(organic chemists)

1
Oxaziridines What Can You Do With A Strained
Three-Membered Heterocycle

• (organic chemists)
• Literature meeting
• Carl Trudel
• February 7th 2011

2
Some Generalities

• 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.
3
Davis Oxaziridines
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.
4
The Program

• Some generalities
• Oxaziridines preparation
• Their properties
• Their reactivity
• Photoisomerisation
• O-transfer agents
• N-transfer agents
• Dipolar cycloaddition agent

5
Oxaziridines Preparation Imines Oxidation
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.
6
Stereochemical considerations

• Syn-directing OH
• Anti to EWG

Wang, Y. Chackalamannil, S. Aube, J. J. Org.
Chem. 2000, 65, 5120-5126.
7
Proposed Mechanism

• 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.
Kovac, F. Int. J. Chem. Kinet. 2007, 39, 492-497.
8
Other Schiff Base Oxydation
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.
9
NH Oxaziridines Ketones Amination
Anreae, S. Schmitz, E. Synthesis 1991, 327-341.
Schulz, M. Becker, D. Rieche, A. ACIE 1965, 4,
525-526.
10
Photololysis of Nitrones

• 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.
11
Some Considerations

• Photochemical epimerization
• Thermal nitrogen inversion is unfavored
• Ring strain increases in TS
• Inductive effect of adjacent O

Boyd, D. R. et al. J. Chem. Soc., Chem. Commun.
1976, 162-163.
Boyd, D. R. J. Chem. Soc., Chem. Commun. 1992,
1078-1079. Boyd, D. R. J. Chem. Soc., Perkin
Trans. 2 1973, 1575-1577.
12
The Program

• Some generalities
• Oxaziridines preparation
• Their properties
• Their reactivity
• Photoisomerisation
• O-transfer agents
• N-transfer agents
• Dipolar cycloaddition agent

13
Photo- Oxaziridine to Amide Rearrangement

• 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.
14
Oxaziridines to Amides

• 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.
15
Oxaziridines to Amides

• Transition metal catalysed process
• Opposed stereoselectivity
• Stereospecific

Suda, K. Sashima, M. Izutsu, M. Hino, F. J.
Chem. Soc., Chem. Commun. 1994, 949-950.
16
Oxaziridines to Amide

• 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.
17
The Program

• Some generalities
• Oxaziridines preparation
• Their properties
• Their reactivity
• Photoisomerisation
• O-transfer agents
• N-transfer agents
• Dipolar cycloaddition agent

18
O Transfer Agents

• 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.
19
Asymetric Enolate Oxidation

• SN2-typem attack
• Racemic oxaziridine

Evans, D. A. et al. J. Am. Chem. Soc. 1985, 107,
4346-4348.
20
Dynamic Kinetic Asymetric Hydroxylation
Reddy, D. S. Shibata, N. Nagai, J. Nakamura,
S. Toru, T. Angew. Chem. Int. Ed. 2009, 48,
803-806.
21
O Transfer to Heteroatom Sulfur Oxidation
Clerici, F. et al. Tetrahedron Asymmetry 2009,
20, 2247-2256. Guillen, F. et al. Tetrahedron
Asymmetry 2007, 18, 2959-2964.
22
Intramolecular Epoxidation

• 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.
23
Intramolecular Epoxidation

• 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.
24
Catalytic Epoxidation

• 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.
25
Oxaziridinium Salt

• Faster than m-CPBA
• CO 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.
26
Oxaziridinium Salt

• Faster than m-CPBA
• CO 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.
27
Improving the Asymmetric Epoxidation
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.
28
Improving Asymmetric Epoxidation

• Oxidation step is less selective at 0C.

Page, P. C. B. et al. J. Org. Chem. 2001, 66,
6926-6931.
29
Improving the Asymmetric Epoxidation
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.
30
Perfluorinated Oxaziridines

• Perfluorinated Oxaziridines are stable up to
  120C
• 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.
31
Perfluorinated Oxaziridines

• And capable of C-H bond activation!
• Enantiospecific
• 3 C-H gt 2 C-H gtgt 1 C-H
• Equatorial gt 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.
32
Catalytic Hydroxylation of 3 C-H Bonds
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.
33
Catalytic Hydroxylation of 3 C-H Bonds
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.
34
The Program

• Some generalities
• Oxaziridines preparation
• Their properties
• Their reactivity
• Photoisomerisation
• O-transfer agents
• N-transfer agents
• Dipolar cycloaddition agent

35
N Transfer Agents

• 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.
36
N-N Bond Formation

• 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.
37
N-O Bond formation
Foot, O. F. Knight, W. Chem. Commun. 2000,
975-976.
38
N-S Bond Formation

• 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.
39
N-S Bond and Sigmatropic Rearrangement
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.
40
N-H Oxaziridines C Aminating Agents

• Very reactive towards nucleophilic attack
• Good aminating agents

Andreae, S. Schmitz, E. Synthesis 1991, 327-341.
41
C-N Bond Formation
Andreae, S. Schmitz, E. Synthesis 1991, 327-341.
Bulman Page, P. C. et al. J. Org. Chem. 2002, 67,
7787-7796.
42
N-Substituted Oxaziridines Issues

• Competitive aldol addition with enolates
• Competitive diamination

Armstrong, A. Edmonds, I. D. Swarbrick, M. E.
Treweeke, N. R. Tetrahedron 2005, 61, 8423-8442.
43
Electrophilic Amination Of Diorganozinc

• Low reactivity of R2Zn towards ketones or
  aldehydes

Ghoraf, M. Vidal, J. Tetrahedron Lett. 2008, 49,
7383-7385.
44
Intramolecular Amination of C-H Bonds

• 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, 2005present
• University of Wisconsin, Madison
• Total synthesis, visible light photocatalysis
• New reactions of oxaziridines.
• Same State as the Green Bay Packers!

45
Intramolecular Amination of C-H Bonds

• 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.
46
The Program

• Some generalities
• Oxaziridines preparation
• Their properties
• Their reactivity
• Photoisomerisation
• O-transfer agents
• N-transfer agents
• Dipolar cycloaddition agent

47
Dipolar Cycloadditions

• 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.
48
Hydroxyamination

• CuCl2/BuN4Cl- 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, 5545-5552.
Williamson, K. S. Yoon, T. P. J. Am. Chem. Soc.,
2010, 132, 4570-4571.
49
Stereoselective Hydroxyamination

• 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.
50
Isoxazolidines Preparation
Partridge, K. M. Guzei, I. A. Yoon, T. P.
Angew. Chem. Int. Ed., 2010, 49, 930-934.
51
Chirality Transfer to Isoxazolidines

• 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.
52
Formal Nitrones Cycloaddition
Troisi, L. et al. Synlett 2010, 18, 2781-2783.
Kivrak, A. Larock, R. C. J. Org. Chem. 2010, 75,
7381-7387.
53
Summary

• Oxaziridines preparation is relatively easy
• Properties widely tuneable
• Amide precusor
• Heteroatom transfer agent
• Limitless 32 Cycloadditions
• Need to be investigated

54
The End