Hf(IV)-catalyzed enantioselective epoxidation of N-alkenyl sulfonamides and N-tosyl imines

Article abstract of DOI:10.1021/ja211880s

Asymmetric epoxidation of allylic and homoallylic amine derivatives catalyzed by Hf(IV)-bishydroxamic acid complexes is described. Under similar conditions, aldimine and ketimine produced oxaziridines. The sulfonyl group is demonstrated to be an effective directing group for these transformations.

Full text of DOI:10.1021/ja211880s

Communication
pubs.acs.org/JACS
Hf(IV)-Catalyzed Enantioselective Epoxidation of N-Alkenyl
Sulfonamides and N-Tosyl Imines
Jose Luis Olivares-Romero, Zhi Li, and Hisashi Yamamoto*
́
Department of Chemistry, The University of Chicago, 5735 South Ellis Avenue, Chicago, Illinois 60637, United States
S
* Supporting Information
Table 1. Screening of Epoxidation Reaction Conditions
ABSTRACT: Asymmetric epoxidation of allylic and
homoallylic amine derivatives catalyzed by Hf(IV)−
bishydroxamic acid complexes is described. Under similar
conditions, aldimine and ketimine produced oxaziridines.
The sulfonyl group is demonstrated to be an effective
a
b
entry
R
solvent
additive
yield /%
ee /%
directing group for these transformations.
1
2
3
Boc-
Ts-
toluene
toluene
CH2Cl2
toluene
toluene
toluene
toluene
toluene
−
−
−
9
68
90
75
13
77
90
89
93
23
5
Ts-
he spectacular success of asymmetric epoxidation during
c
4
Ts-
4 Å MS
MgSO4
MgO
MgO
MgO
12
37
46
13
T
the past century is one of the most important achieve-
ments in modern organic synthesis.1,2 The Sharpless epoxida-
tion of allylic alcohol may be the ground-breaking accomplish-
ment among them. Recently, vanadium-, zirconium-, and
hafnium-catalyzed asymmetric epoxidation of allylic, homo-
allylic, and bishomoallylic alcohols has been reported in our
laboratory.3 In all of these transformations, the hydroxyl group
in the substrates acts as an effective directing anchor between
the metal catalyst and the olefin. Herein we wish to report that
the ‘sulfonyl’ group is able to act as a new and excellent direct-
ing anchor for the asymmetric epoxidation reactions.
d
5
Ts-
d
6
d
Ts-
7
Ns-
Mbs-
de
,
8
49
a
b
Isolated yield after chromatographic purification. Enantiomeric
excess values were determined by chiral HPLC or chiral gas
chromatography. 100 mg of MS were added. 20 mol % additive
c
d
e
was added. Mbs- = 4-methoxybenzenesulfonyl.
Table 2. Screening of Bis-Hydroxamic Acid Ligand
We recently reported zirconium- and hafnium-catalyzed
asymmetric epoxidations using C2-symmetric chiral bishydroxa-
mic acid (BHA) ligand 13i for the efficient epoxidation of
homoallylic alcohols and bishomoallylic alcohols.4 The success
of these methods depends on a stereochemically wider catalytic
space for the oxidation process than that of typical Ti- and V-
catalyzed reactions. We therefore anticipated that these
catalysts could be effective toward not only the hydroxyl but
also other functional groups. The use of amines as directing
groups in asymmetric epoxidation5 is appealing because the
chiral epoxide-bearing amine products will be potentially very
useful building blocks for the synthesis of enantiomerically pure
complex molecules, in particular, of biologically active com-
pounds. Despite the considerable progress that has been made
in asymmetric epoxidation, allylic amines are still a long-
standing challenge in asymmetric oxidation. We thus naively
tested the hafnium-catalyzed epoxidations of various derivatives
of allylic amines. Indeed, the Hf(IV)−BHA-1 complex showed
catalytic activity toward various derivatives of allylic amines.
Among the various groups tested, p-methoxybenzenesulfonyl
and p-tolylsulfonyl groups are shown to be effective (Table 1):
N-allyl p-methoxybenzenesulfonyl gave a 49% yield and 93% ee
of its corresponding epoxide (entry 8, Table 1). Careful
examination of reaction conditions, including metal, solvent,
and additive screening, disclosed the optimum conditions for
this reaction (Table 1). It should be noted that the reactivity
a
b
entry
BHA
yield /%
ee /%
1
2
3
4
5
1
2
3
4
5
46
90
12
13
23
4
9
12
21
traces
a
b
Isolated yield after chromatographic purification. Enantiomeric
excess values were determined by chiral HPLC.
Received: December 20, 2011
Published: March 15, 2012
© 2012 American Chemical Society
5440
dx.doi.org/10.1021/ja211880s | J. Am. Chem. Soc. 2012, 134, 5440−5443

Journal of the American Chemical Society
Communication
Table 3. Epoxidation of N-Alkenyl Sulfonamides
a
b
c
All reactions were performed in the presence of 2.0 equiv of CHP as oxidant. Isolated yield after chromatographic purification. Enantiomeric
d
excess values were determined by chiral HPLC. 20 mol % catalyst and 40 mol % additive were used. Ts- = p-toluenesulfonyl. Mbs- = 4-
methoxybenzenesulfonyl.
and enantioselectivity can be significantly improved by
introducing inorganic additives such as magnesium oxide.6
Inspired by these promising results, the effect of sulfonyl
protective groups was investigated (entries 7 and 8, Table 1).
Electron-rich 4-methoxybenzenesulfonamide (Mbs) gave a
better yield than electron-deficient 4-nitrobenzenesulfonamide
(Ns).
We further tried to tune the stereochemical environment
about the hafnium ion by using different ligands (Table 2).
However, most of the attempts have been unsuccessful since
they could not give better enantioselectivity. Even changing the
phenyl groups in BHA-1 to a 2,4,6-trimethyl, 2,4,6-isopropyl, or
trityl group will result in a significantly decreased enantiose-
lectivity (entries 2, 3, 4, Table 2). Adding a chloro substituent
to the phenyl groups also decreased both the reactivity and
enantioselectivity (entry 5, Table 2).
sulfonamides with aromatic substituents having 3,5-di-tert-butyl
and 3,4-dimethoxy afforded the product with moderate to good
enantioselectivity (entries 2 and 4, Table 3). In general,
substrates bearing the 4-methoxybenzenesulfonyl moiety
afforded the product in high yield and enantioselectivity up
to 93% (entries 3, 7, 10, 13, 16, Table 3) in comparison with
substrates having the p-tolylsulfonyl group (entries 8, 11, 14,
17, Table 3). The reaction was more enantioselective for Z-
substituted olefins (entries 5−9) than E-olefins (entries 10−
12). Also, 3,3-disubstituted (entries 13, 14, Table 3) compared
to 2,3- and 2-disubstituted allylic amines (entries 15−18 Table
3) provide higher reactivities and selectivities. Epoxidation of
homoallylic amine derivatives was also performed. Although the
reactivity and selectivity was lower than that of allylic amine
derivatives, the reaction still gave 67% enantioselectivity
(entries 19−21). In general, the best substrates for this
epoxidation are 3,3-disubstituted allylic amines bearing a 4-
methoxybenzenesulfonyl group. Finally, we evaluated the
selectivity using the 2-(trimethylsilyl)ethanesulfonamide as a
The scope of the allyl and homoallyl amines with different
substituted patterns was subjected to the optimum epoxidation
conditions, and the results are shown in Table 3. N-Alkenyl
5441
dx.doi.org/10.1021/ja211880s | J. Am. Chem. Soc. 2012, 134, 5440−5443

Journal of the American Chemical Society
Communication
protecting group since this group can be easily removed;7 to
our delight we found almost the same selectivity as that utilizing
the p-tolylsulfonyl group (entries 1 and 22, Table 3). This
result demonstrates that our protocol can be useful in the
preparation of enantiomerically enriched epoxides.
The electronic nature of the sulfonyl group had an effect on
both reactivity and enantioselectivity, with the electron-
donating p-methoxy derivative displaying higher reactivity and
selectivity than the Ts- group and the electron withdrawing Ns-
group (Table 1, entries 6, 7, 8). To gain more insight into the
mode of coordination, a series of control experiments were
conducted. Changing the NH-sulfonyl group to the O-sulfonyl
or CH2-sulfonyl group still allowed the asymmetric epoxidation
to take place. These facts suggest the sulfonyl oxygen, instead of
the amide nitrogen, play a major role as the directing group
interacting with the metal and, rather amazingly, the reaction may
proceed through a sulfonyl-oxygen directed pathway (Chart 1).8
and the metal. This new coordination mode could be useful for
many other types of compounds containing Lewis basic oxygen
atoms.
In order to expand the scope of the reaction, the sulfonyl-
directed oxidation reaction was also applied to the oxidation of
N-tosyl aldimines and ketimines (Table 4).10 Gratifyingly,
highly enantioselective epoxidation reaction was observed not
only for simple aldimines (entries 1−3, Table 4) but also for a
more challenging ketimine (entry 4, Table 4).
In conclusion, we have discovered an unprecedented
enantioselective epoxidation of N-alkenyl amine derivatives
catalyzed by a hafnium−BHA catalyst system. The reaction
likely undergoes a sulfonyl-oxygen-directing process. This is the
first report on a directing group other than hydroxyl in metal-
catalyzed asymmetric epoxidation, and its application will
considerably broaden the avenues for asymmetric epoxida-
tion.11 We have demonstrated that the BHA−Hf(IV) system is
able to catalyze a highly enantioselective oxaziridination of
N-tosyl imines. Utilization of this protocol toward other
asymmetric processes and elucidation of the mechanism are
underway.
Chart 1. Epoxidation of Allylic Sulfonate, Sulfonamide, and
a
,b
Sulfones
ASSOCIATED CONTENT
* Supporting Information
■
S
Representative experimental procedures and necessary charac-
terization data for all compounds are provided. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
yamamoto@uchicago.edu
■
Notes
a
Isolated yield after chromatographic purification. bEnantiomeric
excess values were determined by chiral HPLC.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
The financial support of the National Institutes of Health
(NIH) (GM068433-05) is greatly appreciated. J.L.O.-R. thanks
Table 4. Oxaziridination of N-Tosyl Imines
■
́
CONACYT (Mexico) for the postdoctoral fellowship.
REFERENCES
■
(1) For reviews see: (a) Katsuki, T.; Martin, V. S. Org. React. 1996,
48, 1. (b) Katsuki, T. In Comprehensive Asymmetric Catalysis; Jacobsen,
E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin, 1999; Vol. 2, p
621. (c) Keith, J. M.; Larrow, J. F.; Jacobsen, E. N. Adv. Synth. Catal.
2001, 343, 5. (d) Chatterjee, D. Coord. Chem. Rev. 2008, 252. (e) Díez,
́
́
D.; Nunez, M. G.; Anton, A. B.; García, P.; Moro, R. F.; Garrido, N.
̃
M.; Marcos, I. S.; Basabe, P.; Urones, J. G. Curr. Org. Synth. 2008, 5,
186. (f) Matsumoto, K.; Sawada, Y.; Katsuki, T. Pure Appl. Chem.
2008, 80, 1071. (g) Wong, O. A.; Shi, Y. Chem. Rev. 2008, 108, 3958.
(2) (a) Illa, O.; Arshad, M.; Ros, A.; McGarrigle, E. M.; Aggarwal, V.
K. J. Am. Chem. Soc. 2010, 132, 1828. (b) Egami, H.; Oguma, T.;
Katsuki, T. J. Am. Chem. Soc. 2010, 132, 5886. (c) Lifchits, O.;
Reisinger, C. M.; List, B. J. Am. Chem. Soc. 2010, 132, 10227.
(d) Tanaka, H.; Nishikawa, H.; Uchida, T.; Katsuki, T. J. Am. Chem.
Soc. 2010, 132, 12034. (e) De Faveri, G.; Ilyashenko, G.; Watkinson,
M. Chem. Soc. Rev. 2011, 40, 1722.
(3) (a) Murase, N.; Hoshino, Y.; Oishi, M.; Yamamoto, H. J. Org.
Chem. 1999, 64, 338. (b) Hoshino, Y.; Murase, N.; Oishi, M.;
Yamamoto, H. Bull. Chem. Soc. Jpn. 2000, 73, 1653. (c) Hoshino, Y.;
Yamamoto, H. J. Am. Chem. Soc. 2000, 122, 10452. (d) Makita, N.;
Hoshino, Y.; Yamamoto, H. Angew. Chem., Int. Ed. 2003, 42, 941.
(e) Zhang, W.; Basak, A.; Kosugi, Y.; Hoshino, Y.; Yamamoto, H.
Angew. Chem., Int. Ed. 2005, 44, 4389. (f) Zhang, W.; Yamamoto, H. J.
Am. Chem. Soc. 2007, 129, 286. (g) Barlan, A. U.; Zhang, W.;
a
All reactions were performed in the presence of 2.0 equiv of CHP as
b
c
oxidant. Isolated yield after chromatographic purification. Enantio-
meric excess values were determined by chiral HPLC. 20 mol %
catalyst and 20 mol % additive were used.
d
The reaction of Boc-protected allylic amine9 (entry 1, Table 1)
also suggests the weak interaction between the carbonyl oxygen
5442
dx.doi.org/10.1021/ja211880s | J. Am. Chem. Soc. 2012, 134, 5440−5443

Journal of the American Chemical Society
Communication
Yamamoto, H. Tetrahedron 2007, 63, 6075. (h) Li, Z.; Zhang, W.;
Yamamoto, H. Angew. Chem., Int. Ed. 2008, 47, 7520. (i) Li, Z.;
Yamamoto, H. J. Am. Chem. Soc. 2010, 132, 7878.
(4) Li, Z. PhD dissertation, The University of Chicago, 2011.
(5) For stereoselective oxidation of allylic amine derivatives with m-
CPBA, see: (a) O’Brien, P.; Childs, A. C.; Ensor, G. J.; Hill, C. L.;
Kirby, J. P.; Dearden, M. J.; Oxenford, S. J.; Rosser, C. M. Org. Lett.
2003, 5, 4955. (b) Bond, C. W.; Cresswell, A. J.; Davies, S. G.;
Fletcher, A. M.; Kurosawa, W.; Lee, J. A.; Roberts, P. M.; Russell, A. J.;
Smith, A. D.; Thomson, J. E. J. Org. Chem. 2009, 74, 6735. (c) Asencio,
G.; Gonzal
Am. Chem. Soc. 1993, 115, 7250. (d) Asencio, G.; Mello, R.; Boix-
Bernardini, C.; Gonzalez-Nunez, M. E.; Castellano, G. J. Org. Chem.
1995, 60, 3692. (e) Asencio, G.; Boix-Bernardini, C.; Andreu, C.;
Gonzalez-Nunez, M. E.; Mello, R.; Edwards, J. O.; Carpenter, G. B. J.
́
ez-Nunez, M. E.; Bernardini, C. B.; Mello, R.; Adam, W. J.
̃
́
̃
́
̃
Org. Chem. 1999, 64, 4705. (f) Davies, S. G.; Fletcher, A. M.;
Kurosawa, W.; Lee, J. A.; Poce, G.; Roberts, P. M.; Thomson, J. E.;
Williamson, D. M. J. Org. Chem. 2010, 75, 7745. (g) Aciro, C.;
Claridge, T. D. W.; Davies, S. G.; Roberts, D. M.; Russel, A. J.;
Thomson, J. E. Org. Biomol. Chem. 2008, 6, 3751. (h) Aciro, C.;
Davies, S. G.; Roberts, D. M.; Russell, A. J.; Smith, A. D.; Thomson, J.
E. Org. Biomol. Chem. 2008, 6, 3762. (i) Aggarwal, V. K.; Fang, G. Y.
Chem. Commun. 2005, 3448. (j) Edwards, A. S.; Wybrow, R. A. J.;
Johnstone, C.; Adams, H.; Harrity, J. P. A. Chem. Commun. 2002,
1542. (k) Bagal, S. K.; Davies, S. G.; Fletcher, A. M.; Lee, J. A.;
Roberts, D. M.; Scott, D. M.; Thomson, J. E. Tetrahedron Lett. 2011,
52, 2216.
(6) The role of MgO is still elusive. ZnO and Al2O3 also improve the
reaction to a lesser extent. The amount of the additive is not very
influential. For example, reactions with 5 mol% to 2 equiv of MgSO4
all gave similar results.
(7) For examples in the use of 2-(trimethylsilyl)ethanesulfonamide as
a protecting group, see: (a) Weinreb, S. M.; Demko, D. M.; Lessen, T.
A.; Demers, J. P. Tetrahedron Lett. 1986, 27, 2099. (b) Garigipati, R. S.;
Weinreb, S. M. J. Org. Chem. 1988, 53, 4143.
(8) For an example of sulfonyl oxygen interacting with a metal
catalyst, see: (a) Tsui, G. C.; Lautens, M. Angew. Chem., Int. Ed. 2010,
́
49, 8938. (b) Csatayova, K.; Davies, S. G.; Lee, J. A.; Ling, K. B.;
Roberts, D. M.; Russell, A. J.; Thomson, J. E. Tetrahedron 2010, 66,
8420.
(9) For enantioselective oxidation of allylic amines bearing a
carbamate moiety, see: Shaus, S. E.; Brandes, B. D.; Larrow, J. F.;
Tokunaga, M.; Hansen, R. B.; Gould, A. E.; Furrow, M. E.; Jacobsen,
E. N. J. Am. Chem. Soc. 2002, 124, 1307.
(10) Recently, Jørgensen et al. reported an excellent enantioselective
oxaziridination; see: Lykke, L.; Rodríguez-Escrich, C.; Jørgensen, K. A.
J. Am. Chem. Soc. 2011, 133, 14932.
(11) For an example of existing nonasymmetric synthesis of a
biologically active molecule via epoxy amine intermediates, see: Sova,
M.; Kovac, A.; Turk, S.; Hrast, M.; Blanot, D.; Gobec, S. Bioorg. Chem.
2009, 37, 217.
5443
dx.doi.org/10.1021/ja211880s | J. Am. Chem. Soc. 2012, 134, 5440−5443