] Accordingly, a Rh-nitrenoid is formed via the coordination of the
amino group in HOSA to Rh, and the sequential loss of sulfate
anion. The higher reaction rate in this case likely originates from the
3 faster dissociation (i.e., NO bond cleavage) of sulfate anion from In summary, we have developed a novel one-pot and HOSA compared to the phenoxide anion from DPH. stereospecific aziridination of unactivated olefins by employing NH as well as Nalkyl hydroxylamine-O-sulfonic acids as powerful aminating agents. This transformation overcomes the Table 4. Direct intermolecular Nalkyl aziridination of structurally drawbacks associated with the previously reported method that diverse olefins using Nalkyl hydroxylamine-O-sulfonic acids utilizes DPH as the stoichiometric aminating agent and finally (NRHOSA) as aminating agents. enables a more environmentally friendly and cost-effective direct NH and Nalkyl aziridination of olefins. We anticipate that this general and operationally simple approach will find wide utility in the preparation of functional group-rich intermediates as well as the synthesis and modification of structurally complex molecules.
Keywords: aziridination • dirhodium catalysis •unprotected aziridines • stereospecific • nitrenoids• hydroxylamine–O- sulfonic acid
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Herein we report a Rh(II)-catalyzed direct and stereospecific NH- and Nalkyl aziridination of olefins that uses hydroxylamine-O-sulfonic acids as inexpensive, readily available and nitro group-free aminating reagents. Unactivated olefins, featuring a wide range of functional groups, are converted to the corresponding NH or Nalkyl aziridines in good to excellent yields. This operationally simple, scalable transformation proceeds efficiently at ambient temperature and is tolerant towards oxygen and trace moisture.
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