Key words
aziridine - oxime - oxime ether - Lewis acid catalyst - S
N2-type ring opening - stereoselectivity
Oxime ethers have been used as valuable synthons for the preparation of a wide spectrum of biologically significant molecular moieties such as chiral α-, β-, and γ-amino acid derivatives,[1] γ-butyrolactones,[2] primary amines,[3] benzofurans,[4] pyrrolidines and piperidines,[5] C-glycosylthreonine and allothreonine,[6] chiral ligands,[7] and α-amino esters.[8] In addition, oxime ethers have also been used as a suitable class of radical acceptors under various photochemical[9] and nonphotochemical conditions,[1b]
[c] as auxiliary linkers,[10] as directing group for C–H functionalization,[11] and as coupling partners in annulation reactions with olefins.[12] The available reports for the synthesis of oxime ethers mainly involve etherification of oximes[13] – another valuable functional group in organic synthesis.[14] Dehydrogenative cross-coupling reaction between allylic sp3 C–H bonds with oximes[15] have also been performed to access oxime ethers. In this context, we realized that regio- and stereospecific synthetic routes to functionalized and structurally diverse oxime amino ethers are scarce in the literature which could nonetheless emerge as potential synthons for valuable biologically active compounds.
In recent years, the small-ring aza-heterocycles have emerged as one of the most advantageous building blocks in organic synthesis.[16] We have been working on Lewis acid catalyzed SN2-type ring-opening transformations of activated aziridines and azetidines to access various value-added aza-heterocyclic compounds either by ring-opening cyclization (ROC)[17] or by domino ring-opening cyclization (DROC)[18] strategies. Notably, aziridin-1-yl oximes have drawn attention from the synthetic chemists owing to their cytotoxic activity that make them potential anticancer agents.[19] Its prevalent chemistry involves the intramolecular ring-opening reactions of the aziridine functionality with the hydroxylamine group under suitable reaction conditions.[19]
[20] A very few literature reports describe intermolecular ring opening of aziridines with hydroxylamine anions in the presence of a strong base,[21] or with the nitrogen center of the oximes[22] or with α-carbanion of the oxime functionalities.[23] Ring opening of aziridines with nitrones is also documented.[18c] We anticipated that a wide variety of oxime amino ethers could easily be obtained via Lewis acid catalyzed intermolecular SN2-type ring opening of activated aziridines with aryl aldehyde oximes. Herein, we wish to report our preliminary results as a letter.
To test the viability of our approach, we performed a preliminary experiment with the reaction of racemic 2-phenyl-N-tosylaziridine (1a) with 1.5 equivalents of 4-methoxybenzaldehyde oxime (2a) in the presence of 40 mol % Cu(OTf)2 as the Lewis acid in dichloromethane at room temperature. To our delight, the ring opening of the aziridine 1a occurred at the benzylic position, and the corresponding 2-phenyl substituted oxime amino ether derivative 3a was formed in 60% yield as a single regioisomer (Scheme [1]). The molecular structure of 3a was characterized by its spectral and analytical data.[24]
Scheme 1 Lewis acid catalyzed ring opening of 2-phenyl-N-tosylaziridine (1a) with 4-methoxybenzaldehyde oxime (2a)
Next to optimize the reaction conditions for achieving better yields of the product, several other non-nucleophilic metal salts as the Lewis acids and solvents, such as 1,2-dichloroethane and tetrahydrofuran, were screened.
Table 1 Optimization Studies for the Lewis Acid Catalyzed Ring Opening of 2-Phenyl-N-tosylaziridine (1a) with 4-Methoxybenzaldehyde Oxime (2a)
|
|
Entry
|
Lewis acid (mol%)
|
Solvent
|
Temp
|
Time
|
Yield (%)a
|
|
1
|
Cu(OTf)2 (40)
|
CH2Cl2
|
rt
|
10 min
|
60
|
|
2
|
Cu(OTf)2 (40)
|
THF
|
rt
|
3 h
|
43
|
|
3
|
Cu(OTf)2 (40)
|
(CH2)2Cl2
|
rt
|
30 min
|
55
|
|
4
|
Sc(OTf)3 (40)
|
CH2Cl2
|
rt
|
1 h
|
53
|
|
5
|
Zn(OTf)2 (40)
|
CH2Cl2
|
rt
|
1.5 h
|
68
|
|
6
|
Yb(OTf)3 (40)
|
CH2Cl2
|
rt
|
2 h
|
41
|
|
7
|
Mg(OTf)2 (40)
|
CH2Cl2
|
rt
|
24 h
|
nr
|
|
8
|
BF3⋅OEt2 (40)
|
CH2Cl2
|
rt
|
1 h
|
76
|
|
9
|
BF3⋅OEt2 (20)
|
CH2Cl2
|
0 °C to rt
|
2 h
|
83
|
a Yields of isolated products after column chromatographic purification.
All the results are shown in Table [1]. The use of Cu(OTf)2 furnished the product in short time with moderate yield (entry 1). Changing the solvents from CH2Cl2 to either THF (entry 2) or 1,2-DCE (entry 3) led to the formation of the product 3a with reduced yields. The yield of the reaction further decreased with Sc(OTf)3 (53%, entry 4). Encouraging result was obtained with Zn(OTf)2, and the desired product could be obtained in 68% yield in 1.5 h (entry 5). The use of water-resistant Lewis acid Yb(OTf)3 afforded 3a in poor yield (41%, entry 6). No reaction was observed when a milder Lewis acid such as Mg(OTf)2 was used (entry 7). Notable increase in the yield was observed when 40 mol% BF3·OEt2 was used, and 3a was obtained in 76% yield (entry 8). The best result was obtained with 20 mol % BF3·OEt2 as the Lewis acid at 0 °C to room temperature, and 3a was obtained in 83% yield (entry 9). When the amount of Lewis acid was further decreased, the reaction was found to be sluggish.
Scheme 2 Ring opening of 2-aryl-N-tosylaziridines 1a–i with 4-methoxybenzaldehyde oxime (2a)
To generalize the strategy a wide range of 2-aryl-N-tosylaziridines bearing variety of substitution patterns on the aryl groups under the optimized reaction condition were studied. All the results are tabulated in Scheme [2]. When the aziridine 1b with a strong electron-donating tert-butyl group at the 4-position of the 2-phenyl group was used, the corresponding ring-opened product 3b was formed as a single regioisomer in good yield (64%). Interestingly, when aziridines 1c –e bearing halogen groups (F, Cl, and Br) at the 4-position of the 2-phenyl group were reacted, the respective oxime amino ethers 3c –e were obtained in high yields. With relatively more sterically constrained aziridines with halogen groups at the 2-position of the 2-phenyl groups 1f (Cl) and 1g (F), the respective oxime amino ethers 3f and 3g were obtained in 67% and 76% yields.
A marginal reduction in yield was observed with 2-(3- halophenyl)-substituted aziridines 1h (Cl) and 1i (F), and the corresponding ring-opened products 3h and 3i were furnished in 71% and 68% yields, respectively.
To study the electronic effect of the N-arylsulfonyl groups, a variety of N-arylsulfonylaziridines 1j–m with varying electron-withdrawing ability on the nitrogen were reacted with 4-methoxybenzaldehyde oxime (2a) under the optimized reaction conditions, and the results are shown in Scheme [3].
Scheme 3 Ring opening of various 2-phenyl-N-arylsulfonylaziridines 1j–m with 4-methoxybenzaldehyde oxime (2a)
The N-benzenesulfonyl aziridine 1j reacted smoothly with 2a and furnished the corresponding product 3j in 74% yield. On the other hand, with strong electron-donating groups such as 2,4,6-Me3 (mesityl; 1k), OMe (1l), or t-Bu (1m) attached with the phenylsulfonyl group of the aziridine, the respective oxime amino ethers 3k–m were formed as single regioisomers in excellent yield (up to 82%).
To further investigate the substrate tolerance, a wide range of aryl aldehyde oximes 2b–g were employed as the nucleophiles. Accordingly, when p-halo-substituted benzaldehyde oxime derivatives 2b (F) and 2c (Br) reacted with 1a, the corresponding oxime amino ethers 3n and 3o were obtained in 82% and 76% yields, respectively. The 3-Br variant 2d was also reacted efficiently, and 3p was formed in good yield (73%). When 2e with a nitro group at the 2-position of the aryl group was reacted with 1a, the corresponding product 3q was obtained in 70% yield. Interestingly, when sterically congested 1-naphthaldehyde oxime (2f) and 2-naphthaldehyde oxime (2g) were employed as the nucleophiles, the reactions proceeded well, and the products 3r and 3s were obtained in 72% and 78% yields, respectively, in short time. All the results are summarized in Scheme [4].
Scheme 4 Ring opening of 2-phenyl-N-tosylaziridine (1a) with various aryl aldehyde oximes 2b–g
Additional significance of our protocol was validated in the synthesis of nonracemic oxime amino ether derivative (R)-3a from (S)-1a. As we demonstrated in our earlier reports that the tetraalkylammonium salts could effectively control the racemization process of the enantiopure aziridines during the reaction,[25] we used a number of such salts in stoichiometric amount to enhance the stereospecificity of the product. After several screenings when (S)-1a was treated with 10.0 equivalents of 2a at –40 °C in the presence of 5 mol% Cu(OTf)2 as the Lewis acid and 3.0 equivalents of tetrabutylammonium tetrafluoroborate (TBABF4) as the additive using 1,2-dichloroethane as the solvent, the desired product 3a was obtained in good yield with up to 72% enantiomeric excess (Scheme [5]).
Scheme 5 Stereospecific synthesis of nonracemic oxime amino ether (R)-3a from (S)-1a
A plausible mechanistic pathway is shown in Scheme [6]. Based on the experimental observations, we propose that the Lewis acid catalyzed ring opening of the activated aziridines with aryl aldehyde oximes proceeds via an SN2-type pathway as demonstrated by us earlier.[17]
[18] At first, the Lewis acid gets coordinated with the nitrogen of the aziridine ring (or with the sulfonyl oxygen) and thereby further activates the aziridine towards nucleophilic attack. Then, the oxygen of the oxime functionality attacks at the benzylic position of the aziridine and after protonation/deprotonation produces the corresponding ring-opened product with high stereospecificity.
Scheme 6 Plausible mechanistic pathway for the formation of oxime amino ethers from activated aziridines and aryl aldehyde oximes
In conclusion, we have developed an operationally simple synthetic route to a wide variety of substituted racemic and nonracemic oxime amino ethers in good to high yields via Lewis acid catalyzed SN2-type ring opening of activated aziridines with aryl aldehyde oximes.[26] We believe that the developed methodology will be useful to the organic and medicinal chemists.
