A protocol for the diastereoselective one-pot preparation of cis–N-Ts-iodoaziridines is described. The generation of diiodomethyllithium, addition to N-Ts aldimines and cyclization of the amino gem-diiodide intermediate to iodoaziridines is demonstrated. Also included is a protocol to rapidly and quantitatively assess the most appropriate stationary phase for purification by chromatography.
The highly diastereoselective preparation of cis–N-Ts-iodoaziridines through reaction of diiodomethyllithium with N-Ts aldimines is described. Diiodomethyllithium is prepared by the deprotonation of diiodomethane with LiHMDS, in a THF/diethyl ether mixture, at -78 °C in the dark. These conditions are essential for the stability of the LiCHI2 reagent generated. The subsequent dropwise addition of N-Ts aldimines to the preformed diiodomethyllithium solution affords an amino-diiodide intermediate, which is not isolated. Rapid warming of the reaction mixture to 0 °C promotes cyclization to afford iodoaziridines with exclusive cis-diastereoselectivity. The addition and cyclization stages of the reaction are mediated in one reaction flask by careful temperature control.
Due to the sensitivity of the iodoaziridines to purification, assessment of suitable methods of purification is required. A protocol to assess the stability of sensitive compounds to stationary phases for column chromatography is described. This method is suitable to apply to new iodoaziridines, or other potentially sensitive novel compounds. Consequently this method may find application in range of synthetic projects. The procedure involves firstly the assessment of the reaction yield, prior to purification, by 1H NMR spectroscopy with comparison to an internal standard. Portions of impure product mixture are then exposed to slurries of various stationary phases appropriate for chromatography, in a solvent system suitable as the eluent in flash chromatography. After stirring for 30 min to mimic chromatography, followed by filtering, the samples are analyzed by 1H NMR spectroscopy. Calculated yields for each stationary phase are then compared to that initially obtained from the crude reaction mixture. The results obtained provide a quantitative assessment of the stability of the compound to the different stationary phases; hence the optimal can be selected. The choice of basic alumina, modified to activity IV, as a suitable stationary phase has allowed isolation of certain iodoaziridines in excellent yield and purity.
The aim of this method is to prepare iodoaziridines that offer potential for further functionalization to aziridine derivatives. The method incorporates a protocol for the quantitative selection of the optimal stationary phase for chromatography.
Aziridines, as three-membered rings, posses inherent ring strain that makes them important building blocks in organic chemistry1. They display a vast array of reactivity often involving aziridine ring opening2,3, particularly as intermediates in the synthesis of functionalized amines4,5, or the formation of other nitrogen containing heterocycles6,7. The synthesis of a range of aziridine derivatives by functionalization of a precursor containing an intact aziridine ring has emerged as a viable strategy8. Functional group–metal exchange, to generate an aziridinyl anion, and reaction with electrophiles has been shown to be effective9,10,11, and recently regio- and stereoselective deprotonation of N-protected aziridines has also been achieved12-15. Very recently, palladium catalyzed cross-coupling methods to form aryl aziridines from functionalized aziridine precursors has been developed by Vedejs16,17, and ourselves18.
The chemistry of heteroatom substituted aziridines opens up fascinating questions of reactivity and stability19. We have been interested in the preparation of iodoaziridines as a novel functional group that offers the potential to provide precursors to a wide range of derivatives with complementary reactivity to existing aziridine functionalization reactions. In 2012 we reported the first preparation of aryl N-Boc-iodoaziridines20, and very recently reported the preparation of aryl and alkyl substituted N-Ts-iodoaziridines21.
The method to access iodoaziridines uses diiodomethyllithium, a reagent which has recently also been employed in the preparation of diiodoalkanes22,23, diiodomethylsilanes22,24, and vinyl iodides25-27. The carbenoid-like nature of this reagent requires preparation and use at low temperatures22,28. The techniques and conditions used for the generation of diiodomethyllithium in the preparation of iodoaziridines are described below.
While silica has emerged as the material of choice for chromatography29, it proved to be unsuitable for the purification of the N-Ts-iodoaziridines. Silica gel is generally the first and only solid phase material employed in flash chromatography in organic chemistry due to the availability and effective separations. However, the acidic nature of silica gel can cause the decomposition of sensitive substrates during purification, preventing isolation of the desired material. While other stationary phases or modified silica gels are available for chromatography30, there was no way to assess compatibility of the target molecule to these different materials. Due to the sensitive nature of the iodoaziridines, we established a protocol to assess the stability of a compound to an array of stationary phases21, which is demonstrated here. This has potential for application in the synthesis of a wide range of compounds with sensitive functional groups. The following protocol provides efficient access to N-Ts iodoaziridines, allowing the diastereoselective synthesis of both alkyl and aromatic cis-iodoaziridines in high yield.
1. Preparation of Iodoaziridines with Diiodomethyllithium
2. Assessment of Product Stability to Stationary Phases for Chromatography
3. Deactivation of Basic Alumina and Purification of the Iodoaziridine
The procedure described affords cis-(±)-2-iodo-3-(4-tolyl)-1-(4-tolylsulfonyl)aziridine as a single diastereoisomer and with excellent purity (Figure 1). Prior to purification, a yield of 59% of the iodoaziridine product was calculated by 1H NMR spectroscopy. However, this iodoaziridine was particularly challenging to purify and underwent significant decomposition on silica. Purification on basic alumina (activity IV) as determined by the stationary phase screen allowed the product to be isolated in 48% yield. The results from the stationary phase screen are illustrated in Figure 2. Following filtration, analysis of the 1H NMR spectra gives a series of yields for the different materials used, with respect to the internal standard. These yields are representative of the isolated yield that can be expected after column chromatography on that specific stationary phase. Basic alumina (activity IV) returns the highest yield (53%), which is closest to the yield calculated by 1H NMR. Therefore, basic alumina (activity IV) was chosen as the stationary phase for column chromatography for the purification of the N-Ts iodoaziridine. The isolated yields, following chromatography, are comparable with those predicted.
A wide selection of iodoaziridines can be accessed by this method in high yield (see Figure 3 for representative examples). Both alkyl and aromatic N-Ts imines are compatible with the reaction, including the sterically demanding tert-butyl and ortho-tolyl examples. The reaction is proposed to occur by deprotonation of diiodomethane by lithium hexamethyldisilazane at -78 °C, forming diiodomethyllithium (Figure 4). On addition of the N-Ts aldimine, nucleophilic addition of the diiodomethane anion to the imine at -78 °C affords the amino gem-diiodide intermediate. Subsequent warming to 0 °C induces a highly diastereoselective cyclization of the amino gem-diiodide intermediate, affording the cis–N-Ts-iodoaziridine exclusively. The cyclization occurs highly stereoselectively with the cis-iodoaziridine being favored over the trans-iodoaziridine due to subtle steric interactions in the cyclization transition state.
During reaction optimization, it was apparent that control of temperature and the timing of the different stages is essential to the outcome of the reaction (Figure 5). Quenching the reaction at -78 °C without warming results in the formation of the N-Ts iodoaziridine and the amino gem-diiodide. However, the products undergo degradation under the reaction conditions, which is avoided by warming and reducing the reaction times.
Figure 1. Formation of the para-tolyl iodoaziridine and the corresponding 1H NMR spectrum of the crude product mixture containing the iodoaziridine and 1,3,5-trimethoxybenzene.
Figure 2. Process for 1H NMR stability study for the para-tolyl iodoaziridine with various stationary phases; the best recovery of iodoaziridine is observed using basic alumina (activity IV) (53%).
Figure 3. Selected scope of the iodoaziridination reaction.
Figure 4. Proposed mechanism of reaction and rationale of diastereoselectivity.
Figure 5. Ratio of iodoaziridine to amino gem-diiodide with varying reaction time and temperature.
A procedure for the diastereoselective preparation of cis–N-Ts-iodoaziridines is described, along with a stability study protocol to quantitatively indicate the best stationary phase for purification of potentially unstable compounds by flash column chromatography. It is envisaged that access to iodoaziridines through this approach will enable methods to access to a wide range of aziridines to be developed, by derivatization of the intact ring.
An appropriate modification to the procedure for imines with an α-proton, is to use imine-toluene sulfinic acid adducts as starting materials in place of the imine due to the improved stability to storage and handling. From this starting material, an extra equivalent of both diiodomethane and LiHMDS should be employed to generate the imine in situ.
In preparation of the LiHMDS solution, the hexamethyldisilazane should be freshly distilled before use. Amine that has not been distilled can result in more of a minor aminal product being formed, through direct addition of the base into the aldimine. This aminal side product is also more prevalent when using commercial LiHMDS solutions, rather than a freshly prepared solution. Commercial nBuLi solutions must be regularly titrated to determine the concentration to control precisely the amount used in reaction. The diiodides and iodoaziridine products are light sensitive and so the reaction should be covered and exposure of the product to light should be minimized. Prolonged exposure to light leads to decomposition, so the isolated iodoaziridines should be stored at -20 °C in the dark.
The procedure described is limited to -branched imines with either the imine or imine-sulfinic acid adducts; only low yields are obtained for primary alkyl imines. This is due to the preferential direct addition of LiHMDS to the aldimine, over the desired addition of diiodomethyllithium, for less sterically hindered substrates.
To our knowledge there is not an available method to quantify the stability of a compound to stationary phases. This is particularly important for new compound classes or new small molecule functional groups. The protocol described here allows a rapid indication of the stability of the iodoaziridine to the various stationary phases, as well as providing a chance to identify decomposition products that could potentially be formed upon column chromatography. The protocol for quantitatively assessing the stability of iodoaziridines to stationary phases has potential for application in the purification of a wide range of compounds with sensitive functional groups, due to the general nature and ease of the setup.
There are a number of critical steps in the protocol. The dropwise addition of the imine/THF solution over 5 min is crucial to the yield of the product obtained. Faster addition times have shown to yield less of the desired iodoaziridine product. Purification on basic alumina (activity IV) is essential; use of silica results in decomposition products being observed. Basic alumina (activity IV) is not commercially available and must be prepared prior to use, as described in the protocol (3.2 and 3.3).
The authors have nothing to disclose.
For financial support we gratefully acknowledge the EPSRC (Career Acceleration Fellowship to J.A.B.; EP/J001538/1), the Ramsay Memorial Trust (Research Fellowship 2009-2011 to J.A.B.), and Imperial College London. Thank you to Prof. Alan Armstrong for generous support and advice.
Hexamethyldisilazane | 999-97-3 | Alfa Aesar | Distill from KOH under argon prior to use. |
n-Butyllithium | 109-72-8 | Sigma Aldrich | 2.5 M in hexanes, titrate prior to use. |
Diiodomethane | 75-11-6 | Alfa Aesar | Contains copper as a stabilizer. |
1,3,5-Trimethoxybenzene | 621-23-8 | Sigma Aldrich | |
Silica | 112945-52-5 | Merck | |
Basic alumina | 1344-28-1 | Sigma Aldrich | |
Neutral alumina | 1344-28-1 | Merck | |
Florisil | 1343-88-0 | Sigma Aldrich | |
THF | All anhydrous solvents were dried through activated alumina purification columns. | ||
Et2O | |||
CH2Cl2 | |||
NMR spectrometer | Bruker AV 400 | n/a | |
NMR processing software | MestReNova | 7.0.2-8636 |