Oxaziridines :
What Can You Do With A Strained
Three-Membered Heterocycle
1
(organic chemists)
Literature meeting
C a r l Tr u d e l
F e b r u a r y 7 th 2 0 11
Some Generalities
2
 First discovered by William D. Emmons in 1956.
 Worked for Rohm and Haas Company's (Dow Chemical
Company)
 HWE (least imaginative of his work!)
 Died in 2001
 Discovery followed by H. Krimm and...
• ... L. Horner!
Emmons, W. D. J. Am. Chem. Soc. 1956, 78, 6208-6209. Horner, L.; Jürgens, E. Chem. Ber. 1957, 90, 2184-2189.
Davis’ Oxaziridines
3
Davis, F. A. et al. J. Am. Chem. Soc.
1988, 110, 8477-8482.
Davis, F. A.; Sheppard, A. C. J. Org. Chem. 1987, 52, 954-955. Evans, D. A. et al. J. Am. Chem. Soc. 1985, 107, 4346-4348.
The Program
4
 Some generalities
 Oxaziridines’ preparation
 Their properties
 Their reactivity
 Photoisomerisation
 “O”-transfer agents
 “N”-transfer agents
 Dipolar cycloaddition agent
Oxaziridines Preparation : Imines Oxidation
5
Emmons, W. D. J. Am. Chem. Soc. 1956, 78, 6208-6209. Horner, L.; Jürgens, E. Chem. Ber. 1957, 90, 2184-2189.
Widmer, J.; Keller-Schierlein, W. Helv. Chim. Acta 1974, 57, 657-664.
Aube, J. et al. J. Am. Chem. Soc. 1995, 117, 5169-5178.
Stereochemical considerations
6
 Syn-directing OH
 Anti to EWG
Wang, Y.; Chackalamannil, S.; Aube, J. J. Org. Chem. 2000, 65, 5120-5126.
Proposed Mechanism
7
 Imine geometry has little effect (stereoselectivity vs specificity).
 Faster for electron poor imines and electron rich peracids.
 Accelerated by protic solvents.
 Electrophilic oxydant (DMDO) generates significant amount of nitrone.
Aube, J. et al. J. Org. Chem. 2000, 65, 5120-5126. Belzecki, C.; Mostowicz, D. J.Org. Chem.1975, 40, 3878-3880. Ogata, Y.;
Sawaki, Y. J. Am. Chem. Soc. 1973, 95, 4687-4692. Nose, Ž.; Kovač, F. Int. J. Chem. Kinet. 2007, 39, 492-497.
Other Schiff Base Oxydation
8
Davis, F. A.; Chattopadhyay, S.; Towson, J. C.; Lal, S.; Reddy, T. J. Org. Chem. 1988, 53, 2087-2089.
Jain, S. L.; Singhal, S.; Sain, B. J. Organomet. Chem. 2007, 692, 2930-2935.
Kraïem, J.; Ben Othman, R.; Ben Hassine, B. C. R. Chim., 2004, 7, 1119-1126.
NH Oxaziridines : Ketones Amination
9
Anreae, S.; Schmitz, E. Synthesis 1991, 327-341. Schulz, M.; Becker, D.; Rieche, A. ACIE 1965, 4, 525-526.
Photololysis of Nitrones
10
 This mechanism may be involved in the photochemical epimerization
of oxaziridines.
Ning, R. Y.; Field, G. F.; Sternbach, L. H. J. Heterocycl. Chem. 1970, 7, 475-478.
Boyd, D. R. et al. J. Chem. Soc., Chem. Commun. 1976, 162-163.
Some Considerations
11
 Photochemical epimerization
Boyd, D. R. et al. J. Chem. Soc., Chem. Commun. 1976, 162-163.
 Thermal nitrogen inversion is unfavored


Ring strain increases in TS‡
Inductive effect of adjacent O
Boyd, D. R. J. Chem. Soc., Chem. Commun. 1992, 1078-1079. Boyd, D. R. J. Chem. Soc., Perkin Trans. 2 1973, 1575-1577.
The Program
12
 Some generalities
 Oxaziridines’ preparation
 Their properties
 Their reactivity
 Photoisomerisation
 “O”-transfer agents
 “N”-transfer agents
 Dipolar cycloaddition agent
Photo- Oxaziridine to Amide Rearrangement
13
 Biradical mechanism
 Concerted alkyl migration
 C-C bond anti to the hydrogen lone pair
Malrieu, J. P. et al. J. Am. Chem. Soc. 1979, 101, 318-322. Lattes, A. et al. J. Am. Chem. Soc. 1982, 104, 3929-3934.
Oxaziridines to Amides
14
 Photochemical process

Apparent «less stable radical» leads to the product

Nitrones also work altough with lower yields
More strained product is obtained

Lattes, A. et al. J. Am. Chem. Soc. 1982, 104, 3929-3934. Girard, J.-P. et al. Org. Lett. 2001, 3, 3067-3070. Aube, J. Chem. Soc.
Rev. 1997, 26, 269.
Oxaziridines to Amides
15
 Transition metal catalysed process


Opposed stereoselectivity
Stereospecific
Suda, K.; Sashima, M.; Izutsu, M.; Hino, F. J. Chem. Soc., Chem. Commun. 1994, 949-950.
Oxaziridines to Amide
16
 Transition metal catalysed process


Stabilised intermediate
Substituent syn to the lone pair migrates
 Towards an atom economic amid synthesis?
Suda, K. et al. J. Chem. Soc., Chem. Commun. 1994, 949-950. Crabtree, R. H. et al. Green Chem. 2007, 9, 976-979.
The Program
17
 Some generalities
 Oxaziridines’ preparation
 Their properties
 Their reactivity
 Photoisomerisation
 “O”-transfer agents
 “N”-transfer agents
 Dipolar cycloaddition agent
“O” Transfer Agents
18
 Can act as O or N transfer agents
 N substituent tunes the reactivity

Steric and electronic effects
Electron poor imine derivatives react faster
 Nucleophiles may react in a SN2 fashion (N-O bond)…
 …Or via a concerted asynchronous TS

 Epoxidations occurs in a spiro transition state
Davis, F. A. et al. J.Org. Chem. 1986, 51, 4240-4245. Houk, K. N. et al. J. Am. Chem. Soc. 1997, 119, 10147-10152.
Asymetric Enolate Oxidation
19
 SN2-typem attack
 Racemic oxaziridine
Evans, D. A. et al. J. Am. Chem. Soc. 1985, 107, 4346-4348.
Dynamic Kinetic Asymetric Hydroxylation
20
Reddy, D. S.; Shibata, N.; Nagai, J.; Nakamura, S.; Toru, T. Angew. Chem. Int. Ed. 2009, 48, 803-806.
O Transfer to Heteroatom : Sulfur Oxidation
21
Clerici, F. et al. Tetrahedron: Asymmetry 2009, 20, 2247-2256. Guillen, F. et al. Tetrahedron: Asymmetry 2007, 18, 2959-2964.
Intramolecular Epoxidation
22
 Intramolecular process proven by competitive experiment with 13C and
18O
labeled oxaziridine
Anderson, D. R.; Woods, K. W.; Beak, P. Org. Lett. 1999, 1, 1415-1417.
Intramolecular Epoxidation
23
 Electron rich alkene
 Regiocontrol via a six-membered ring transition state
Armstrong, A.; Draffan, A. G. J. Chem. Soc., Perkin Trans. 1 2001, 2861-2873.
Catalytic Epoxidation
24
 Phosphonio imine can be converted in situ in oxaziridine oxidant.
 Reaction takes 3 to 45 hours
 Concerted mechanism
 Electron rich alkene reacts first
 Cyclohexene derivatives showed increased reactivity over linear alkene
Prieur, D.; El Kazzi, A. e.; Kato, T.; Gornitzka, H.; Baceiredo, A. Org. Lett. 2008, 10, 2291-2294.
Oxaziridinium Salt
25
 Faster than m-CPBA
 C=O directed (vs O-H)
Hanquet, G. et al.Tetrahedron Lett. 1993, 34, 7271-7274. Lusinchi, X.; Hanquet, G. Tetrahedron 1997, 53, 13727-13738. Bohé,
L.; Lusinchi, M.; Lusinchi, X. Tetrahedron 1999, 55, 141-154.
Oxaziridinium Salt
26
 Faster than m-CPBA
 C=O directed (vs O-H)
 Stoechiometric oxaziridinium gave 42% ee.
 5 mol% of iminium, oxone/NaHCO3 system at RT
Hanquet, G. et al.Tetrahedron Lett. 1993, 34, 7271-7274. Lusinchi, X.; Hanquet, G. Tetrahedron 1997, 53, 13727-13738. Bohé,
L.; Lusinchi, M.; Lusinchi, X. Tetrahedron 1999, 55, 141-154.
Improving the Asymmetric Epoxidation
27
Page, P. C. B. et al. J. Org. Chem. 1998, 63, 2774-2777. Page, P. C. B. et al. J. Org. Chem. 2001, 66, 6926-6931.
Improving Asymmetric Epoxidation
28
 Oxidation step is less selective at 0°C.
Page, P. C. B. et al. J. Org. Chem. 2001, 66, 6926-6931.
Improving the Asymmetric Epoxidation
29
Page, P. C. B. et al. J. Org. Chem. 1998, 63, 2774-2777. Page, P. C. B. et al. J. Org. Chem. 2001, 66, 6926-6931.
Perfluorinated Oxaziridines
30
 Perfluorinated Oxaziridines are stable up to 120°C
 Fairly strong oxidant
 Oxidizes sulfides to sulfoxides or sulfones, pyridine and tertiary amines
to N-Oxides, silanes to silanol and alcohol and ethers to ketones…
 Can perform epoxidation on unactivated or electron poor alkenes.
Petrov, V. A.; Resnati, G. Chem. Rev. 1996, 96, 1809. Resnati, G. et al. J. Org. Chem. 1994, 59, 5511-5513.
Perfluorinated Oxaziridines
31
 … And capable of C-H bond activation!
 Enantiospecific
 3° C-H > 2° C-H >> 1° C-H
 Equatorial > Axial
 Oxidized alcohol and ethers
Resnati, G. et al. J. Org. Chem. 1994, 59, 5511-5513. Sorochinsky, A. E.et al. Tetrahedron 1997, 53, 5995-6000.
Catalytic Hydroxylation of 3° C-H Bonds
32
Brodsky, B. H.; Du Bois, J. J. Am. Chem. Soc. 2005, 127, 15391-15393. Litvinas, N. D.; Brodsky, B. H.; Du Bois, J. Angew.
Chem. Int. Ed. 2009, 48, 4513-4516.
Catalytic Hydroxylation of 3° C-H Bonds
33
Brodsky, B. H.; Du Bois, J. J. Am. Chem. Soc. 2005, 127, 15391-15393. Litvinas, N. D.; Brodsky, B. H.; Du Bois, J. Angew.
Chem. Int. Ed. 2009, 48, 4513-4516.
The Program
34
 Some generalities
 Oxaziridines’ preparation
 Their properties
 Their reactivity
 Photoisomerisation
 “O”-transfer agents
 “N”-transfer agents
 Dipolar cycloaddition agent
“N” Transfer Agents
35
 Can act as O or N transfer agents
 N substituent tunes the reactivity



Smaller alkyl groups
Carbonyl derivatives
R1 and/or R2 are EWG
 Betaine intermediate?
Vidal, J. et al. Chem. Euro. J. 1997, 3, 1691-1709.
N-N Bond Formation
36
 Bulkier amines
 Aminoesters
 Anilines
 One-pot 1,3,5-pyrazoles
Vidal, J. et al. Tetrahedron Lett. 1998, 39, 8845-8848. Armstrong, A. et al. Org. Lett. 2005, 7, 713-716.
N-O Bond formation
37
Foot, O. F.; Knight, W. Chem. Commun. 2000, 975-976.
N-S Bond Formation
38
 Competitive oxidation pathway
 Solvant and temperature play an important role
 Not a steric effect
Vidal, J. et al. Chem. Euro. J. 1997, 3, 1691-1709. Armstrong, A.; Cooke, R. S. Chem. Commun. 2002, 904-905.
N-S Bond and Sigmatropic Rearrangement
39
Armstrong, A.; Cooke, R. S. Chem. Commun. 2002, 904-905. Armstrong, A. et al. J. Org. Chem. 2006, 71, 4028-4030. Armstrong,
A.; Cooke, R. S.; Shanahan, S. E. Org. Biomol. Chem. 2003, 1, 3142.
N-H Oxaziridines : C Aminating Agents
40
 Very reactive towards nucleophilic attack
 Good aminating agents
Andreae, S.; Schmitz, E. Synthesis 1991, 327-341.
C-N Bond Formation
41
Andreae, S.; Schmitz, E. Synthesis 1991, 327-341. Bulman Page, P. C. et al. J. Org. Chem. 2002, 67, 7787-7796.
N-Substituted Oxaziridines Issues
42
 Competitive aldol addition with enolates
 Competitive diamination
Armstrong, A.; Edmonds, I. D.; Swarbrick, M. E.; Treweeke, N. R. Tetrahedron 2005, 61, 8423-8442.
Electrophilic Amination Of Diorganozinc
43
 Low reactivity of R2Zn towards ketones or aldehydes
Ghoraf, M.; Vidal, J. Tetrahedron Lett. 2008, 49, 7383-7385.
Intramolecular Amination of C-H Bonds
44
 Teshik P. Yoon





A.B., Harvard University (Evans), 1996
M.S., Caltech (Carreira), 1998
Ph.D., Caltech (MacMillan), 2002
Postdoc, Harvard (Jacobsen), 2002-2005
Assistant Professor of Chemistry, 2005–present
 University of Wisconsin, Madison
 Total synthesis, visible light photocatalysis…
 …New reactions of oxaziridines.
 Same State as the Green Bay Packers!
Intramolecular Amination of C-H Bonds
45
 Various exemples, 61 – 87% yields
 Aliphatic oxaziridines work as well.
 Hemiaminal can also be trapped with other reagent to afford, in one
pot, ketoamine, homoallylamine, etc.
Allen, C. P.; Benkovics, T.; Turek, A. K.; Yoon, T. P. J. Am. Chem. Soc. 2009, 131, 12560-12561.
The Program
46
 Some generalities
 Oxaziridines’ preparation
 Their properties
 Their reactivity
 Photoisomerisation
 “O”-transfer agents
 “N”-transfer agents
 Dipolar cycloaddition agent
Dipolar Cycloadditions
47
 Three cycloaddition pathway should be tuneable with appropriate
reaction conditions.
Michaelis, D. J.; Ischay, M. A.; Yoon, T. P. J. Am. Chem. Soc. 2008, 130, 6610-6615.
Hydroxyamination
48
 CuCl2/BuN4+Cl- showed enhanced reactivity
 N-Nosyl oxaziridines were proven more reactive
 A FeIII has been developped.
Knappke, C. E. I.; Jacobi von Wangelin, A. ChemCatChem, 2010, 2, 1381-1383. Yoon, T. P. et al. J. Org. Chem. 2009, 74, 55455552. Williamson, K. S.; Yoon, T. P. J. Am. Chem. Soc., 2010, 132, 4570-4571.
Stereoselective Hydroxyamination
49
 Cationic or radical pathways are proposed
Yoon, T. P. et al. J. Org. Chem. 2009, 74, 5545-5552.
Shao, P.-L.; Chen, X.-Y.; Ye, S. Angew. Chem. Int. Ed., 2010, 49, 8412-8416.
Isoxazolidines Preparation
50
Partridge, K. M.; Guzei, I. A.; Yoon, T. P. Angew. Chem. Int. Ed., 2010, 49, 930-934.
Chirality Transfer to Isoxazolidines
51
 Carbonyl imine intermediate
 Thermally allowed, conrotatory electrocyclic
 EWG increase the lifetime of the intermediate
 Stereospecific
 Chirality can be transfered from N-substituent in thermal cycloaddition
Partridge, K. M.; Guzei, I. A.; Yoon, T. P. Angew. Chem. Int. Ed., 2010, 49, 930-934. Troisi, L. et al. Tetrahedron: Asymmetry 2008,
19, 2246-2251.
Formal Nitrones Cycloaddition
52
Troisi, L. et al. Synlett 2010, 18, 2781-2783. Kivrak, A.; Larock, R. C. J. Org. Chem. 2010, 75, 7381-7387.
Summary
53
 Oxaziridines preparation
is relatively easy
 Properties widely
tuneable



Amide precusor
Heteroatom transfer agent
Limitless [3+2] Cycloadditions
 Need to be investigated
The End
54