Chemistry of Oxaziridines

Transcription

1 Chemistry of xaziridines An Evans Group Afternoon Seminar abi Magomedov December 1, C Preparation 2. Configurational stability 3. Acid- and base-catalyzed reactions of oxaziridines 4. eteroatom transfer reactions: 4.1 -transfer reactions 4.2 -transfer reactions 5. earrangements 6. Single electron transfer chemistry Leading references: Emmons, W. D. J. Am. Chem. Soc. 1957, 79, 5739 addadin, M. J.; Freeman, J. P. in Small ing eterocycles- Part 3, J. Wiley & Sons, Y 1985, p. 284 Davis, F. A.; Sheppard, A. C. Tetrahedron 1989, 45, 5703 Davis, F. A.; Chen, B.-C. Chem. ev. 1992, 92, 919

2 Preparation: Imine xidation with Peroxy Compounds m-cpba 56% Wilmer elv. Chim. Acta 1974, 57, 657 oxone S 2 80% S 2 Davis J. Am. Chem. Soc. 1988, 110, (S)-α-MBA 2. m-cpba 70% Aube J. Am. Chem. Soc. 1995, 117, 5169

3 chanism of Peroxy Acid xidation of Imines Two-step mechanism m-cpba Ar slow fast Concerted mechanism m-cpba Ar 1. eaction is stereoselective but not stereospecific. 2. Imines are oxidized in preference to olefins at low temperature. 3. Kinetic study and study of solvent effects support the two-step mechanism. gata J. Am. Chem. Soc. 1973, 95, Theoretical study also suggests the two-step mechanism. Plesnicar J. Am. Chem. Soc. 1979, 101, 1107 Aube J. rg. Chem. 2000, 65, 5120

4 Preparation via Electrophilic Amination of Ketones 3, acl or 2 S % eaction is preferred for preparation of oxaziridines unsubstituted at nitrogen. Success of reaction is highly substrate dependent: works well also with C, butanone, and chloral. Modified aschig's process 2 Cl 3 2 C Addition of acetone to the classical ammoniahypochlorite process resulted in better yields of hydrazine. Schmitz Synthesis 1991, 327

5 ther thods of Preparation Conjugate addition of hydroxamic acids to propiolates + MM, C 86-95% = aryl, alkyl, alkenyl MM = -methylmorpholine yu Tetrahedron Lett. 1998, 39, 6227 otolysis of nitrones Cl hν 78% Cl offmann-la oche J. rg. Chem. 1970, 35, 2243 Cl Bu t 1:1 inclusion complex with diol hν Cl 51% Bu t 100% ee Toda Chem. Lett. 1987, 2283 Cl (-)-diol Cl

6 Configurational Stability and chanisms of Epimerization at itrogen otochemical epimerization hν chiral non-racemic racemic Boyd Chem. Commun. 1976, 162 Thermal epimerization chiral non-racemic G i 31.9 kcal/mol chiral non-racemic Torre JCS, Perkin II 1978, 401

7 Barriers for itrogen Inversion in xaziridines Two major reasons for high energetic barrier for inversion: 1. ing strain increases on going from ground state to the inversion transition state. 2. Inductive effect of adjacent atom increases the s-character of the lone pair on and makes it more pyramidal. 1 2 Alk G i kcal/mol The bigger -alkyl group the smaller the inversion barrier: Alk = i-pr 32 kcal/mol but Alk = t-bu 26 kcal/mol. Boyd JCS, Perkin II 1973, 1575 When atom is connected to substituents capable of π-conjugation or hyperconjugation, the inversion barriers are smaller. G i 23.4 kcal/mol no Tetrahedron Lett. 1973, 4107 G i 11.8 kcal/mol; G r (-C) 10.3 kcal/mol Jennings JCS, Chem. Commun. 1992, 1078 P 2 S 2 G i 13.2 kcal/mol Jennings JCS, Perkin II 1991, 1281 G i 20.6 kcal/mol Jennings J. Am. Chem. Soc. 1987, 109, 8099

8 3-Aryl-substituted oxaziridines Acid-Catalyzed ing pening of xaziridines 2 C % Emmons Chem. eteroc. Comp. 1964, 19, Alkyl-substituted oxaziridines 1 2 m-cpba 65-75% Cl/ Black Austr. J. Chem. 1975, 28, %

9 ecent Example of Acid-Catalyzed ing pening C 2 C 2 C 2 m-cpba + hν, Et 51-67% 20-31% C 2 i-pr TMS-Tf C a u i-pr TMS a b b C a 13% C 2 eathcock J. rg. Chem. 1995, 60, 1131 i-pr TMS C u 71%

10 Base-Catalyzed ing pening of xaziridines chanism B E2 + k /k D = 4-6 astetter J. rg. Chem. 1982, 47, 419 K, Et 20 o C, 4 h 96% Lusinchi Tetrahedron 1974, 30, 2825 unreactive Synthesis of - ketimines t-buk 2. Cl/Et Cl 90% 3 = 4 = 52% 3 = 4 = Et 1 = ; 2 = or Boyd Tetrahedron Lett. 1982, 23, 2907

11 eteroatom Transfer eactions Generally, oxaziridines with small substituents on nitrogen act as aminating agents, whereas those with bulky or electron-withdrawing groups on nitrogen preferentially transfer the oxygen atom. xygen transfer reagents: 1. -sulfonyl oxaziridines 2. -phosphinoyl oxaziridines 3. oxaziridinium salts 4. perfluorinated oxaziridines eactivity order of oxygenating reagents toward olefins: f F f m-cpba > S 2 > > > 1 2 P 2 eactivity order of oxidation substrates in reaction with -sulfonyl oxaziridines: M > > > > 2 Si 3 EWG typical conditions -78 o C, <15 min rt, <30 min o C 60 o C, 3-12 h unreactive itrogen transfer reagents: 1. -unsubstituted oxaziridines 2. -alkyl oxaziridines 3. -acyl oxaziridines

12 chanism of eaction of Enolates with xaziridines chanism involves an S 2-type attack of enolate on oxaziridine oxygen to form a hemiaminal intermediate that collapses to give oxygenated product and imine. M M X c + S 2 TF, -78 o C 2 S X c M K eq K eq > 1 for M = Li K eq < 1 for M = a 2 S X c X c S 2 + M X c Evans J. Am. Chem. Soc. 1985, 107, 4346 EtMgBr + S 2 TF, -78 o C then 4 Cl 2 S Et detected by M Davis Tetrahedron Lett. 1987, 28, 5115

13 Asymmetric Enolate xidation with -Sulfonyl xaziridines 1. Auxilliary-induced asymmetric oxidations. 2. Asymmetric oxidation of prochiral enolates with non-racemic oxaziridines. 3. Double asymmetric induction. Evans auxiliary method 1 amds -78 o C, TF S dr yield, % C 2 94: :10 77 C 2 C=C 2 95: amds -78 o C, TF S dr yield, % C 2 95:5 85 i-pr 99:1 86 Evans J. Am. Chem. Soc. 1985, 107, 4346

14 xidation of Chiral Amide Enolates with -Sulfonyl xaziridines 2-Pyrrolidinemethanol auxiliary LDA S 2 dr 97:3, 85% 2M 2 S 4 amds S 2 dr 96:4, 83% 2M 2 S 4 Si M e M M Davis Tetrahedron Lett. 1985, 26, 3539 Li as a counterion a as a counterion

15 xidation of Enders ydrazones with -Sulfonyl xaziridines 3 3 LDA Ac 2 1 * S * 2 2 For 1 = -benzylation (a/dmf then BnCl) was required before the oxidative cleavage of the auxiliary overall yield, % ee, % conf. C C C 74 >96 S n-ex Bn n-ex Et Bn 55 >96 S Enders Tetrahedron Lett. 1988, 29, 2437

16 xidation of Prochiral Enolates with on-racemic xaziridines 1 amds -78 o C oxaziridine 1 (S) + () 1 S 2 X X ' X yield, % ee, % conf S S Cl S S t-bu Davis J. Am. Chem. Soc. 1990, 112, 6679 ' t-bu S S M M Proposed model for asymmetric induction xidation of tertiary acyclic ketones gave poor enantioselectivity under a number of conditions. 1. base 2. oxaziridine Davis J. rg. Chem. 1987, 52, to 21% ee

17 Double Asymmetric Induction Experiments 1. LDA TF/MPA 2. oxaziridine dr 96:4 (S) S 2 E E TF Li S Li Si The proposed model does not, however, explain why -phenylsulfonyl 3-phenyloxaziridine gave new stereocenter with () configuration. Davis J. rg. Chem. 1987, 52, 5288 (-)-CS Asymmetric conjugate addition-oxidation cascade Bu t Li then (+)-CS dr 96:4, 86% Bn (2,3) Bu t owever, if substrate contains benzyl group instead of phenyl, dr 40:60 is observed in favor of (2S,3) diastereomer. Davis Tetrahedron 1994, 50, 3975

18 chanism of xygen Transfer to lefinic Double Bond Questions to be addressed: 1. Planar or spiro transition state 2. Synchronous or asynchronous transition state Preliminary experimental (Davis) and theoretical (Bach) studies favored structure 1. Calculations done at more advanced level (ouk; Bach) favored spiro transition states 2 and 4. Transition structures (B3LYP/6-31G*) for epoxidations of ethylene by performic acid, dioxirane, peroxynitrous acid, and oxaziridine. ouk J. Am. Chem. Soc. 1997, 119, 10147

19 FM ational for Spiro Transition State FM interactions in the transition states of epoxidations: (a) alkene M-oxidant LUM and (b) oxidant M-alkene LUM. Thus, epoxidation reaction by oxaziridines has late spiro asynchronous transition state. ouk J. Am. Chem. Soc. 1997, 119, 10147

20 Stepwise eaction of eutral -ucleophile With xaziridine S 2 TF S 2 S 2 direct oxygen atom transfer S 2 71% yield as a mixture of isomers Dmitrienko J. Am. Chem. Soc. 1997, 119, S S 2 S 2 p- 2 S 2 10 equiv. p- 2 exclusive product not detected

21 The Endocyclic estriction Test: Asynchronous Transition State S 2 Is capable of intramolecular epoxidation via synchronous transition state. Does not isomerize in CCl 3 (<0.05 M) at 60 o C. Ar 2 S u Ar S Is capable of intramolecular epoxidation via asynchronous transition state but not synchronous. eadily isomerizes at 60 o C. Ar 2 S Ar u S CDCl M 60 o C * S * * S S Transition state for this intramolecular reaction is electronically similar to those of intermolecular reactions as ρ = 0.95±0.20 and is close to the value reported by Davis. 13 C, 18 - substrate * Beak rg. Lett. 1999, 1, 1415

22 Catalytic Asymmetric Epoxidations with xaziridinium Salts Iminium salts can be converted to oxaziridinium salts by reaction with nucleophilic oxidants which do not oxidize alkenes. anquet system BF 4 KS 4 BF 4 KS 5 33% ee 2 norephedrine 1. C 2. TFA 1. acl 2. a 3. 3 BF 4 BF 4 anquet Tetrahedron Lett. 1993, 34, 7271 BF 4 structure by X-ray

23 Catalytic Epoxidation with Binaphtyl-derived xaziridinium alkenes 5 mol% oxone, ac 3 C/water, rt BF 4 epoxides alkene time, h yield, % ee, % trans-stilbene (,) trans-α-methylstilbene (,) 1-phenylcyclohexane (,) 1-methylcyclohexane (1S,2) styrene (D) m-cpba 3 BF 4 reaction is stereospecific with respect to alkene geometry. more substituted alkenes are more reactive. the corresponding oxaziridine did not provide the epoxide under the reaction conditions. BF 4 Aggarwal JCS, Chem. Commun. 1996, % ee (,)

24 Page s System for Catalytic Asymmetric Epoxidation 1. Br 2 2. Br Br 1. amine 2. ab 4 65% 70% B 4 alkenes oxone, a 2 C 3 C/water, 0 o C iminium salt epoxides alkene mol% yield, % ee, % conf. 1--cyclohexene (,) 1--cyclohexene (,) trans-stilbene (,) trans-α-methylstilbene (,) Page J. rg. Chem. 1998, 63, 2774

25 Intramolecular Epoxidation of Unsaturated xaziridiniums Bn ( ) n Tf 2. aq. ac 3 2 ( ) n n yield, % n-bu 1 39 n-pr 1 56 n-bu Bn 2 2. oxone ac 3 47% Bn 1. Tf 2. aq. ac 3 48% m-cpba 75% Armstrong SynLett 1998, 646

26 Asymmetric Intramolecular Epoxidation: Spiro Transition State 1. Tf 2. aq. ac 3 60% ~83% de 81% ee 1. Tf 2. aq. ac 3 40% S >90% de 94% ee Armstrong Tetrahedron Lett. 1999, 40, 4453 ouk J. Am. Chem. Soc. 2000, 122, 2948

27 Epoxidations with Perfluorinated xaziridines Preparation (C 4 F 9 ) 3 Epoxidation reactions 10 mol% SbF 5 1 d, 120 o C 85% C 3 F 7 F CFCl 3 /CCl 3-40 o C, 40 min 86% C 4 F 9 m-cpba 68% esnati Chem. ev. 1996, 96, 1809 C 3 F 7 F C 4 F 9 stable up to 120 o C CFCl 3 /CCl 3-40 o C, 40 min 80% CFCl 3 /CCl 3 rt, 16 h 82% esnati J. rg. Chem. 1996, 61, 8805

28 xidation of Unactivated C- Bonds C 3 F 7 F C 4 F 9 CFCl 3, rt yield, % 70 Ac 68 C(C 3 )(C 2 ) 2 C 79 Ac Ac C(C 3 )(C 2 ) 2 C 66 Ac Br CC 2 Ac 58 oxidation is enantiospecific. 3 o C- > 2 o C- >> 1 o C- equatorial C- > axial C- groups with -I effect increase the reaction time. compatible with C, ester, al, and ketone functionalities. oxidizes 2 o and to ketones. esnati J. rg. Chem. 1994, 59, 5511 Cl Br C 3 F 7 F C 4 F 9 CFCl 3, rt 99% ee 97% ee Cl esnati rg. Lett. 1999, 1, 281 Br

29 -Amination with - xaziridines Amination of secondary amines Et 2, rt 20 min Et 2 Et 2 aq. Cl Et 2 3 Cl 93% substrate product yield, % Bu 2 Bu 2 3 Cl 75 (CC 2 C 2 ) 2 (CC 2 C 2 ) 2 =c-c Schmitz J. Prakt. Chem. 1985, 327, 445 Amination of primary amines 2 C 1. oxaziridine o C, 3 h C i-pr Bn yield, % Schmitz Synthesis, 1991, 327

30 -Acylamidation with xaziridines 2 + rt -C 92% 2 + rt -C 69% Boc C = 50% = 41% 90% Schmitz Liebigs Ann. Chem. 1969, 725, 1 + C + 70% Boc Boc Boc Et 2, rt Boc = C 2 78% = C 77% C C Collet J. rg. Chem. 1993, 58, 4791

31 More Efficient eagent for -Acylamidation 3 P Boc chloral, reflux Cl 3 C Boc oxone 84% (2 steps) Cl 3 C Boc morpholine -78 o C 92% Boc 2 C 2 Cl 2 Boc C C oxaziridine conditions yield, % C Boc 24 h, rt 44% Cl 3 C Boc 3 h, 0 o C 56% Bn oxaziridine Bn Boc C C 4-78 o C C Collet Tetrahedron Lett. 1998, 39, % C 4

32 Amination of C- acidic compounds Amination of Carbon ucleophiles oxaziridine aq. a 2 Bn 90% Bn 79% Schmitz Synthesis 1991, 327 oxaziridine aq. a Epamination of alkenes 1 2 Ar toluene, oxaziridine 1 2 Ar temperatures above 100 o C are required. reaction is stereoselective. with a few exceptions, only aromatic alkenes react. Ar 1 2 yield, % 4-ClC C C toluene, oxaziridine 20% Schmitz J. Geterozikl. Soedin. 1974, 12, 1629

33 Amination of Enolates Li Bu t C TF, -78 o C Boc Boc 35% Bu t + C Bu t substantial amount Boc Boc Aldol addition is a problem. Could orthosubstituted oxaziridines be used to slower the aldol addition? 38% 33% Collet J. rg. Chem. 1993, 58, Si 3 C Boc LDA, TF, -100 o C 1 2 Si 3 Boc yield, % dr 2 Bu t 27 90:10 Et Et 2 Bu t 37 93:7 n-pr n-pr 2 Bu t 29 94:6 Enders Tetrahedron: Asymmetry 1998, 9, 3709

34 -Amination eactions % 54% 2 18 b 2 a a b Schmitz Synthesis 1991, 327

35 Synthetically Useful -Amination Procedure m-cpba 0 o C, 1 h 49% 2 1. K, DMPU, 0 o C % alcohol product yield, % Ellman J. rg. Chem. 1999, 64, 6528

36 -Boc-ydroxylamines via -Amination of Alcoholates LiMDS, -78 o C Boc Boc CCl 3 > 95% Boc Boc Boc 80% Boc 50% 85% 96% Boc Boc Boc 80% 50% 87% Knight JCS, Chem. Commun. 2000, 975

37 xaziridine to Amide earrangement: Puzzling Selectivity hν more strained product not observed hν or hν dr 95:5 dr 80:20 oxaziridine did not epimerize at during irradiation as evidenced by 1 M. less stable radical leads to the product. Lattes J. Am. Chem. Soc. 1982, 104, 3929

38 Stereoelectronic Effect Both experimental and theoretical studies suggest that the C-C bond anti to the nitrogen lone pair is cleaved more easily. hν 85% Bu t Bu t dr 93:7 Bu t structure by X-ray structure by X-ray Lattes J. Am. Chem. Soc. 1982, 104, 3929 Theoretical study ruled out the concerted mechanism for the rearrangement with very high E a and strongly supported the mechanism involving - bond cleavage to form biradical intermediate. s a s a s a a s C E 19.8 kcal/mol A B C A 0 kcal/mol Malrieu J. Am. Chem. Soc. 1979, 101, 318 B kcal/mol

39 ecent Applications of otochemical earrangement C 2 C 2 hν, C 68% (+)-alloyohimbane Aube J. Am. Chem. Soc. 1994, 116, BnC 2 C 6 6, 80 o C BnC m-cpba for 3 steps: = Bn, 35% = n-bu, 37% BnC hν, C 6 6 BnC egedus J. Am. Chem. Soc. 1998, 120, 12468

40 Lewis Acid-Catalyzed earrangement: eversal of Selectivity Mn(tpp)Cl C, 40 o C 98% dr 98:2 Mn(tpp)Cl C, 40 o C tpp = tetraphenylporphyrin 94% dr 98:2 Mn(tpp)Cl C, 40 o C 96% dr 94:6 reaction is stereospecific: substituent syn to the lone pair migrates. e-transfer reagents, such as Cu(tpp), Fe(tpp), and Co(tpp), showed no catalytic activity. reactions are complete in min with 2 mol% of the catalyst. Suda JCS, Chem. Commun. 1994, 949

41 Possible Explanation of the bserved Stereospecificity L.A. L.A. 120 o counterclockwise L.A. a s a s a 60 o 60 o 60 o s A clockwise 60 o ~ s L.A. ~ a s s a a s a B As Lewis acid is very big and anionic oxygen is highly solvated in C, rotamer A looks better than B. ne may argue though, that upon counterclockwise rotation to reach A, substituent a should pass. o eclipsing of substituents is required to reach structure B upon clockwise rotation.

42 Single Electron Transfer eactions of xaziridines Generalized reactivity pattern: set products Minisci Tetrahedron 1970, 26, mol% [Cu(P 3 )Cl] 4 TF reflux 63% >95% ee 5 mol% [Cu(P 3 )Cl] 4 TF reflux 62% >97:3 dr Aube J. Am. Chem. Soc. 1992, 114, 5466

43 Proposed chanism Cu I set Cu II Cu II -C 3 C -Cu I Cu II Cu II Aube J. Am. Chem. Soc. 1992, 114, 5466

44 eaction Pathway for Diastereomeric xaziridine Cu I set Cu II Cu II -Cu I Cu II Cu II Aube J. Am. Chem. Soc. 1992, 114, 5466

45 Conclusions xaziridines are readily available by a number of synthetic methods. itrogen inversion barrier in oxaziridines is high enough to allow preparation of non-racemic compounds. -Sulphonyl oxaziridines are widely used as reagents for the oxygenation of enolates. xaziridinium salts are very promising reagents for the catalytic asymmetric epoxidation of alkenes. Perfluorinated oxaziridines are powerful oxidants, and can oxidize electron deficient olefins and unactivated C- bonds. - and -acyl oxaziridines are useful reagents for the electrophilic amination of amines, - and C-nucleophiles. Catalytic variants of this reaction are still to be developed. The stereospecific photochemical rearrangement of oxaziridines is a valuable method of lactam synthesis. The stereospecific Lewis acid-catalyzed rearrangement of -aryl oxaziridines provides complementary selectivity to that observed in the photochemical reaction. Single-electron transfer to oxaziridines proceeds under mild conditions to generate nitrogencentered radicals. This reaction may find application in a synthesis of complex molecules via cascade bond formation.