以手性硫催化劑進行不對稱氮丙啶化反應之研究

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(1)國立臺灣師範大學化學系碩士學位論文 Department (Graduate institute) of Chemistry, National Taiwan Normal University. 以手性硫催化劑進行不對稱氮丙啶化反應之研究 Asymmetric and Catalytic Sulfur-Ylide Mediated Aziridination. 研究生: 王上華 (Shang-Hua Wang) 指導教授: 陳榮傑博士 (Dr. Rong-Jie Chein). 中華民國一 O 三年七月.

(2) 中文摘要. 以市售的 5-溴基戊酸乙酯、4-正丁基溴苯或 3,5-二苯基溴苯經由五步驟可得硫化物衍生物 2d - 2g。我們以硫化物 2d - 2g 作為催化劑進行不對稱氮丙啶反應之應用，探討氫鍵催化劑對亞胺的活化作用，並成功合成出苯乙烯基氮丙啶，得到良好的產率及鏡像選擇性。. 關鍵字: 鋶偶極體；不對稱催化；手性；鏡像異構物選擇性；氮丙啶 i.

(3) Abstract. Novel chiral tetrahydrothiophene derivatives 2b – g were synthesized from commercially. available. 5-bromovalerate. and. 4-butylbromobenzene. or. 3,5-diphenylbromobenzene. We demonstrate the application of these chiral sulfur catalysts in asymmetric aziridination of cinnamyl bromide and imines, and also investigate the promotion of the catalytic process by hydrogen bond catalyst such as ureas and thioureas. Vinyl-aziridines 9e - s were successfully obtained in good to excellent yields with high enantioselectivity and moderate diastereoselectivity.. Keyword: sulfide ylide; asymmetric catalysis; chirality; enantioselectivity; aziridines ii.

(4) 謝誌兩年多的碩士研究生活總算是告一段落，因為這一路上得到許多人的幫助和鼓勵，才能順利的完成這篇論文。首先，我非常感謝我的父母這二十幾年來無怨無悔的付出，從小到大都不曾給我壓力地讓我自由發展，無條件尊重我的想法、支持我的選擇、支柱我經濟上的需求，因為有我摯愛的家人在背後默默的關懷和鼓勵，我才能無後顧之憂的完成碩士學位。再來，我也非常感謝我的指導教授陳榮傑老師這兩年來的敦敦教誨，面對問題時，老師總是耐心的循循善誘幫助我尋找解決方法，且安全整潔的實驗環境、完善的實驗設備，也減少了許多實驗操作上的困難，在寫論文及口試期間老師也是給我極大的幫助，讓我可以順利如期的完成論文考試。另外，也要感謝姚清發老師及吳學亮老師百忙之中抽空擔任我的口試委員，提供我許多論文上的建議，使我的論文可以更趨完善。除此之外，我也要謝謝 RJ Lab 的所有成員，庭儀、昱庭、Pavan Kumar、 Bikshapathi Martha、迺彬、士哲、Ravi Kumara、京瑩、欣怡、孟婷、翊豪、致誠等學長姊弟妹，在實驗和論文上給我的幫助和指導，並教導我許多知識和技能，同時也常常鼓勵我，讓我更有信心的完成論文。還有，謝謝臺灣師範大學化學系及中研院化學所提供的設備和人員，也因為同時擁有兩邊的資源才能讓我的論文更加順利。最後，我要謝謝我的好夥伴欣欣，幫我處理許多師大的行政業務，也常常去妳家打擾，使我在台北的碩士生活並不孤單。也謝謝我的大學同學們，呸呸、詠詠、瑩臻、蜜桃、鳳鳳、詩詩、江江、郁筑、lichen、雅憶、月婷、鳳凰等共同分享彼此的喜怒哀樂、互相加油鼓勵，期許我們都能擁有更好的未來! 無盡感謝給所有曾經幫助、鼓勵我的人，感謝天。. 上華謹致一○三年八月. iii.

(5) Table of Contents 中文摘要 ................................................................................................................... i Abstract ..................................................................................................................... ii 謝誌 ......................................................................................................................... iii Table of Contents ..................................................................................................... iv List of Schemes ........................................................................................................ vi List of Figures ......................................................................................................... vii List of Tables .......................................................................................................... viii List of Abbreviations ................................................................................................ ix Chapter 1 1-1. 1-2. Chapter 2 2-1. 2-2. Introduction .......................................................................................... 1 Chiral thioether ...................................................................................... 1 1-1-1. Epoxidation................................................................................... 2. 1-1-2. Aziridination ................................................................................. 5. 1-1-3. Cyclopropanation .......................................................................... 6. Aziridine .................................................................................................. 7 1-2-1. Aziridination ................................................................................. 8. 1-2-2. Aziridination by using sulfonium ylides ....................................... 11. 1-2-3. Aziridination in an one-pot reaction ............................................ 13. Results and discussion ...................................................................... 16 Chiral sulfide catalysts ........................................................................... 16 2-1-1. Preparation of chiral sulfide catalysts 1a-d .................................. 16. 2-1-2. Preparation of the derivatives of chiral sulfide catalysts .............. 18. Aziridination .......................................................................................... 19 2-2-1. Screening of the substrate of bromide 10a-e ................................ 19. 2-2-2. Screening of sulfide catalysts ...................................................... 21 iv.

(6) 2-2-3. Screening of the solvents............................................................. 23. 2-2-4. Screening of hydrogen-bonding catalysts 11a-r ........................... 25. 2-2-5. Screening of solvents combined with urea derivatives 11b-c ....... 28. 2-2-6. Aziridine with various substituents .............................................. 30. 2-2-7. Further exploration...................................................................... 35. 2-2-8. Mechanism ................................................................................. 39. Chapter 3. Conclusion ......................................................................................... 40. Chapter 4. Experimental section .......................................................................... 41. 4-1. General information ............................................................................... 41. 4-2. Procedure and spectroscopic data ........................................................... 42. References ............................................................................................................... 71 Appendix................................................................................................................. 74. v.

(7) List of Schemes. Scheme 1.1 The result of asymmetric aziridination by using copper catalyst. .......... 9 Scheme 1.2 Aziridination with racemic sulfide. ...................................................... 11 Scheme 1.3 Asymmetric aziridination used chiral sulfonium ylides. ...................... 12 Scheme 1.4 Asymmetric aziridination with benzyl sulfonium salt. ........................ 12 Scheme 1.5 Aziridination catalyzed by a camphor-derived chiral sulfide in one pot. ................................................................................................................................ 13 Scheme 1.6 Aziridination of using a C2-symmetric sulfide in an one pot reaction. . 13 Scheme 1.7 Aziridination of using organometallic catalyst. ................................... 14 Scheme 1.8 Aziridination of using the [2,2,1] bicyclic sulfide. .............................. 14. vi.

(8) List of Figures. Figure 1.1 The mechanism of epoxidation via sulfonium salt................................... 3 Figure 1.2 Results of asymmetric epoxidation by using different sulfides. ............... 3 Figure 1.3 The mechanism of asymmetric epoxidation by using metallic catalyst. ... 4 Figure 1.4 The results of epoxidation via metal carbene by using different sulfides. 4 Figure 1.5 The results of asymmetric aziridination by using different sulfide. .......... 5 Figure 1.6 The results of cyclopropanation by using [2,2,2] bicyclic sulfide 27 ....... 6 Figure 1.7 Aziridine-containing compounds. ........................................................... 7 Figure 1.8 The strategies of aziridination. ................................................................ 8 Figure 1.9 Aziridination via three kinds of nucleophiles. ....................................... 10 Figure 1.10 Aziridination with tetrahydrothiophene chiral sulfide. ........................... 15 Figure 2.1 Preparation of chiral sulfide catalysts 1a-c. ........................................... 17 Figure 2.2 Preparation of derivatives of chiral sulfide catalysts 2a-f. ..................... 18 Figure 2.3 The mechanism of aziridination by using sulfide catalyst. ..................... 39. vii.

(9) List of Tables. Table 2.1 The result of screening different bromide. .............................................. 20 Table 2.2 The result of screening sulfide catalysts. ................................................ 22 Table 2.3 The results of screening the solvents. ..................................................... 24 Table 2.4 Optimization of aziridine with hydrogen bonding catalysts..................... 26 Table 2.5 The results of screening of solvents combined with urea derivatives....... 29 Table 2.6 The results of oximes 7e-s. ..................................................................... 31 Table 2.7 The results of imines 8e-s. ...................................................................... 32 Table 2.8 The results of aziridination with various substituents. ............................. 34 Table 2.9 The results of 9e, 9i with NaI. ................................................................ 35 Table 2.10 The results of imine 8m with hydrogen bonding catalysts 11b-d............. 37 Table 2.11 The results of imine 8i with hydrogen bonding catalysts 11a-c. .............. 38. viii.

(10) List of Abbreviations. d.r.. diastereomeric ratio. e.e.. enantiomeric excess. M. metal. TBAI. tetrabutylazanium iodide. PTSA. p-toluenesulfonic acid. mCPBA. meta-chloroperoxybenzoic acid. Ar. aryl. Ph. phenyl. Bn. benzyl. Me. methyl. Et. ethyl. Ts. tosyl. TMS. trimethylsilyl. NMR. nuclear magnetic resonance. HPLC. high-performance liquid chromatography. equvi.. equivalent. DCM. dichloromethane. MeCN. acetonitrile. THF. tetrahydrofuran. DMF. N,N-dimethylformamide. mp. melting point. ix.

(11) Chapter 1 1-1. Introduction. Chiral thioether. Chiral thioether catalysts attract much attention from chemists in the fields of asymmetric synthesis because of its extensive applications of optically active reagents such as sulfide ylide, bromoetherification, P-S ligand and so on. Thioethers are characterized by a divalent sulfur atom that possesses a strong nucleophilicity and a high affinity to soft metals but a weak affinity to hard acids. In addition, the sulfur atom can stabilize both positive and negative charges at the neighboring carbon.1. There are mainly two type of application with chiral thioethers in sulfur-ylide chemistry: one is to prepare chiral sulfonium salt, which is then used stoichiometrically to prepare a wide range of optically active compounds; the other with more challenges is directly using chiral sulfide in an one-pot reaction such as epoxidation, aziridination, cyclopropanation and so forth. We believed in its potential to extend the development of sulfur-catalysted asymmetric reaction.. 1.

(12) 1-1-1. Epoxidation. It is important for transformation from sulfide to sulfur ylide in an one-pot reaction for epoxidation2 and two methods have to be discussed.. The first method: Sulfur ylides were afforded by the reaction of sulfides with alkyl bromide and the treatments of base to proceed deprotonation. Then, the sulfide ylides react with aldehydes to form epoxides as shown in Figure 1.1. So far, several sulfide ylides were explored by numerous researchers for epoxidation, which as summarized in Figure 1.2. In most of case, the better results were obtained by using stoichiometric amount of chiral sulfide. Furukawa and Dai et al. reported the successful example of using champhor-derived sulfide 20, 23 for asymmetric epoxidation. The used of catalytic amount of sulfide gave moderate to high yield and up to 47% e.e.. In 2013, our lab achieved high yield and good enantioselectivity by using catalytic amount of sulfides 2a and accelerated the reaction rate efficiently, although the d.r. ratio was not extraordinary.. 2.

(13) Figure 1.1. The mechanism of epoxidation via sulfonium salt.. catalyst. reporting groups # of synthetic steps. 20, Furukawa3 2 steps. 21, Metzner4,4b 2 steps. 22, Goodman5 3 steps. time for epoxidation catalyst loading yield trans/cis e.e.. 1.5 d 50 mol% 50% 100/0 47% (R,R). 2d 100 mol% 92% 94/6 84% (S,S). 7d 100 mol% 59% 93/7 97% (R,R). reporting groups # of synthetic steps. 23, Dai6 2 steps. 24, Saito7 5 steps. 2a, Chein8 6 steps. time for epoxidation catalyst loading yield trans/cis e.e.. 15 h 20 mol% 97% 100/0 42% (R,R). 4d 100 mol% 72% 96/4 56% (S,S). 1d 20 mol% 92% 77/23 86% (R,R). catalyst. Figure 1.2. Results of asymmetric epoxidation by using different sulfides. 3.

(14) The second method is using metal carbenes as an intermediate, which is more reactive than alkyl halides and therefore promots ylide formation even with less reactive sulfides. Metallocarbene is obtained by decomposition of the diazo compound in the presence of a transition metal complex and reacts with sulfide to form the sulfur ylide. The sulfide ylide then reacts with the aldehyde to sulfide returns to catalytic cycle (Figure 1.3). Around 80% yield, over 90% e.e. and good diastereoselectivity (trans/cis = 98/2) were reported by Prof. Aggarwal in 1996 and 2001 under this condition (Figure 1.4).. Figure 1.3. The mechanism of asymmetric epoxidation by using metallic catalyst.. catalyst. reporting groups # of synthetic steps. 25, Aggarwal9 2 steps. 26, Aggarwal10 4 steps. catalyst loading metal loading yield trans/cis e.e.. 20 mol% 5 mol% Cu(acac)2 73% 98/2 94% (R,R). 5 mol% 1 mol% Rh2(OAc)4 82% 98/2 94% (R,R). Figure 1.4. The results of epoxidation via metal carbene by using different sulfides. 4.

(15) 1-1-2. Aziridination. Aggarwal et al. reported a catalytic aziridination using an organometallic compound as a catalyst in moderate to good results (Figure 1.5). The mechanism followed Figure 1.3 and imine was used as the start material. In 2014, a transition metal-free aziridination derived from Corey-Chaykovsky reaction was reported by our lab using asymmetric organocatalyst (S)-2a with high optical purity (95-98% e.e.) and good to high yield.. catalyst. reporting groups # of synthetic steps. 25, Aggarwal11 2 steps. 26, Aggarwal12 4 steps. 2a, Chein13 4 steps. catalyst loading metal loading yield trans/cis e.e.. 20 mol% 1 mol% Rh2(OAc)4 41-91% 3/1-5/1 88-95% (R,R). 20 mol% 1 mol% Rh2(OAc)4 33-82% 2/1-8/1 73-98% (R,R). 20 mol% -73-93% 54/46-83/17 95-98% (R,R). Figure 1.5. The results of asymmetric aziridination by using different sulfide.. 5.

(16) 1-1-3. Cyclopropanation. Since the [2,2,1] bicyclic sulfide 26 designed by Aggarwal et al. failed to give good yields on cyclopropanation of electron-poor alkenes. They further designed new sulfide [2,2,2] bicyclic sulfide 27, with provided better result than sulfide 26 (Figure 1.6).. catalyst. Figure 1.6. reporting groups # of synthetic steps. 27, Aggarwal12 4 steps. catalyst loading metal loading additive yield trans/cis e.e.. 20 mol% 1 mol% Rh2(OAc)4 20 mol% BnEt3N+Cl50-73% 4/1-1/7 91-92% (R,R) or (S,S). The results of cyclopropanation by using [2,2,2] bicyclic sulfide 27. 6.

(17) 1-2. Aziridine. Aziridine, a three-membered heterocycle with nitrogen atom, is a reactive substrate in ring-opening reactions with several nucleophiles due to their ring strain. This stable but strain-loaded three-membered ring allows regio- and stereoselective installation of a wide range of functional groups. On the other hand, they are important building blocks in organic synthesis, because amines, amino alcohols, diamines, and other useful nitrogen-containing molecules can be conveniently accessed. The aziridine functionality is also present in a small number of naturally occurring molecules.14 The biological properties of aziridine contained compounds such as mitomycins, azicemicins, ficellomycinare are of significant interest (Figure 1.7). The antibiotic and antitumor properties of these compounds are well known.. Figure 1.7. Aziridine-containing compounds. 7.

(18) 1-2-1. Aziridination. According to the literature, there are at least two ways to synthesize aziridines, one by using olefins and another by using imines as start materials (Figure 1.8).15. Figure 1.8. The strategies of aziridination.. Several groups reported asymmetric aziridinations according to Route A by using (N-(p-toluenesulfonyl)imino)phenyliodinane as the nitrene precursor and chiral copper as the catalyst. For example, aziridination from cinnamate esters was reported by Prof. Evans in 199316 using copper(I) triflate (CuOTf) as the catalyst and oxazoline as a ligand in moderate yields (60-70%) and high enantioselectivity (94-97%). In Prof. Jacobsen17 and Prof. Scott18’s reports, they used copper(I) triflate (CuOTf) and copper(I) tetra(acetonitrile) tetrafluoroborate (Cu(MeCN)4BF4) as catalysts with chiral diimine ligands 29, 30, respectively, higher yields and high enantioselectivities (80-90%) were achieved on chromene derivatives (Scheme 1.1).. 8.

(19) Scheme 1.1. The result of asymmetric aziridination by using copper catalyst.. 9.

(20) Three types of different nucleophiles such as carbenes, carbenoids, and ylides are better nucleophiles, which react well with imine as shown in Route B (Figure 1.9).. Figure 1.9. Aziridination via three kinds of nucleophiles.. The following section, we will give more detail about processing aziridination with sulfur ylides.. 10.

(21) 1-2-2. Aziridination by using sulfonium ylides. In 1996, Dai et al. reported a racemic aziridination, which used racemic sulfides via the ylide route (Scheme 1.4).6 At first, they tried to treat sulfonium ylides with imines containing different protection group on the nitrogen atom. Only aziridine with tosyl group containing imines were obtained in good yield. Moreover, they optimized this condition by screening different solvents, base, and sulfonium ylides. The best condition was applied to others aryl imine and the reaction completed within several minutes.. Scheme 1.2. Aziridination with racemic sulfide.. Afterword, in 1997, they developed a method to asymmetric aziridination by using a camphor derived chiral sulfide ylide (Scheme 1.5).19 At. first,. 3-bromo-1-(trimethylsilyl)propyne was treated with the chiral sulfide to give a chiral sulfonium ylides followed by the addition of imines. Aziridines with R or S form were occurred by using sulfonium ylides with exo or endo form. The trans/cis ratio was over 1/99, e.e. were 78% and 56%, respectively.. 11.

(22) Scheme 1.3. Asymmetric aziridination used chiral sulfonium ylides.. In 2010, Aggarwal et al. synthesized a sulfide with 98% e.e. from (R)-Limonene in only one step (Scheme 1.6).20 The chiral sulfide was treated with benzyl bromide and LiOTf to form chiral sulfonium ylides followed by the reaction with imines to form aziridines. The reaction under this condition was very fast (only one hour). They also explored a broad scope of imines, and high yields and excellent enantioselectivities were obtained.. Scheme 1.4. Asymmetric aziridination with benzyl sulfonium salt.. 12.

(23) 1-2-3. Aziridination in an one-pot reaction. Saito et al. used a camphor-derived chiral sulfide simply in the one-pot with a mixture of N-sulfonyl imine, bromide under basic condition.7,21 Steric hindrance of the chiral catalyst resulting in long reaction time when catalytic amount was used. Thus, sulfide was raised to stoichiometry and then got good results (Scheme 1.7).. Scheme 1.5. Aziridination catalyzed by a camphor-derived chiral sulfide in one-pot.. In 2007, Huang et al. also reported an one-pot method in enantioselective syntheses of aziridines using two equivalents of C2-symmetric sulfide (Scheme 1.8).22 They also optimized the condition by adding TBAI as a phase-transfer catalyst to improve the yield. Following this optimal conditions, they got results in moderate to good yields d.r. ratio and e.e... Scheme 1.6. Aziridination of using a C2-symmetric sulfide in one-pot reaction.. 13.

(24) Aggarwal et al. obtained good result by employing mentallocarbene as the catalyst for epoxidation in 1994.9 And later, they extended this method for the preparation of asymmetric aziridines from imines and diazo compounds in the presence of catalytic amounts of metal salts and sulfides (Scheme 1.2). Using sulfonium ylide, high enantioselectivity (89-95%) was achieved in this aziridination process.11. Scheme 1.7. Aziridination of using organometallic catalyst.. In 2001, Aggarwal et al. generated the diazocompound in situ from tosyl hydrazones and used it for asymmetric aziridination catalyzed by a new class of chiral sulfides ([2,2,1] bicyclic sulfide), that is more stable and easier to scale up than previous catalyst 26. After optimization this reaction gave good yield, high enantioselectivity, and moderate to high diastereoselectivity (Scheme 1.3).12. Scheme 1.8. Aziridination of using the [2,2,1] bicyclic sulfide. 14.

(25) In 2013, our lab first synthesized a novel chiral sulfide catalyst (S)-2a from 5-bromopentanoic acid in 6 steps and applied it successfully for the epoxidation of benzyl bromide and aryl aldehyde with up to 92% e.e. excellent yield and good diastereoselectivity.. 8. Further, in 2014, the synthesis of (S)-2a was shortened from. 5-bromovalerate (to 5 steps) and extended its application to aziridination with high enantioselectivity and good to excellent yield (Figure 1.10).13 Although, compared to other published, the diastereoselectivity was not the best one. As forementioned, it was worth to further explore the applications of catalyst (S)-2a and improve the diastereoselectivity, and we are going to discuss this issue in the next chapter.. Figure 1.10 Aziridination with tetrahydrothiophene chiral sulfide.. 15.

(26) Chapter 2. 2-1. Results and discussion. Chiral sulfide catalysts. 2-1-1. Preparation of chiral sulfide catalysts 1a-d. We prepared a series of tetrahydro-thiophene-derived chiral sulfides 1a–d, which were readily available through the procedure reported previously (Figure 2.1).13 First, commercially available ethyl 5-bromovalerate 3 was reacted with phenylmagnesium bromide to afford diphenylalcohol 4a that were dehydrated in hot toluene in the presence of PTSA. Optically active epoxide 6a was achieved from diphenylethylene 5a subjected to Shi asymmetric epoxidation condition afterwards we obtained (S)-(thiolan-2-yl)diphenylmethanol 1a by the cyclization. After recrystallization, we got 1a with more than 99% e.e.. The racemic mixture 1d was prepared by the treatment of 5a with mCPBA, and then transformed the racemic epoxide 6d to 1d by cyclization.. Same synthetic sequence was adopted for the preparation of another two chiral sulfide catalysts 1b-c (e.e. = 94 and 97%, respectively) obtained from 4-butylbromobenzene and 3,5-diphenylbromobenzene. Purpose of making different chiral sulfide was to observe the different in diastereomeric ratio and enantiomeric excess of following aziridination reaction.. 16.

(27) Figure 2.1 Preparation of chiral sulfide catalysts 1a-c.. 17.

(28) 2-1-2. Preparation of the derivatives of chiral sulfide catalysts. O-protection. of. 1a–c. with. benzyl. 1-bromomethylpentafluorobenzene,. bromide,. 4-butylbromobenzene,. 2-(chloromethyl)pyridine hydrochloride,. respectively, under basic conditions in DMF yielded corresponding catalysts 2a–f for the following aziridination process (Figure 2.2).. Figure 2.2 Preparation of derivatives of chiral sulfide catalysts 2a-f.. 18.

(29) 2-2. Aziridination. Our success with asymmetric epoxidations8 and aziridinations13 by way of optically active sulfide catalyst (S)-2a and only using catalytic amount in an one-pot reaction encouraged us to apply our sulfide catalysts to explore another substrate in aziridination.. 2-2-1. Screening of the substrate of bromide 10a-e. From the literature survey, we chose different bromides 10a-e as substrates which were screened for aziridination reaction using racemic derivative of sulfide catalyst 2g and followed the condition reported by our lab very recently.13 Results for the reaction of imine with methyl bromoacetate (10a), 3-bromo-1-(trimethylsilyl)-1-propyne (10b), 2-bromoacetonitrile (10c), bromomethyl phenyl sulfone (10d), and cinnamyl bromide (10e) under the optimized condition were summarized in Table 2.1. The imine 8e derived from cinnamyl bromide 10e could be employed and afforded trans and cis in a ratio of 60:40 in near 65 % yield (Table 2.1, entry 5). Unfortunately, in other substrates 10a-c (Entries 1–3), almost there were no reaction even though the reaction time was extended up to 3 to 6 days. In entry 4, we also could get product 9d in 55 % yield, but cis compound was major. Based on the above results, we decided the vinyl-aziridine 9e as the model substrate to search the condition for the following asymmetric aziridination.. 19.

(30) Table 2.1. a b c d e. The result of screening different bromide.. R = COOMe R = C≡CTMS R = CN R = SO2Ph R = (E)C=CPh. entry. bromide. time (days). trans/cisa. yield (%)b. 1. 10a. 4. -. 0c. 2. 10b. 3. -. 0c. 3. 10c. 6. -. 0c. 4. 10d. 6. 12/88. 55. 5. 10e. 1. 60/40. 64. a. Ratio was determined by 1H NMR. b Isolated yield. c. No reaction.. 20.

(31) 2-2-2. Screening of sulfide catalysts. Even though we obtained aziridine 9e in respect yield, there still needed to improve the diastereomeric ratio (Table 2.1, entry 5). In order to improve d.r. and determined the e.e., next we focused on screening of various chiral sulfide catalysts 2a-f for aziridination reaction. The result of using chiral sulfide catalysts in aziridination reaction with cinnamyl bromide and imine were showed in Table 2.2. As previously mentioned, we thought that d.r. might be enhanced if the substituted group was bulkier, however, it was not as expected from the result. We observed that an increase in the bulkiness of the aryl substituents on sulfide catalyst did not improve the diastereomeric ratio of the reaction (Table 2.2, entries 2-3). Even though we protected the alcohol with strong electron-donating group (Table 2.2, entry 4) or electron-withdrawing (Table 2.2, entries 5-6), they was no improvement in diastereomeric ratio. In most of the cases, the enantiomeric excess was up to 90 %, except the result in Table 2.2, entry 6. Hence, we concluded 2a was selected sulfide catalyst for the latter.. 21.

(32) Table 2.2. The result of screening sulfide catalysts.. entry. Sulfide. trans/cisa. e.e. (%)b. yield (%)c. 1. 2a. 66/34. 89. 82. 2. 2b. 66/34. 87. 81. 3. 2c. 55/45. 87. 63. 4. 2d. 59/41. 90. 66. 5. 2e. 61/39. 89. 64. 6. 2f. 60/40. 56. 60. a. Ratio was determined by 1H NMR. b e.e. Of trans aziridine was determined by HPLC with a Chiralcel-OD column. c Isolated yield.. 22.

(33) 2-2-3. Screening of the solvents. The effects of solvent on this reaction were investigated and the results were shown in Table 2.3. In order to judge the reaction rate, we fixed the reaction time for 24 hours.. Out of six solvents we used, acetonitrile and dichloromethane were found to be suitable solvents for this reaction, it was showed that dichloromethane was the best solvent in comparison with acetonitrile, because of the d.r. and e.e. (Table 2.3, entries1-2). The start materials were not consumed in THF, trifluorotoluene and DMF and the yields were only 12, 29 and 7%, respectively (Table 2.3, entries 3-5). There was almost no reaction in toluene (Table 2.3, entries 6). The results of enantiomeric excess were similar in all.. 23.

(34) Table 2.3. The results of screening the solvents.. entry. solvent. trans/cisa. e.e. (%)b. yield (%)c. 1. MeCN. 66/34. 89. 82. 2. DCM. 68/32. 90. 78. 3. THF. 65/35. 91. 12. 4. trifluorotoluene. 67/33. 95. 29. 5. DMF. 76/24. 92. 7. 6. toluene. -. -. 0d. a. Ratio was determined by 1H NMR. b e.e. Of trans aziridine was determined by HPLC with a Chiralcel-OD column. c Isolated yield. d No reaction.. 24.

(35) 2-2-4. Screening of hydrogen-bonding catalysts 11a-r. Clearly, the diastereomeric ratio in forming the above-mentioned vinyl-aziridines under existing condition was low. According to previous research, Prof. Jacobsen23 and Prof. Corey24 published an asymmetric variant of the Strecker reaction using hydrogen-bonding organocatalysts that activate imine electrophiles. Thus, we turned our effort to improve the diastereoselectivity of this aziridination by exposure of hydrogen-bonding catalyst was presented.. Recently, a large number of hydrogen-bonding catalysts were reported in the literature used for various reactions. As 18 hydrogen-bonding catalysts 11a-r were in hand from our lab, we put our attention as promoters of the aziridination. Following this optimization, a lot of catalysts 11a-r were examined in the asymmetric aziridination reaction (Table 2.4). We found that, in the presence of hydrogen-bonding catalysts, there was a marginally improvement of d.r. and e.e. ratio and seemed to have no significant difference between achiral 11a-c and chiral 11d-r hydrogen-bonding catalysts. Because of the cost of chiral hydrogen-bonding catalysts 11d-r in mind, we preferred using achiral hydrogen bonding catalysts 11a-c as the additives.. 25.

(36) Table 2.4. Optimization of aziridine with hydrogen bonding catalysts.. entry. H-bonding catalyst. trans/cisa. e.e. (%)b. yield (%)c. 1. none. 68/32. 90. 78. 2. 11a. 68/32. 86. 76. 3. 11b. 71/29. 92. 80. 4. 11c. 71/29. 92. 48. 5. 11d. 69/31. 94. 83. 6. 11e. 68/32. 92. 67. 7. 11f. 70/30. 92. 72. 8. 11g. 69/31. 93. 75. 9. 11h. 68/32. 92. 50. 26.

(37) 10. 11i. 68/32. 92. 42. 11. 11j. 69/21. 93. 61. 12. 11k. 70/30. 91. 89. 13. 11l. 71/29. 91. 82. 14. 11m. 64/36. 91. 89. 15. 11n. 70/30. 92. 63. 16. 11o. 69/31. 90. 84. 17. 11p. 69/31. 91. 83. 18. 11q. 67/33. 92. 78. 19. 11r. 70/30. 92. 76. a. Ratio was determined by 1H NMR.. b. e.e. Of trans aziridine was determined by HPLC with a Chiralcel-OD column. Isolated yield.. c. 27.

(38) 2-2-5. Screening of solvents combined with urea derivatives 11b-c. In order to optimize the conditions for the aziridination, the effects of the combination of solvents and urea derivatives on this reaction were investigated. The results of urea 11b and thiourea 11c catalyst in acetonitrile, dichloromethane, tetrahydrofuran, trifluorotoluene, DMF and toluene, respectively, were summarized in Table 2.5. No matter which hydrogen-bonding catalysts was inside, the case in dichloromethane was revealed as the more suitable solvent. It was found that urea catalyst 11b was the best promoter in comparison of thiourea catalyst 11c with respect to the higher yield (Table 2.5, entry 3). In addition, the result was nothing different by using 0.2 equiv. urea catalyst 11b (Table 2.5, entry 4). Finally, we used 0.1 equiv. 11b for the following optimization.. 28.

(39) Table 2.5. The results of screening of solvents combined with urea derivatives.. entry. solvent. H-bonding catalyst. trans/cisa. e.e.(%)b. yield (%)c. 1. MeCN. 11b. 63/37. 89. 55. 2. MeCN. 11c. 63/37. 89. 63. 3. DCM. 11b. 71/29. 92. 80. 4d. DCM. 11b. 73/27. 93. 82. 5. DCM. 11c. 71/29. 92. 50. 6. THF. 11b. 66/34. 91. 15. 7. THF. 11c. 65/35. 90. 39. 8. trifluorotoluene. 11b. 72/28. 91. 48. 9. trifluorotoluene. 11c. 71/29. 93. 28. 10. DMF. 11b. 72/28. 91. 9. 11. DMF. 11c. 62/38. 94. 21. 12. toluene. 11b. 64/36. 91. 8. 13. toluene. 11c. 69/31. 93. 4. a. Ratio was determined by 1H NMR. b e.e. Of trans aziridine was determined by HPLC with a Chiralcel-OD column. c Isolated yield. d. The reaction used 0.2 equiv. 11b.. 29.

(40) 2-2-6. Aziridine with various substituents. Hence, the optimal condition of the vinyl-aziridination was found, and then we focus on intention toward preparation of imine. At first, we started to synthesize oximes 7e-s from various aldehydes, and then treated with diphenylphosphine chloride to form corresponding imines 8e-s, the procedure was adopted describe in the literature.25, 26 All of the schemes and results were shown in Table 2.6, 2.7 and the overall yields was 45-70 %.. 30.

(41) Table 2.6 The results of oximes 7e-s.. 31.

(42) Table 2.7 The results of imines 8e-s.. 32.

(43) Having various imines 8e-s in hand, they were subjected to aziridination reaction by treating with potassium carbonate, sulfide (S)-2a, urea catalyst 11b in dichloromethane and then followed by addition of cinnamyl bromide 10e to generate the corresponding vinyl-aziridines 9e-s. Furthermore, we also explored the results in absence of urea catalyst 11b which were shown in Table 2.8.. According to the results, the respectable diastereomeric ratio in good to high yield and moderate to high e.e. was achieved. It was worthy to notice that reaction rate was faster in the presence of urea catalyst 11b under such condition, especially, the reaction time of the most electron rich groups (9s) were even decreased from 8 days to 1day. Interestingly, there was up to 25 % increase in yield and optical purity in some case by addition of the promoter 11b. The exception occurred in the reaction of ortho-substituent (9k, o, r), whether electron rich (9k, o) or electron poor (9r), the trans/cis ratio of the product was rather low and even reverse due to steric hindrance in ortho-position. As the forementioned results, undoubtedly there was a correlation between urea catalyst 11b and aziridination.. 33.

(44) Table 2.8. a b. The results of aziridination with various substituents.. Isolated yield. Ratio was determined by 1H NMR.. c. e.e. Of trans aziridine was determined by HPLC.. d. With urea catalyst 11b (0.1 equiv.). 34.

(45) 2-2-7. Further exploration. After several efforts for the improvement of d.r. still trapped up to now, hence we tried to optimize by the addition of sodium iodide, considering that fact it having an influence on aziridination in our prior report. We chose two substrates 8e, 8i for the trial depending on their diverse reaction rate. Unfortunately, the results of both were not only seemed to have any significant effect but also diminished the reaction rate in the presence of sodium iodide (Table 2.9).. Table 2.9. The results of 9e, 9i with NaI.. entry. imine. additive. trans/cisa. time (h). e.e. (%)b. yield (%)c. 1. 8e. none. 71/29. 24. 92. 80. 2. 8e. NaI. 72/28. 60. 92. 80. 3. 8i. none. 76/24. 48. 96. 88. 4. 8i. NaI. 74/26. 96. 93. 74. a. Ratio was determined by 1H NMR. b e.e. Of trans aziridine was determined by HPLC with a Chiralcel-OD column. c Isolated yield.. 35.

(46) Besides, it was found that imines of electron-donating group affording better results by the obviously hydrogen-bonding activation. We attempted to investigate the correlation hydrogen-bonding catalysts and the electron rich substituents.. The trial showed that the electron rich 8m treated with chiral and achiral urea catalyst 11b, f and chiral and achiral thiourea catalysts 11b, c (Table 2.10) for 24 hours. The reaction was finished by using urea catalyst 11b for 24 hours (Entry 2), while the starting material was not consumed in entries 3-5 (yields of entries 3-5 were 60, 74 and 77%, respectively). From the results, urea catalyst 11b was observed as the best promoter, thus the other catalysts 11c-d retarded the reaction rate under this reaction.. 36.

(47) Table 2.10 The results of imine 8m with hydrogen bonding catalysts 11b-d.. entry H-bonding catalyst. trans/cisa. e.e. (%)b. yield (%)c. 1d. none. 71/29. 90. 82. 2. 11b. 74/26. 91. 88. 3. 11c. 70/30. 92. 60. 4. 11d. 72/28. 93. 74. 5. 11f. 72/28. 93. 77. a. Ratio was determined by 1H NMR. b e.e. Of trans aziridine was determined by HPLC with a Chiralcel-OD column. c d. Isolated yield. After 2.5 days, start material was consumed.. 37.

(48) We were also interested in the effect about the association with achiral hydrogen-bonding catalysts 11a-c with another strong electron rich imine 8i (Table 2.11), while the best result (Table 2.11, entry 2) was still found by using urea catalyst 11b.. In the event, urea catalyst 11b played an important role in the asymmetric vinyl-aziridination under this condition on aziridination.. Table 2.11 The results of imine 8i with hydrogen bonding catalysts 11a-c.. a. entry. H-bonding catalyst. trans/cisa. time (h). e.e. (%)b. yield (%)c. 1. none. 70/30. 72. 87. 80. 2. 11a. 72/28. 44. 94. 84. 3. 11b. 76/24. 48. 96. 88. 4. 11c. 71/29. 56. 91. 73. Ratio was determined by 1H NMR.. b. e.e. Of trans aziridine was determined by HPLC with a Chiralcel-OD column. c Isolated yield.. 38.

(49) 2-2-8. Mechanism. As mentioned in the proposed catalytic cycle (Figure 2.3). The cinnamyl bromide attacked the chiral sulfide (S)-2b to form sulfonium salt 12. Further up on deprotonation 12 converted to sulfur ylide 13. The 13 existed in to conformation 13a and 13b, but the 13b was more favored conformation due to the steric hindrance. On the other hand, the imines were activated by urea catalyst via hydrogen bonding that made imines more electrophilic which further attacked by sulfur ylide to form 14. The 14 favored more anti-phase (Si phase, 14b) which on elimination of sulfide catalyst form trans aziridine.. Figure 2.3. The mechanism of aziridination by using sulfide catalyst. 39.

(50) Chapter 3. Conclusion. We have synthesized (S)-diphenyl(tetrahydrothiophen-2-yl)methanol and its derived 1a-1c in 4 steps from commercially available ethyl 5-bromovalerate and proceeded O-protection to obtain corresponding chiral sulfides 2a-f. Successfully, we extend the application of catalytic sulfide by synthesizing vinyl-aziridines. Faster reaction rate, higher yield and e.e. were achieved under dual-catalyst system by adding hydrogen-bond donor catalyst (urea catalyst 11b). It is still a challenge to improve diastereoselectivity in the catalytic one-pot aziridination.. 40.

(51) Chapter 4. 4-1. Experimental section. General information. All reactions were carried out under an inert atmosphere unless mentioned otherwise, and standard syringe–septa techniques were followed. Solvents were freshly dried and purified by conventional methods prior to use. The progress of all the reactions were monitored by TLC, using TLC glass plates precoated with silica gel 60 F254 (Merck). Column chromatography was performed on silica gel Geduran® Si 60 (Merck). Optical rotation values were measured with Jasco P-2000 polarimeter, and IR spectra were recorded with Thermo Nicolet iS-5 FT-IR spectrophotometer, λmax in cm-1. 1H and 13C NMR spectra were recorded with Bruker AV-III 400 MHz, Bruker AV-400, or AV-500 MHz spectrometers and chemical shifts were measured in δ(ppm) with residual solvent peaks as internal standards (CDCl3, δ 7.26 ppm in 1H NMR, δ 77 ppm in 13C NMR). Coupling constants J, measured in Hz. MALDI-mass spectra were conducted on an Applied Biosystems 4800 Proteomics Analyzer (Applied Biosystem, Foster City) equipped with an Nd/YAG laser (335nm) operating at a repetition rate of 200 Hz. HR EI (LR EI)-mass spectra were recorded on a JMS-700 double focusing mass spectrometer (JEOL, Tokyo, Japan) with a resolution of 8000(3000) (5% valley definition) and HR (LR) ESI (Electrospray)-mass spectra were recorded using dual ionization ESCi® (ESI/APCi) source options, Waters LCT premier XE (Waters Corp., Manchester, UK). Melting points were recorded on Buchi M-565 apparatus. The determination of ee was performed via chiral phase HPLC analysis using Agilent 1200 series HPLC workstation. 41.

(52) 4-2. Procedure and spectroscopic data. General procedure for synthesis of (S)-2-((Benzyloxy)diarylmethyl)tetrahydrothiophene 2b-2g. To a stirred solution of ((S)-thiolan-2-yl)diarylmethanol (3.7 mmol) in DMF (7.4 mL) at 0 °C was added sodium hydride (296 mg, 7.4 mmol). The reaction mixture was warmed to room temperature and stirred for 1 h. The corresponding bromide (0.53 mL, 4.4 mmol) was then slowly added to the reaction mixture. After 16 h, the reaction mixture was quenched with sat. NH4Cl (5 mL) at 0 °C, extracted with Et 2O (5 mL × 3), dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography (EtOAc/hexane, 1:49) to give the pure product.. (S)-2-((Benzyloxy)diphenylmethyl)tetrahydrothiophene (2a)13. White solid; Yield - 92% (1.2 g); Rf (10% EtOAc/hexane) 0.5; Prepared as shown in general experimental procedure.; 1H NMR (400 MHz, CDCl3) δ 7.57−7.55 (m, 2H), 7.44 (d, J = 7.2 Hz, 2H), 7.34−7.16 (m,11H), 4.66 (t, J = 7.2 Hz, 1H), 4.38 (d, J = 11.6 Hz, 1H), 4.21 (d, J = 11.5 Hz, 1H), 2.63 (m, 1H), 2.32 (ddd, J = 10.1, 8.2, 6.1 Hz, 1H), 1.98 (td, J = 12.7, 6.0 Hz, 1H), 1.84 (m, 1H), 1.64 (m, 1H), 1.34 (tt, J = 11.9, 5.9 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 129.3, 128.8, 128.0, 127.4, 127.2, 127.1, 127.0, 126.9, 126.9, 85.9, 65.5, 53.8, 32.6, 31.6, 30.2.. 42.

(53) (S)-2-((Benzyloxy)bis(4-(tert-butyl)phenyl)methyl)tetrahydrothiophene (2b). Colorless liquid; Yield - 95% (1.7 g); Rf (2% EtOAc/hexane) 0.35; Prepared as shown in general experimental procedure.; 1H NMR (400 MHz, CDCl3) δ 7.44 (d, J = 8.3 Hz, 2H), 7.38 – 7.27 (m, 6H), 7.27 – 7.20 (m, 1H), 7.10 (dd, J = 8.2, 5.1 Hz, 4H), 4.66 (t, J = 7.1 Hz, 1H), 4.37 (d, J = 11.7 Hz, 1H), 4.19 (d, J = 11.7 Hz, 1H), 2.73 – 2.64 (m, 1H), 2.60 (dd, J = 15.7, 8.0 Hz, 4H), 2.38 (ddd, J = 10.2, 8.0, 6.2 Hz, 1H), 2.01 (td, J = 12.9, 5.9 Hz, 1H), 1.85 (ddd, J = 20.0, 12.9, 7.3 Hz, 1H), 1.76 – 1.65 (m, 1H), 1.60 (ddd, J = 19.8, 10.3, 4.8 Hz, 4H), 1.37 (dtd, J = 12.0, 7.4, 5.0 Hz, 5H), 0.93 (td, J = 7.3, 3.8 Hz, 6H);. 13. C NMR (100MHz, CDCl3) δ141.9, 141.7, 140.5, 139.6, 138.7, 129.3, 128.9,. 128.1, 127.4, 127.0, 127.0, 126.9, 85.9, 65.5, 54.4, 35.2, 35.2, 33.5, 33.4, 32.7, 31.8, 30.3, 29.7, 22.4, 14.0, 14.0; HRMS-ESI (m/z): Calcd for C32H40OS [(M+Na)+] 495.2698, found [(M+Na)+] 495.2691.. (S)-2-(Di([1,1':3',1''-terphenyl]-5'-yl)(benzyloxy)methyl)tetrahydrothiophene(2c). White solid; Yield - 93% (2.3 g); Rf (5% EtOAc/hexane) 0.38; Prepared as shown in general experimental procedure.; 1H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 1.6 Hz, 2H), 7.81 (dd, J = 3.3, 1.6 Hz, 3H), 7.77 (t, J = 1.6 Hz, 1H), 7.70 – 7.60 (m, 8H), 7.45 (dd, J = 16.1, 8.6 Hz, 10H), 7.37 (dd, J = 8.3, 6.6 Hz, 6H), 7.32 – 7.26 (m, 1H), 4.88 (t, 43.

(54) J = 7.2 Hz, 1H), 4.63 (d, J = 11.9 Hz, 1H), 4.52 (d, J = 11.9 Hz, 1H), 2.87 – 2.76 (m, 1H), 2.53 (ddd, J = 10.2, 8.3, 6.0 Hz, 1H), 2.18 (td, J = 12.7, 5.9 Hz, 1H), 2.10 – 1.98 (m, 1H), 1.87 – 1.73 (m, 1H), 1.64 – 1.53 (m, 1H); 13C NMR (100MHz, CDCl3) δ 144.3, 142.5, 141.2, 141.3, 141.1, 141.1, 140.4, 139.3, 128.7, 128.3, 127.3, 127.3, 127.1, 127.0, 126.9, 125.4, 125.1, 86.7, 66.1, 54.3, 33.1, 31.9, 30.4 ; MALDI (m/z): Calcd for C48H40OS [(M+Na)+] 687.2692, found [(M+Na)+] 687.2694.. (S)-2-(((4-(Tert-butyl)benzyl)oxy)diphenylmethyl)tetrahydrothiophene (2d). Coloress liquid; Yield - 66% (1.0 g); Rf (5% EtOAc/hexane) 0.55; Prepared as shown in general experimental procedure.; 1H NMR (400 MHz, CDCl3) δ 7.66 – 7.60 (m, 2H), 7.54 – 7.47 (m, 2H), 7.40 – 7.26 (m, 8H), 7.19 (d, J = 8.0 Hz, 2H), 4.74 (t, J = 7.2 Hz, 1H), 4.41 (d, J = 11.3 Hz, 1H), 4.25 (d, J = 11.3 Hz, 1H), 2.79 – 2.69 (m, 1H), 2.68 – 2.61 (m, 2H), 2.43 (ddd, J = 10.2, 8.1, 6.1 Hz, 1H), 2.09 (td, J = 12.8, 5.8 Hz, 1H), 1.92 (dddd, J = 13.0, 9.0, 7.1, 5.9 Hz, 1H), 1.83 – 1.69 (m, 1H), 1.69 – 1.59 (m, 2H), 1.51 – 1.34 (m, 3H), 0.98 (t, J = 7.3 Hz, 3H); 13C NMR (100MHz, CDCl3) δ 143.4, 142.2, 141.7, 141.7, 136.4, 135.5, 129.4, 129.0, 128.4, 128.2, 127.8, 127.5, 127.3, 127.1, 127.0, 85.9, 65.5, 53.9, 35.3, 33.6, 32.8, 31.7, 30.3, 22.3, 13.9; MALDI (m/z): Calcd for C48H40OS [(M+Na)+] 439.2066, found [(M+Na)+] 439.2065.. 44.

(55) (S)-2-(((Perfluorophenyl)methoxy)diphenylmethyl)tetrahydrothiophene (2e). White solid; Yield - 64% (1.1 g); Rf (2% EtOAc/hexane) 0.48; Prepared as shown in general experimental procedure.; 1H NMR (400 MHz, CDCl3) δ 7.51 (dt, J = 4.5, 2.5 Hz, 2H), 7.41 – 7.23 (m, 8H), 4.62 (t, J = 7.2 Hz, 1H), 4.52 (d, J = 10.1 Hz, 1H), 4.31 (d, J = 10.1 Hz, 1H), 2.79 – 2.67 (m, 1H), 2.44 (ddd, J = 10.2, 8.3, 6.0 Hz, 1H), 1.98 (td, J = 12.7, 5.7 Hz, 1H), 1.90 – 1.78 (m, 1H), 1.72 (dddd, J = 15.1, 12.3, 8.6, 6.2 Hz, 1H), 1.48 (dt, J = 11.6, 5.5 Hz, 1H);. 13. C NMR (100MHz, CDCl3) δ 146.9, 144.4, 142.9,. 141.0, 138.6, 136.2, 129.3, 128.6, 127.6, 127.6, 127.4, 127.2, 112.1, 86.5, 53.8, 53.5, 32.9, 31.5, 30.3; MALDI (m/z): Calcd for C24H19OSF5 [(M+Na)+] 473.0968, found [(M+Na)+] 473.0957.. (S)-2-((Diphenyl(tetrahydrothiophen-2-yl)methoxy)methyl)pyridine (2f). To a stirred solution of ((S)-thiolan-2-yl)diphenylmethanol (0.9 mmol) in DMF (1.9 mL) at 0 °C was added sodium hydride (132 mg, 3.3 mmol). The reaction mixture was warmed. to. room. temperature. and. stirred. for. 1. h.. The. 2-(chloromethyl)pyridine hydrochloride (232 mg, 1.4 mmol) was then slowly added to the reaction mixture. After 16 h, the reaction mixture was quenched with sat. NH 4Cl (5 45.

(56) mL) at 0 °C, extracted with Et 2O (5 mL × 3), dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography (EtOAc/hexane, 1:49) to give the colorless liquid as pure product (71% (230 mg)); Rf (10% EtOAc/hexane) 0.35; 1H NMR (400 MHz, CDCl3) δ 8.48 (d, J = 4.9 Hz, 1H), 7.72 (td, J = 7.7, 1.8 Hz, 1H), 7.64 (d, J = 7.8 Hz, 1H), 7.58 (dt, J = 4.6, 2.5 Hz, 2H), 7.51 – 7.43 (m, 2H), 7.38 – 7.24 (m, 6H), 7.20 – 7.13 (m, 1H), 4.73 (t, J = 7.2 Hz, 1H), 4.51 (d, J = 13.4 Hz, 1H), 4.40 (d, J = 13.4 Hz, 1H), 2.77 – 2.66 (m, 1H), 2.41 (ddd, J = 10.2, 8.1, 6.1 Hz, 1H), 2.08 (td, J = 12.8, 5.8 Hz, 1H), 1.95 – 1.83 (m, 1H), 1.74 (tdd, J = 8.7, 7.1, 4.3 Hz, 1H), 1.43 (dt, J = 11.8, 5.7 Hz, 1H);. 13. C NMR (100MHz, CDCl3) δ 159.4, 148.6, 142.8,. 141.3, 136.5, 129.3, 129.0, 127.5, 127.5, 127.3, 127.1, 121.9, 120.8, 86.3, 66.7, 53.8, 32.7, 31.7, 30.2; MALDI (m/z): Calcd for C23H23OS [(M+Na)+] 384.1392, found [(M+Na)+] 384.1396.. General procedure for synthesis of Oximes7e-7s25. The hydroxylamine hydrochloride (1.1 g, 16.2 mmol) and sodium acetate (1.1 g, 13.8 mmol) were taken in round bottomed flask to that 12 ml of water was added followed by the slow addition of the correspondingaldehyde (0.96ml, 9.4 mmol) and stirred for 3 hat room temperature. After the reaction completed, extracted with diethyl ether (10 ml × 3), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (EtOAc/hexanes, 1:19) to give the pure oxime. 46.

(57) Benzaldehydeoxime (7e)25. Colorless liquid; Yield - 90% (1.0 g); Rf (20% EtOAc/Hexane) 0.3; Prepared as shown in general experimental procedure.; 1H NMR (400 MHz, CDCl3) δ 9.07 (s, 1H), 8.19 (s, 1H), 7.59 (m, 2H), 7.46 – 7.36 (m, 3H); 13C NMR (100MHz, CDCl3) δ 150.4, 131.9, 130.1, 128.8, 127.0.. 4-(Trifluoromethyl)benzaldehydeoxime (7f)27. White solid; Yield - 77% (834 mg); Rf (20% EtOAc/Hexane) 0.45; Prepared as shown in general experimental procedure.; 1H NMR (500 MHz, CDCl3) δ 8.91 (s, 1H), 8.21 (s, 1H), 7.69- 7.63 (m, 4H); 13C NMR (125 MHz, CDCl3) δ 149.3, 135.3, 131.9 (q, 2JC-F = 32.7 Hz), 127.3, 125.8 (d, 3JC-F = 2.52 Hz) , 123.8 (q, 1JC-F = 272.5 Hz).. 4-Chlorobenzaldehyde oxime (7g)28. White solid; Yield - 87% (968 mg); Rf (20% EtOAc/Hexane) 0.48; Prepared as shown in general experimental procedure.; 1H NMR (500 MHz, CDCl3) δ 8.52 (s, 1H), 8.12 (s, 1H), 7.51 (d, J = 6.4 Hz, 2H), 7.36 (d, J = 6.4 Hz, 2H); CDCl3) δ 149.3, 136.0, 130.4, 129.1, 128.2. 47. 13. C NMR (125 MHz,.

(58) 4-Fluorobenzaldehyde oxime (7h)29. White solid; Yield - 94% (1.05 g); Rf (20% EtOAc/Hexane) 0.48; Prepared as shown in general experimental procedure.; 1H NMR(400 MHz, CDCl3) δ 8.40 (s, 1H), 8.13 (s, 1H), 7.57 (m, 2H), 7.08 (m, 2H); 13C NMR(100 MHz, CDCl3) δ 163.8 (d, 1JC-F = 268.3 Hz) , 149.3, 128.9(d, 3JC-F = 8.3 Hz), 128.1 (d, 4JC-F = 2.8 Hz), 115.9 (d, 2JC-F= 21.9 Hz).. 4-Methoxybenzaldehyde oxime (7i)29. White solid; Yield - 82% (905 mg); Rf (20% EtOAc/Hexane) 0.44; Prepared as shown in general experimental procedure.; 1H NMR(500 MHz, CDCl3) δ 8.92 (s, 1H), 8.12 (s, 1H), 7.52 (d, J = 6.8 Hz, 2H), 6.91 (d, J = 7.2 Hz, 2H), 3.82 (s, 3H); 13C NMR(125 MHz, CDCl3) δ 161.1, 149.9, 128.5, 124.6, 114.2, 55.3.. 3-Methoxybenzaldehyde oxime (7j)30. White solid; Yield - 89% (975 mg); Rf (20% EtOAc/Hexane) 0.45; Prepared as shown in general experimental procedure.; 1H NMR(500 MHz, CDCl3) δ 8.23 ( bs, 1H), 8.13 (s, 1H), 7.32 – 7.28 (m, 1H), 7.16- 7.11 (m, 2H), 6.96 – 6.93 (m, 1H), 3.83 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 159.9, 150.3, 133.3, 129.8, 120.1, 116.4, 111.3, 55.3. 48.

(59) 2-Methoxybenzaldehyde oxime (7k)28. White solid; Yield - 84% (920 mg); Rf (20% EtOAc/Hexane) 0.45; Prepared as shown in general experimental procedure.; 1H NMR(400 MHz, CDCl3) δ 8.81 (bs, 1H), 8.50 (s, 1H), 7.66 (d, J = 8 Hz, 1H), 7.38 – 7.33 (m, 1H), 6.98 – 6.91 (m, 2H), 3.87 (s, 3H); 13. C NMR(100 MHz, CDCl3) δ 157.6, 146.7, 131.1, 127.3, 120.8, 120.6, 111.2, 55.5.. 4-((Hydroxyimino)methyl)benzonitrile (7l)31. Pale yellow solid; Yield - 90% (501 mg); Rf (20% EtOAc/Hexane) 0.22; Prepared as shown in general experimental procedure.;1H NMR(400 MHz, CDCl3) δ 8.14 (s, 1H), 7.74 – 7.64 (m, 5H); 13C NMR(100 MHz, CDCl3) δ 148.7, 136.4, 132.5, 127.4, 118.4, 113.3, 77.3, 77.0, 76.7.. 4-Methylbenzaldehyde oxime (7m)31. White solid; Yield - 84% (940 mg); Rf (20% EtOAc/Hexane) 0.45; Prepared as shown in general experimental procedure.; 1H NMR (400 MHz, CDCl3) δ 8.11 (s, 1H), 7.47 (d, J = 8 Hz, 2H), 7.26 (s, 1H), 7.19 (d, J = 8 Hz, 2H), 2.37 (s, 3H); 13C NMR (100MHz, CDCl3)δ 150.3, 140.3, 129.5, 129.2, 127.0, 21.4. 49.

(60) 3-Methylbenzaldehyde oxime (7n)32. White solid; Yield - 87% (975 mg); Rf (20% EtOAc/Hexane) 0.4; Prepared as shown in general experimental procedure.; 1H NMR(500 MHz, CDCl3) δ 8.97 (s, 1H), 8.17 (s, 1H), 7.42 – 7.31 (m, 2H), 7.29 (m, 1H), 7.22 (d, J = 8 Hz, 1H), 2.38 (s, 3H);. 13. C. NMR(125 MHz, CDCl3) δ 150.5, 138.5, 131.8, 130.9, 128.7, 127.6, 124.3, 21.3.. 2-Methylbenzaldehyde oxime(7o)27. White solid; Yield - 84% (947 mg); Rf (20% EtOAc/Hexane) 0.58; Prepared as shown in general experimental procedure.; 1H NMR (500 MHz, CDCl3) δ 8.43 (s, 1H), 8.36 (s, 1H), 7.67 – 7.66 (m, 1H), 7.31-7.27 (m, 1H), 7.23 – 7.19 (m, 2H), 2.44 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 149.3, 136.8, 130.8, 130.2, 129.8, 126.7, 126.2, 19.7.. [1,1'-Biphenyl]-4-carbaldehyde oxime (7p)27. White solid; Yield - 64% (346 mg); Rf (20% EtOAc/Hexane) 0.54; Prepared as shown in general experimental procedure.; 1H NMR (400 MHz, CDCl3) δ 8.65 (s, 1H), 8.23 (s, 1H), 7.71 – 7.58 (m, 6H), 7.47 (t, J = 7.5 Hz, 2H), 7.39 (t, J = 7.3 Hz, 1H);. 13. C. NMR (100 MHz, CDCl3) δ 150.1, 142.8, 140.2, 130.8, 128.9, 127.7, 127.5, 127.5, 127.0.. 50.

(61) 2-Naphthaldehyde oxime (7q)29. Pale yellow solid; Yield - 62% (339 mg); Rf (20% EtOAc/Hexane) 0.46; Prepared as shown in general experimental procedure.; 1H NMR(400 MHz, CDCl3) δ 8.30 (s, 1H), 7.89 (s, 1H), 7.88 – 7.81 (m, 4H), 7.75 (s, 1H), 7.53 – 7.49 (m, 2H);. 13. C NMR(100. MHz, CDCl3) δ 150.6, 134.2, 133.2, 129.7, 128.7, 128.5, 128.3, 127.9, 127.0, 126.6, 122.8.. 2-Bromobenzaldehyde oxime (7r)28. White solid; Yield - 85% (918 mg); Rf (20% EtOAc/Hexane) 0.54; Prepared as shown in general experimental procedure.; 1H NMR (400 MHz, CDCl3) δ 8.54 (s, 1H), 7.96 (s, 1H), 7.82 (d, J = 7.8 Hz, 1H), 7.63 – 7.55 (m, 1H), 7.37 – 7.19 (m, 3H); 13C NMR (125 MHz, CDCl3) δ 149.9, 133.2, 131.2, 127.6, 127.5.. 3,4-Dimethoxybenzaldehyde oxime (7s)28. White solid; Yield - 78% (425 mg); Rf (20% EtOAc/Hexane) 0.49; Prepared as shown in general experimental procedure.; 1H NMR(400 MHz, CDCl3) δ 8.26 (s, 1H), 8.08 (s, 1H), 7.21 (d, J = 2.0 Hz, 1H), 7.04-7.01 (m, 1H), 6.85 (d, J = 8.0 Hz, 1H), 3.90 (s, 6H); 13. C NMR(100 MHz, CDCl3) δ 150.8, 150.2, 149.3, 124.8, 121.6, 110.8, 108.0, 55.9,. 55.8. 51.

(62) General procedure for synthesis of Imines 8e-8s26. (E)-N-Arylmethylene-P,P-diphenylphosphinic amide 8e-8s. To a solution of oxime (0.1 mL, 1.0 mmol) in DCM/hexane (1:1, 5 mL) triethylamine (0.20 mL, 1.1 mmol) was added at -40 oC and stirred for 10 min, diphenylphosphinic chloride (0.15 mL, 1.1 mmol) was slowly added to the reaction at same temperature. The reaction mixture was gradually allowed to warm to room temperature and stirred overnight, evaporated under reduced pressure. The residue was purified by flash column chromatography (EtOAc/hexane, 1:4) to give the pure product.. (E)-N-Benzylidene-P,P-diphenylphosphinic amide (8e)26. White solid; Yield - 50% (152 mg); Rf (50% EtOAc/hexane) 0.3; Prepared as shown in general experimental procedure.; 1H NMR (400 MHz, CDCl3) δ 9.32 (d, J = 32.1 Hz, 1H),8.03 – 7.89 (m, 6H), 7.55 – 7.40 (m,9H); 13C NMR (100 MHz, CDCl3) δ 173.6 (d, JC-P = 7.6 Hz), 135.7 (d, JC-P = 24.7 Hz), 133.50, 132.8 (d, JC-P = 126.7 Hz), 131.7 (d, JC-P = 1.9 Hz), 131.4 (d, JC-P = 9.1 Hz), 130.0, 128.8, 128.3 (d, JC-P = 12.5 Hz).. 52.

(63) (E)-N-(4-(Trifluoromethyl)benzylidene)-P,P-diphenylphosphinic amide (8f)33. White solid; Yield - 72% (268 mg); Rf (50% EtOAc/hexane) 0.45; Prepared as shown in general experimental procedure.; 1H NMR (400 MHz, CDCl3) δ 9.38 (d, J = 31.5 Hz, 1H), 8.13 (d, J = 8.2 Hz, 2H), 7.99 – 7.90 (m,4H), 7.77 (d, J = 8.2 Hz, 2H),7.56 – 7.43 (m, 6H); 13C NMR (100 MHz, CDCl3) δ 172.2 (d, JC-P = 7.5 Hz),138.6 (d, JC-P =24.7Hz), 134.8 (q, JC-F = 32.6 Hz), 133.0, 132.1 (d, JC-P = 2.1Hz), 131.7, 131.6 (d, JC-P =9.2 Hz), 130.3, 128.6 (d, JC-P = 12.6 Hz), 126.0 (d, JC-P = 3.4 Hz), 123.6 (q, JC-F = 270 Hz).. (E)-N-(4-Chlorobenzylidene)-P,P-diphenylphosphinic amide (8g)33. White solid; Yield - 58% (191 mg); Rf (50% EtOAc/Hexane) 0.33; Prepared as shown in general experimental procedure.; 1H NMR (400 MHz, CDCl3) δ 9.28 (d, J = 31.7 Hz, 1H), 7.96 – 7.90 (m, 6H), 7.53 – 7.43 (m, 8H); 13C NMR (125 MHz, CDCl3) δ 172.3 (d, J C-P = 7.3 Hz), 140.0, 134.3 (d, J C-P = 25.2 Hz), 132.8 (d, J C-P = 151.6 Hz), 131.9, 131.6 (d, J C-P = 9.07 Hz), 131.3, 129.4, 128.5 (d, J C-P = 12.6 Hz). 53.

(64) (E)-N-(4-Fluorobenzylidene)-P,P-diphenylphosphinic amide (8h)34. White solid; Yield - 78% (906 mg); Rf (50% EtOAc/Hexane) 0.41; Prepared as shown in general experimental procedure.; 1H NMR (400 MHz, CDCl3) δ 9.28 (d, J = 31.8 Hz, 1H), 8.07 – 7.99 (m, 2H), 7.98 – 7.88 (m, 4H), 7.54 – 7.41 (m, 6H), 7.23 – 7.15 (m, 2H); 13. C NMR (100 MHz, CDCl3) δ 172.1 (d, J C-P = 7.4 Hz), 166.1 (d, J C-F = 2.9 Hz),. 133.5, 132.5 (d, J C-P = 9.4 Hz), 132.2, 131.8 (d, J C-F = 2.1 Hz), 131. 6 (d, J C-P = 9.2 Hz) 128.5 (d, J C-P = 12.5 Hz), 116.3 (d, J C-P = 22 Hz).. (E)-N-(4-Methoxybenzylidene)-P,P-diphenylphosphinic amide (8i)35. White solid; Yield - 55% (184 mg); Rf (50% EtOAc/Hexane) 0.2; Prepared as shown in general experimental procedure.; 1H NMR (400 MHz, CDCl3) δ 9.23 (d, J = 32.1 Hz, 1H), 8.02 – 7.88 (m, 6H), 7.55 – 7.38 (m, 6H), 6.99 (d, J = 8.7 Hz, 2H), 3.87 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 172.6 (d, J C-P = 7.4 Hz), 164.1 ,133.4 (d, JC-P= 127.2 Hz), 132.3, 131.6, 131.5, 129.1 (d, JC-P= 25.4 Hz), 128.4 (d, J C-P = 12.5 Hz), 114.3, 55.5.. (E)-N-(3-Methoxybenzylidene)-P,P-diphenylphosphinic amide (8j)33. 54.

(65) Colourless oil; Yield - 64% (215 mg); Rf (50% EtOAc/Hexane) 0.3; Prepared as shown in general experimental procedure.; 1H NMR (400 MHz, CDCl3) δ 9.28 (d, J = 31.9 Hz, 1H), 7.96 – 7.91 (m, 4H), 7.58 – 7.40 (m, 9H) , 7.13 (dd, J = 8.2, 2.6 Hz, 1H), 3.89 (s, 3H);. 13. C NMR (100 MHz, CDCl3) δ 173.7 (d, J C-P =7.7 Hz), 160.0, 137.1,. 132.9 (d, J C-P =128.1 Hz), 131.8 (d, J C-P =2.9 Hz), 131.6 (d, J C-P = 9.4 Hz), 130.0, 128.6 (d, J C-P =12.5 Hz), 123.7, 120.0, 113.6, 55.5.. (E)-N-(2-Methoxybenzylidene)-P,P-diphenylphosphinic amide (8k). White solid; Yield - 61% (205 mg); Rf (50% EtOAc/Hexane) 0.48; Prepared as shown in general experimental procedure.; 1H NMR (400 MHz, CDCl3) δ 9.80 (d, J = 32.6 Hz, 1H), 8.23 (dd, J = 7.8, 1.8 Hz, 1H), 7.94 (m, 1.5 Hz, 4H), 7.55 – 7.40 (m, 7H), 7.04 (t, J = 7.5 Hz, 1H), 6.96 (d, J = 8.4 Hz, 1H), 3.88 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 173.7 (d, J C-P = 7 Hz), 160.0, 137.2 (d, J C-P = 25 Hz), 132.9 (d, J C-P = 126 Hz), 131.8 (d, J C-P = 3 Hz), 131.6 (d, J C-P = 10 Hz), 130.0, 128.5 (d, J C-P = 13 Hz), 123.7, 120.0, 113.6, 55.5.. (E)-N-(4-Cyanobenzylidene)-P,P-diphenylphosphinic amide (8l)36. Pale yellow solid; Yield - 69% (227 mg); Rf (50% EtOAc/Hexane) 0.31; Prepared as shown in general experimental procedure.; 1H NMR(400 MHz, CDCl3) δ 9.35 (d, J = 31.2 Hz, 1H), 8.09 (d, J = 8.2 Hz, 2H), 7.99 – 7.86 (m, 4H), 7.79 (d, J = 8.2 Hz, 2H), 55.

(66) 7.56 – 7.40 (m, 6H); 13C NMR(100 MHz, CDCl3) δ 171.6 (d, J C-P = 8 Hz), 139.0 (d, J C-P=. 25 Hz), 132.6, 132.1, 131.5 (d, J C-P = 9 Hz), 130.5 128.6 (d, J C-P = 13 Hz), 117.9,. 116.5.. (E)-N-(4-Methylbenzylidene)-P,P-diphenylphosphinic amide (8m)33. White solid; Yield - 62% (194 mg); Rf (50% EtOAc/Hexane) 0.38; Prepared as shown in general experimental procedure.; 1H NMR (400 MHz, CDCl3) δ 9.28 (d, J = 32.1 Hz, 1H), 8.00 – 7.85 (m, 6H), 7.57 – 7.38 (m, 6H), 7.29 (d, J = 7.9 Hz, 2H), 2.42 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 173.5 (d, JC-P = 7.6 Hz), 144.6, 133.4 (d, JC-P = 24.9 Hz), 133.2 (d, JC-P = 126.4 Hz), 131.6, 131.5 (d, JC-P = 9.1 Hz), 130.2, 129.6, 128.4 (d, JC-P = 12.4 Hz), 21.8.. (E)-N-(3-Methylbenzylidene)-P,P-diphenylphosphinic amide (8n)37. White solid; Yield - 70% (236 mg); Rf (50% EtOAc/Hexane) 0.3; Prepared as shown in general experimental procedure.; 1H NMR (400 MHz, CDCl3) δ 9.29 (d, J = 32.4 Hz, 1H), 7.96-7.91 (m, 4H), 7.83 (s, 1H), 7.79 (t, J = 4.4 Hz, 1H), 7.52 – 7.42 (m, 6H), 7.39 (d, J = 5.2 Hz, 2H), 2.44 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 174.0 (d, J C-P = 7.5 Hz) , 138.8, 135.9 (d, J C-P = 24.7 Hz), 133.1 (d, J C-P = 106.7 Hz), 131.7, 131.6 (d, J C-P = 9.2 Hz),130.3, 128.8, 128.4 (d, J C-P = 12.5 Hz), 127.8, 21.2.. 56.

(67) (E)-N-(2-Methylbenzylidene)-P,P-diphenylphosphinic amide (8o)37. White solid; Yield - 60% (191 mg); Rf (50% EtOAc/Hexane) 0.35; Prepared as shown in general experimental procedure.; 1H NMR(400 MHz, CDCl3) δ 9.62 (d, J = 32.6 Hz, 1H), 8.14 (d, J = 7.7 Hz, 1H), 8.02 – 7.90 (m, 3H), 7.53 – 7.41 (m, 11H), 7.36 – 7.21 (m, 2H), 2.68 (s, 3H) ;. 13. C NMR (100 MHz, CDCl3) δ 172.3 (d, J C-P = 7.6 Hz), 141.0,. 133.7 (d, J C-P = 27.8 Hz), 132.9 (d, J C-P = 59.0 Hz), 131.6 (d, J C-P = 9.3 Hz), 129.8, 128.5 (d, J C-P = 12.5 Hz), 126.4, 19.7.. (E)-N-([1,1'-Biphenyl]-4-ylmethylene)-P,P-diphenylphosphinic amide (8p)38. White solid; Yield - 82% (312 mg); Rf (50% EtOAc/Hexane) 0.4; Prepared as shown in general experimental procedure.; 1H NMR(400 MHz, CDCl3) δ 9.37 (d, J = 32.0 Hz, 1H), 8.09 (d, J = 8.3 Hz, 2H), 7.97 (m, 1.4 Hz, 4H), 7.73 (d, J = 8.3 Hz, 2H), 7.68 – 7.61 (m, 2H), 7.55 – 7.36 (m, 9H); 13C NMR(100 MHz, CDCl3) δ 173.2 (d, J C-P = 7.6 Hz), 146.4, 139.9, 134.7 (d, J C-P = 25 Hz), 133.6, 132.4, 131.8 (d, J C-P = 2 Hz), 131.6 (d, J C-P = 9 Hz), 130.7, 129.0, 128.5 (d, J C-P = 20 Hz), 128.3, 127.6, 127.3.. (E)-N-(Naphthalen-2-ylmethylene)-P,P-diphenylphosphinic amide (8q)37. 57.

(68) White solid; Yield - 83% (294 mg); Rf (50% EtOAc/Hexane) 0.4; Prepared as shown in general experimental procedure.; 1H NMR (400 MHz, CDCl3) δ 9.47 (d, J = 31.9 Hz, 1H), 8.34 (s, 1H), 8.22 (dd, J = 8.6, 1.5 Hz, 1H), 8.03 – 7.86 (m, 7H), 7.65 – 7.54 (m, 2H), 7.54 – 7.43 (m, 6H);. 13. C NMR (100 MHz, CDCl3) δ 173.7 (d, J C-P = 7.6 Hz),. 136.1, 134.4, 133.7, 132.9, 132.4, 131.8, 131.6 (d, J C-P = 10 Hz), 129.4, 128.86, 128.7, 128.5 (d, J C-P = 12.5 Hz), 128.0, 126.9, 123.8.. (E)-N-(2-Bromobenzylidene)-P,P-diphenylphosphinic amide (8r)33. Colorless oil; Yield - 78% (303 mg); Rf (50% EtOAc/Hexane) 0.45; Prepared as shown in general experimental procedure.; 1H NMR (400 MHz, CDCl3) δ 9.65 (d, J = 31.2 Hz, 1H), 8.29 (dd, J = 7.4, 2.2 Hz, 1H), 8.01 – 7.88 (m, 4H), 7.63 (m, 1H), 7.55 – 7.35 (m, 8H); 13C NMR (100 MHz, CDCl3) δ 172.7 (d, J C-P = 6.3 Hz), 134.6 (d, J C-P = 25 Hz), 134.1 (d, J C-P = 74 Hz), 133.3, 132.0, 131.9 (d, J C-P = 2 Hz), 131.6 (d, J C-P = 9 Hz), 129.8, 128.5 (d, J C-P = 13 Hz), 128.0, 127.6.. (E)-N-(3,4-dimethoxybenzylidene)-P,P-diphenylphosphinic amide (8s)35. White solid; Yield - 58% (211 mg); Rf (50% EtOAc/Hexane) 0.13; Prepared as shown in general experimental procedure.; 1H NMR (400 MHz, CDCl3) δ 9.18 (d, J = 32.0 Hz, 1H), 7.93 -7.88 (m, 4H), 7.61 (s, 2H), 7.49-7.43 (m, 6H), 6.92 (d, J = 8.1 Hz, 1H), 3.95 58.

(69) (s, 3H), 3.92 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 172.9 (d, J C-P = 7.1 Hz) , 154.0, 149.5, 133.1 (d, J C-P = 127.5 Hz), 131.6, 131.5, 131.4, 129.1 (d, J C-P = 25.3 Hz), 128.4 (d, J C-P = 12.4 Hz), 126.8, 110.2 (d, J C-P = 62.7 Hz), 56.0, 56.0.. General procedure for Synthesis of Aziridine 9e-9s. To a flame-dried shlenk. tube containing. O-benzyl(Thiolan-2-yl)diphenylmethyl. ether. K2CO3(67.9 mg, 0.49 mmol), (11.8. mg,. 0.03. mmol),. 1,3-bis(3,5-bis(trifluoromethyl)phenyl)urea (7.9 mg, 0.02 mmol), imine (50mg, 0.16 mmol) and 0.5 ml of dichloromethane were added. To that finally cinnamyl bromide (48.5 µL, 0.33 mmol) was added and stirred, the reaction was monitored by TLC. After completion the reaction mixture was diluted with dichloromethane and filtered through Celite® , filtrate was evaporated in vacuo to yield the crude product. This was further purified by flash column chromatography (EtOAc/hexane, 1:3) to yield pure the corresponding products.. ((2R,3R)-2-Phenyl-3-((E)-styryl)aziridin-1-yl)diphenylphosphine oxide (9e). White solid; Yield - 80% (55 mg); Rf (30% EtOAc/hexane) 0.43; Prepared as shown in general experimental procedure.; Mp 151-152 oC; [α]26D = -55.87 (c 1.0, CHCl3); IR (neat): 3061, 1637, 1454, 1437, 1193, 1124, 1070, 967, 934, 752, 693 cm-1 ; 1H NMR (400 MHz, CDCl3) δ 7.92 – 7.87 (m, 4H), 7.44 – 7.20 (m, 16H), 6.73 (dd, J = 16.0, 9.6 59.

(70) Hz, 1H), 6.50 (d, J = 16.0 Hz, 1H), 4.03 (dd, J = 16.0, 2.8 Hz, 1H), 3.31 (ddd, J = 12.4, 9.6, 2.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 137.2 (d, JC-P = 3.4 Hz), 136.3, 134.8, 133.8 (d, JC-P = 48.1 Hz), 132.6 (d, JC-P = 42.6 Hz), 131.7, 131.6, 131.5, 131.4, 128.5 (d, JC-P = 2.2 Hz), 128.4, 128.3, 128.3, 128.2, 127.7 (d, JC-P = 1.8 Hz), 126.4, 126.1, 125.9 (d, JC-P = 7.4 Hz), 52.4 (d, JC-P = 7.8 Hz), 43.7 (d, JC-P = 5.2 Hz); 31P NMR (162 MHz, CDCl3) δ 30.77; HRMS-ESI (m/z): Calcd for C28H24NOP [(M+Na)+] 444.1493, found [(M+Na)+] 444.1499; enantioselectivity was determined by HPLC analysis (Chiralcel-OD, 1.0 mL/min, 254 nm, hexane/i-PrOH 20/1); retention time: 10.5 min (enantiomer) and 20.8 min (major).. ((2R,3R)-2-((E)-Styryl)-3-(4-(trifluoromethyl)phenyl)aziridin-1-yl)diphenylphosp hine oxide (9f). White solid; Yield- 80% (52 mg); Rf (50% EtOAc/hexane) 0.45; Prepared as shown in general experimental procedure.; Mp 152-156 oC; [α]26D = -36.59 (c 1.0, CHCl3); IR (neat): 3058, 1619, 1438, 1324, 1166, 1123, 932, 826, 728, 693 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.95 – 7.87 (m, 4H), 7.60 – 7.58 (m, 2H), 7.47 – 7.26 (m, 13H), 6.71 (dd, J = 16.0, 9.6 Hz, 1H), 6.52 (d, J = 16.0 Hz, 1H), 4.06 (dd, J = 15.6, 2.8 Hz, 1H), 3.30 (ddd, J = 12.4, 9.6, 2.8 Hz, 1H);. 13. C NMR (100 MHz, CDCl3) δ 141.4, 136.1,. 135.3, 133.5 (d, JC-P = 60.3 Hz), 132.5, 131.9, 131.6, 131.5, 131.5, 131.4, 130.0 (q, JC-F = 32.1 Hz), 128.5, 128.4, 128.3, 128.0, 126.4 (d, JC-P = 2.1 Hz), 125.5 (d, JC-P = 3.3 Hz), 125.2 (d, JC-P = 7.2 Hz), 121.3 (d, JC-F = 270.4 Hz), 52.7 (d, JC-P = 7.6 Hz), 43.0 (d, JC-P = 4.8 Hz);. 31. P NMR (162 MHz, CDCl3) δ 30.89; HRMS-ESI (m/z): Calcd for 60.

(71) C29H23NOPF3 [(M+Na)+] 512.1367, found [(M+Na)+] 512.1372; enantioselectivity was determined by HPLC analysis (Chiralcel-AD, 1.0 mL/min, 254 nm, hexane/i-PrOH 4/1); retention time: 12.1 min (enantiomer) and 24.8 min (major).. ((2R,3R)-2-(4-Chlorophenyl)-3-((E)-styryl)aziridin-1-yl)diphenylphosphine oxide (9g). White solid; Yield - 90% (60 mg); Rf (50% EtOAc/hexane) 0.33; Prepared as shown in general experimental procedure.; Mp 141-145 oC; [α]27D = -35.08 (c 1.0, CHCl3); IR (neat): 3058, 1596, 1493, 1192, 1124, 932, 838, 753, 693, 539 cm-1 ; 1H NMR (400 MHz, CDCl3) δ 7.89 – 7.85 (m, 4H), 7.44 – 7.22 (m, 16H), 6.68 (dd, J = 16.0, 9.6 Hz, 1H), 6.50 (d, J = 16.0 Hz, 1H), 3.98 (dd, J = 16.0, 2.8 Hz, 1H), 3.27 (ddd, J = 12.4, 9.6, 2.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 136.2, 135.8, 135.1, 133.6 (d, JC-P = 59.5 Hz), 133.5, 132.4 (d, JC-P = 54.1 Hz), 131.8, 131.7, 131.5 (d, JC-P = 4.6 Hz), 131.4, 128.5, 128.3, 128.2, 127.8, 127.5, 126.4, 125.5 (d, JC-P = 7.3 Hz), 52.4 (d, JC-P = 7.8 Hz), 43.0 (d, JC-P = 5.1 Hz); 31P NMR (162 MHz, CDCl3) δ 30.87; HRMS-ESI (m/z): Calcd for C28H23NOPCl [(M+H)+] 456.1284, found [(M+H)+] 456.1277; enantioselectivity was determined by HPLC analysis (Chiralcel-AD, 1.0 mL/min, 254 nm, hexane/i-PrOH 4/1); retention time: 15.7 min (enantiomer) and 33.4 min (major).. 61.

(72) ((2R,3R)-2-(4-Fluorophenyl)-3-((E)-styryl)aziridin-1-yl)diphenylphosphine oxide (9h). White solid; Yield - 95% (65 mg); Rf (30% EtOAc/hexane) 0.30; Prepared as shown in general experimental procedure.; Mp 147-150 oC; [α]23D = -57.48 (c 1.0, CHCl3); IR(neat): 3058, 1606, 1511, 1438, 1193, 1125, 932, 840, 753, 693 cm-1 ; 1H NMR (400 MHz, CDCl3) δ 7.92 – 7.85 (m, 4H), 7.43 – 7.22 (m, 13H), 7.02 (t, J = 8.4 Hz, 2H), 6.68 (dd, J = 16.0, 9.6 Hz, 1H), 6.50 (d, J = 15.6 Hz, 1H), 3.98 (dd, J = 16.0, 2.8 Hz, 1H), 3.27 (ddd, J = 12.4, 9.6, 2.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 162.4 (d, JC-F = 244.7 Hz), 136.2, 134.9, 133.7 (d, JC-P = 61.0 Hz), 132.9, 132.4 (d, JC-P = 55.5 Hz), 131.7, 131.6, 131.5 (d, JC-P = 6.8 Hz), 131.4, 128.5, 128.4, 128.3 (d, JC-P = 4.1 Hz), 128.2, 127.7, 127.6, 126.4, 125.6 (d, JC-P = 7.3 Hz), 115.4 (d, JC-P = 21.6 Hz), 52.3 (d, JC-P = 7.7 Hz), 43.0 (d, JC-P = 5.1 Hz);. 31. P NMR (162 MHz, CDCl3) δ 30.81;. HRMS-ESI (m/z): Calcd for C28H23NOPF [(M+Na)+] 462.1399, found [(M+Na)+] 462.1400; enantioselectivity was determined by HPLC analysis (Chiralcel-OD, 1.0 mL/min, 254 nm, hexane/i-PrOH 9/1); retention time: 6.9 min (enantiomer) and 21.0 min (major).. ((2R,3R)-2-(4-Methoxyphenyl)-3-((E)-styryl)aziridin-1-yl)diphenylphosphine oxide (9i). White solid; Yield - 88% (59 mg); Rf (50% EtOAc/hexane) 0.50; Prepared as shown in 62.

(73) general experimental procedure.; Mp 149-152 oC; [α]26D = -42.02 (c 0.8, CHCl3); IR (neat): 3050, 1612, 1514, 1438, 1302, 1250, 933, 836, 752, 693 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.88 – 7.86 (m, 4H), 7.42 – 7.21 (m, 13H), 6.88 – 6.86 (m, 2H), 6.70 (dd, J = 16.0, 9.6 Hz, 1H), 6.49 (d, J = 15.6 Hz, 1H), 3.97 (dd, J = 16.0, 2.8 Hz, 1H), 3.80 (s, 3H), 3.28 (ddd, J = 12.4, 9.6, 2.8 Hz, 1H);. 13. C NMR (100 MHz, CDCl3) δ. 159.3, 136.4, 134.6, 133.9 (d, JC-P = 53.2 Hz), 132.7 (d, JC-P = 47.7 Hz), 131.7, 131.6, 131.5, 131.4, 129.2 (d, JC-P = 3.6 Hz), 128.5, 128.4, 128.3 (d, JC-P = 3.2 Hz), 128.2, 127.7, 127.3, 126.4, 126.0 (d, JC-P = 7.4 Hz), 114.0, 55.3, 52.1 (d, JC-P = 7.8 Hz), 43.5 (d, JC-P = 5.3 Hz); 31P NMR (162 MHz, CDCl3) δ 30.79; HRMS-ESI (m/z): Calcd for C29H26NO2P [(M+H)+] 452.1779, found [(M+H)+] 452.1782; enantioselectivity was determined by HPLC analysis (Chiralcel-OD, 1.0 mL/min, 254 nm, hexane/i-PrOH 9/1); retention time: 7.5 min (enantiomer) and 22.7 min (major).. ((2R,3R)-2-(3-Methoxyphenyl)-3-((E)-styryl)aziridin-1-yl)diphenylphosphine oxide (9j). White solid; Yield - 94% (63 mg); Rf (50% EtOAc/hexane) 0.50; Prepared as shown in general experimental procedure.; Mp 145-146 oC; [α]26D = -48.63 (c 1.0, CHCl3); IR (neat): 3056, 1601, 1491, 1438, 1198, 1124, 936, 753, 695 cm-1 ; 1H NMR (400 MHz, CDCl3) δ 7.93 – 7.88 (m, 4H), 7.43 – 7.21 (m, 12H), 6.95 (d, J = 7.6 Hz, 1H), 6.88 (s, 1H), 6.82 (dd, J = 8.0, 2.4 Hz, 1H), 6.69 (dd, J = 16.0, 9.6 Hz, 1H), 6.49 (d, J = 16.0 Hz, 1H), 3.99 (dd, J = 16.0, 2.8 Hz, 1H), 3.79 (s, 3H), 3.29 (ddd, J = 12.4, 9.6, 2.8 Hz, 1H); 13. C NMR (100 MHz, CDCl3) δ 159.8, 138.9 (d, JC-P = 3.5 Hz), 136.2, 134.8, 133.8 (d, 63.

(74) JC-P = 54.9 Hz), 132.5 (d, JC-P = 49.4 Hz), 131.7, 131.6, 131.5, 131.4, 129.5, 128.4, 128.4, 128.3 (d, JC-P = 2.7 Hz), 128.2, 127.7, 126.4, 125.8 (d, JC-P = 7.4 Hz), 118.5, 113.3, 111.5, 55.2, 52.2 (d, JC-P = 7.8 Hz), 43.6 (d, JC-P = 5.1 Hz); 31P NMR (162 MHz, CDCl3) δ 30.81; HRMS-ESI (m/z): Calcd for C29H26NO2P [(M+Na)+] 474.1599, found [(M+Na)+] 474.1598; enantioselectivity was determined by HPLC analysis (Chiralcel-OD, 1.0 mL/min, 254 nm, hexane/i-PrOH 9/1); retention time: 7.8 min (enantiomer) and 12.5 min (major).. ((2R,3R)-2-(2-Methoxyphenyl)-3-((E)-styryl)aziridin-1-yl)diphenylphosphine oxide (9k). Colorless liquid; Yield - 92% (62 mg); Rf (30% EtOAc/hexane) 0.30; Prepared as shown in general experimental procedure.; [α]27D = -62.34 (c 0.9, CHCl3); IR (neat): 3056, 1587, 1494, 1438, 1247, 1194, 1124, 935, 754, 693 cm-1 ; 1H NMR (400 MHz, CDCl3) δ 7.95 – 7.91 (m, 4H), 7.41 – 7.20 (m, 13H), 6.94 (t, J = 7.6 Hz, 1H), 6.81 (d, J = 8.0 Hz, 1H), 6.73 (dd, J = 16.0, 9.6 Hz, 1H), 6.49 (d, J = 16.0 Hz, 1H), 4.41 (dd, J = 16.0, 2.8 Hz, 1H), 3.69 (s, 3H), 3.25 (ddd, J = 12.4, 9.6, 2.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 158.3, 136.5, 134.4, 134.2 (d, JC-P = 54.7 Hz), 132.9 (d, JC-P = 49.2 Hz), 131.8, 131.7, 131.6, 131.5, 128.5, 128.4, 128.3 (d, JC-P = 4.6 Hz), 128.1 (d, JC-P = 4.4 Hz), 127.6, 126.5, 126.4, 125.6, 120.4, 110.2, 55.2, 51.5 (d, JC-P = 7.6 Hz), 39.4 (d, JC-P = 5.1 Hz);. 31. P NMR (162 MHz, CDCl3) δ 30.53; HRMS-ESI (m/z): Calcd for. C29H26NO2P [(M+H)+] 452.1799, found [(M+H)+] 452.1781; enantioselectivity was determined by HPLC analysis (Chiralcel-OD, 1.0 mL/min, 254 nm, hexane/i-PrOH 9/1); retention time: 9.1 min (enantiomer) and 13.7 min (major). 64.

(75) 4-((2R,3R)-1-(Diphenylphosphoryl)-3-((E)-styryl)aziridin-2-yl)benzonitrile (9l). White solid; Yield - 93% (63 mg); Rf (30% EtOAc/hexane) 0.33 Prepared as shown in general experimental procedure.; Mp 181-182 oC; [α]29D = -10.28 (c 1.0, CHCl3); IR (neat): 3050, 2226, 1640, 1609, 1438, 1194, 1124, 930, 827, 754, 693, 597 cm-1; 1H NMR (400 MHz, CDCl3) δ7.90 – 7.84 (m, 4H), 7.63 – 7.61 (m, 2H), 7.46 – 7.41 (m, 4H),7.39 – 7.30 (m, 4H), 7.28 – 7.23 (m, 5H), 6.68 (dd, J = 16.0, 9.6 Hz, 1H), 6.52 (d, J = 16.0 Hz, 1H), 4.03 (dd, J = 15.6, 2.8 Hz, 1H), 3.29 (ddd, J = 12.4, 9.6, 2.8 Hz, 1H); 13. C NMR (100 MHz, CDCl3) δ 142.8, 135.9, 135.6, 133.3 (d, JC-P = 67.8 Hz), 132.2,. 132.0 (d, JC-P = 64.2 Hz), 131.9, 131.7, 131.4, 131.3, 128.5, 128.4 (d, JC-P = 2.4 Hz), 128.3, 128.0, 126.8, 126.4, 124.9 (d, JC-P = 7.1 Hz), 118.6, 111.5, 52.9 (d, JC-P = 7.6 Hz), 42.9 (d, JC-P = 4.8 Hz); 31P NMR (162 MHz, CDCl3) δ 30.89; HRMS-ESI (m/z): Calcd for C29H23N2OP [(M+H)+] 447.1620, found [(M+H)+] 447.1628; enantioselectivity was determined by HPLC analysis (Chiralcel-AS, 0.7 mL/min, 254 nm, hexane/i-PrOH 9/1); retention time: 19.8 min (major) and 24.8 min (enantiomer).. ((2R,3R)-2-((E)-Styryl)-3-(p-tolyl)aziridin-1-yl)diphenylphosphine oxide (9m). White solid; Yield - 88% (60 mg); Rf (30% EtOAc/hexane) 0.40 Prepared as shown in general experimental procedure.; Mp 146-148 oC; [α]26D = -43.98 (c 1.0, CHCl3); IR (neat): 3056, 3026, 1682, 1574, 1493, 1392, 1193, 932, 829, 751, 693 cm-1 ; 1H NMR (400 MHz, CDCl3) δ 7.92 – 7.87 (m, 4H), 7.42 – 7.12 (m, 13H), 7.15 – 7.13 (m, 2H) 65.

(76) 6.70 (dd, J = 16.0, 9.6 Hz, 1H), 6.48 (d, J = 15.6 Hz, 1H), 3.98 (dd, J = 16.0, 2.8 Hz, 1H), 3.27 (ddd, J = 12.3, 9.6, 2.8 Hz, 1H);. 13. C NMR (100 MHz, CDCl3) δ 137.4, 136.3,. 134.6, 133.9 (d, JC-P = 48.4 Hz), 132.6 (d, JC-P = 42.8 Hz), 131.7, 131.6, 131.5, 131.4, 129.2, 128.4, 128.4, 128.4, 128.3, 128.2, 128.1, 127.6, 126.4, 126.0, 52.3 (d, JC-P = 7.8 Hz), 43.6 (d, JC-P = 5.2 Hz), 21.1; 31P NMR (162 MHz, CDCl3) δ 30.79; HRMS-ESI (m/z): Calcd for C29H26NOP [(M+H)+] 436.1830, found [(M+H)+] 436.1825; enantioselectivity was determined by HPLC analysis (Chiralcel-OD, 1.0 mL/min, 254 nm, hexane/i-PrOH 100/7); retention time: 7.2 min (enantiomer) and 20.2 min (major).. ((2R,3R)-2-((E)-Styryl)-3-(m-tolyl)aziridin-1-yl)diphenylphosphine oxide (9n). White solid; Yield - 92% (63 mg); Rf (30% EtOAc/hexane) 0.38 Prepared as shown in general experimental procedure. Mp 144-146 oC; [α]29D = -74.95 (c 1.0, CHCl3); IR (neat): 3057, 1640, 1608, 1438, 1197, 1124, 937, 753, 716, 693 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.92 – 7.88 (m, 4H), 7.43 – 7.20 (m, 12H), 7.15 (d, J = 7.6 Hz, 2H), 7.09 (d, J = 7.2 Hz, 1H), 6.70 (dd, J = 16.0, 9.6 Hz, 1H), 6.49 (d, J = 15.6 Hz, 1H), 3.98 (dd, J = 15.6, 2.8 Hz, 1H), 3.29 (ddd, J = 12.4, 9.6, 2.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 138.2, 137.2, 136.4, 134.7, 134.0 (d, JC-P = 50.0 Hz), 132.7 (d, JC-P = 44.1 Hz), 131.8, 131.6, 131.6, 131.5, 128.5, 128.3 (d, JC-P = 4.3 Hz), 128.2, 127.7, 127.0, 126.4, 126.0 (d, JC-P = 7.3 Hz), 121.1, 52.3 (d, JC-P = 7.8 Hz), 43.8, 21.4; 31P NMR (162 MHz, CDCl3) δ 30.79; HRMS-ESI (m/z): Calcd for C29H26NOP [(M+Na)+] 458.1650, found [(M+Na)+] 458.1653; enantioselectivity was determined by HPLC analysis (Chiralcel-OD, 1.0 mL/min, 254 nm, hexane/i-PrOH 9/1); retention time: 6.3 min 66.