Copper(II)-catalyzed aminohydroxylation of olefins

Article abstract of DOI:10.1021/ja067894t

We report a novel copper(II)-catalyzed aminohydroxylation in which both heteroatoms of an N-sulfonyl oxaziridine are added across an alkene in a regioselective fashion. A variety of styrenes and electron-rich alkenes can be aminohydroxylated using this protocol. Preliminary investigations indicate that this new process is a rare non-oxenoid reaction of N-sulfonyl oxaziridines, involving a stepwise, polar mechanism rather than a concerted process. Copyright

Full text of DOI:10.1021/ja067894t

Published on Web 01/30/2007
Copper(II)-Catalyzed Aminohydroxylation of Olefins
David J. Michaelis, Christopher J. Shaffer, and Tehshik P. Yoon*
Department of Chemistry, UniVersity of WisconsinsMadison, 1101 UniVersity AVenue, Madison, Wisconsin 53706
Received November 4, 2006; E-mail: tyoon@chem.wisc.edu
The osmium-catalyzed aminohydroxylation of olefins was first
discovered in 1976 by Sharpless and co-workers and remains the
This new aminohydroxylation constitutes a rare example of a
non-oxenoid reaction of oxaziridine 1. To the best of our knowledge,
the only previous report of a reaction in which both heteroatoms
of an N-sulfonyl oxaziridine are transferred to an organic substrate
was an unexpected aminohydroxylation of indoles observed by
Dmitrienko during studies toward a synthesis of the alkaloid
1
method of choice for construction of â-amino alcohols. This
structural motif is common to a variety of bioactive natural products
and chiral reagents for stereoselective synthesis. However, given
the poor regioselectivity observed in the osmium-catalyzed ami-
2
10
nohydroxylation of styrenes as well as the expense and toxicity
FR900482. This reaction only occurred using electron-rich 2,3-
of osmium compounds, there has been significant interest in the
discovery of complementary protocols. Several groups have recently
dialkyl indoles, and other electron-rich olefins such as enamines
failed to undergo aminohydroxylation.
reported palladium(II)-catalyzed olefin aminohydroxylation utilizing
In contrast, the scope of this new copper-catalyzed process seems
to be significantly broader. Experiments probing the range of
styrenes that undergo this new reaction are summarized in Table
2. Styrenes bearing electron-withdrawing (entry 2) and electron-
donating (entry 3) para substituents can be aminohydroxylated
3
PhI(OAc)
2
as the terminal oxidant. In this communication, we
report that copper(II) salts catalyze the regioselective aminohy-
4
droxylation of olefins using N-sulfonyl oxaziridines. This process
represents a novel reaction of oxaziridines and a promising new
alternative to the known osmium- and palladium-catalyzed ami-
nohydroxylation methods.
Table 2. Aminohydroxylation of Styrenic Olefins
The discovery of this new reactivity arose from our interest in
developing Lewis acid-catalyzed oxidation reactions. Hypothesizing
5
that Lewis acid activation of oxaziridines would increase their
electrophilicity and, consequently, their ability to epoxidize olefins,
we initially explored the effect of metal salts on the reaction between
oxaziridine 1 and styrene (Table 1). As expected from earlier reports
6
of oxaziridine reactivity, only a trace of styrene oxide is formed
in the absence of Lewis acidic additives even after extended reaction
times (entry 1). Upon addition of 10 mol % of Cu(OAc) , however,
2
we observed the regioselective formation of aminal 2 instead of
the expected epoxide (entry 2). This new aminohydroxylation
reaction occurs in the presence of a variety of copper(II) salts
2
(entries 2-5). Using Cu(TFA) , the most effective metal salt
screened, efficient aminohydroxylation was observed at catalyst
loadings as low as 2 mol % (entry 6). Under our optimized
7
conditions, the addition of 10 mol % of HMPA increased the
solubility of the copper catalyst and improved the reproducibility
8,9
of the reaction (entry 7).
Table 1. Development of Optimized Aminohydroxylation
Conditions
%
conversionb
drb
entrya
conditions
time (h)
epoxide
aminal
cis:trans
1
2
3
4
5
6
7
no catalyst
192
24
24
24
24
24
24
6
-
-
-
-
4
-
62
91
>95
>95
92
-
10 mol % of Cu(OAc)2
10 mol % of Cu(OTf)2
10 mol % of CuCl2
1.8:1
>9:1
1:1.6
2.5:1
3.3:1
1.8:1
10 mol % of Cu(TFA)2
2 mol % of Cu(TFA)2
2 mol % of Cu(TFA)2 +
a
Unless otherwise noted, reactions were performed using 1.5 equiv of
-
>95
oxaziridine, 2 mol % of Cu(TFA)2, and 10 mol % of HMPA in CH2Cl2
10 mol % of HMPA
0.5 M) at ambient temperature. b Isolated yields and diastereomeric ratios
(
c
represent the averaged results of two reproducible experiments. Ratios were
determined by H NMR analysis of the unpurified reaction mixture.
a
1
Reactions were performed with 1 equiv of styrene and 2 equiv of
b
d
oxaziridine in CH2Cl2 (0.5 M) at ambient temperature. Conversions and
diastereomeric ratios were determined by H NMR analysis of the unpurified
Reaction was conducted with 10 mol % of Cu(TFA)2 in CH2Cl2 (0.125
1
M) at 35 °C. e Refers to the 4,5-trans-isomers. Only traces of the 4,5-cis-
reaction mixture.
isomers could be observed.
1866
9
J. AM. CHEM. SOC. 2007, 129, 1866-1867
10.1021/ja067894t CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Table 3. Aminohydroxylations Using Non-styrenic Olefins
Scheme 1
Scheme 2
a
Reactions were performed using 2 mol % of Cu(TFA)2 and 10 mol %
of HMPA at ambient temperature. b Reactions were performed using 10
easily, although the former require extended reaction times to
achieve good yields. Substitution at the ortho and meta positions
of the arene is also tolerated (entries 4 and 5), as are R and â
substituents on the alkene (entries 6 and 7). Cyclic (entry 8) and
condensed polycyclic styrenes (entry 9) are also excellent substrates
c
mol % of Cu(TFA)2 and 20 mol % of HMPA at 35 °C. Diastereomeric
ratios were determined by 1H NMR analysis of the unpurified reaction
mixture.
In summary, we have discovered a novel copper(II)-catalyzed
reaction of oxaziridines that effects regioselective aminohydrox-
ylation of styrenes and electron-rich olefins. Studies to better
elucidate the mechanism of this reaction, further explore the
substrate scope, and develop enantioselective aminohydroxylations
based on this new methodology are currently underway in our
laboratory.
for aminohydroxylation, as are tri- and tetrasubstituted styrenic
olefins (entries 10 and 11).11
In order to rationalize this unusual reactivity, we initially
considered a mechanism involving Lewis acid-catalyzed ring
opening of a transient epoxide intermediate, as the copper(II)-
catalyzed synthesis of 1,3-dioxolanes from aryl epoxides and
aldehydes is well precedented.12 However, treatment of styrene
oxide with N-benzylidene benzenesulfonamide in the presence of
Cu(TFA) does not produce aminohydroxylated product 2, which
2
precludes the intermediacy of an epoxide.
We also considered the possibility that the copper(II) salt was
serving as a one-electron reductant of the oxaziridine, in analogy
Acknowledgment. We gratefully acknowledge the University
of WisconsinsMadison, the NSF (CHE-0645447), the NIH Chem-
istry-Biology Interface Training Program (GM08505, fellowship
to D.J.M.), and the donors of the Petroleum Research Fund,
administered by the ACS (PRF# 44783-G1), for financial support.
Supporting Information Available: Experimental procedures and
spectral data for all new compounds are provided. This material is
available free of charge via the Internet at http://pubs.acs.org.
to the copper(I)-catalyzed radical rearrangements of N-alkyl ox-
aziridines developed by Aub e´ .13 We disfavor this mechanism for
two major reasons: (1) one-electron reduction of 1 should result
in a nitrogen-centered radical, which would be expected to produce
the aminal regioisomeric to 2; and (2) this mechanism would require
a copper(III) intermediate that is unlikely to form in the absence
of strongly donating coordination environment, yet aminohydrox-
References
(1) Sharpless, K. B.; Chong, A. O.; Oshima, J. J. Org. Chem. 1976, 41, 177-
179.
(
2) (a) Brunko, M.; Schlingloff, G.; Sharpless, K. B. Angew. Chem., Int. Ed.
Engl. 1997, 35, 2024-2055. (b) Reddy, K. L.; Sharpless, K. B. J. Am.
Chem. Soc. 1998, 120, 1207-1217.
ylation proceeds efficiently even using electron-poor Cu(OTf)
without added ligands (Table 1, entry 2).
2
(
3) (a) Alexanian, E. J.; Lee, C.; Sorensen, E. J. J. Am. Chem. Soc. 2005,
127, 7690-7691. (b) Liu, G. S.; Stahl, S. S. J. Am. Chem. Soc. 2006,
Our current working hypothesis is depicted in Scheme 1. The
available data are consistent with Lewis acid activation of the
oxaziridine and nucleophilic attack by the styrenic olefin. Ring
closure of the sulfonamide onto the resulting benzylic cation results
in the observed aminoalcohol-derived benzylidene aminal. This
ionic mechanism is consistent with the observation that styrenes
bearing electron-rich substituents react considerably more rapidly
than those bearing electron-withdrawing substituents (Table 2,
entries 2 and 3).
The reaction of stilbenes in this transformation provides ad-
ditional evidence for a cationic mechanism (Scheme 2). Amino-
hydroxylation of either cis- or trans-stilbene gives aminals 3 and 4
as a 2:1 mixture of diastereomers. This stereoconvergent behavior
is consistent with the carbocationic intermediate in Scheme 1. Also
consistent with a polar mechanism is the diminished reactivity of
aliphatic alkenes such as 1-octene (Table 3, entry 1). Conversely,
non-styrenic substrates that would produce stabilized carbocationic
intermediates react smoothly under our standard conditions. Thus,
enol ethers (entry 2), dienes (entry 3), and allyl silanes (entry 4)
can be aminohydroxylated using our new methodology.
1
28, 7179-7181. (c) Schultz, M. J.; Sigman, M. S. J. Am. Chem. Soc.
2
006, 128, 1460-1461.
(4) (a) Davis, F. A.; Jenkins, R.; Yocklovich, S. G. Tetrahedron Lett. 1978,
1
9, 5171-5174. (b) Davis, F. A.; Sheppard, A. C. Tetrahedron 1989, 45,
5
703-5742. (c) Davis, F. A. J. Org. Chem. 2006, 71, 8993-9003.
(5) The activation of an N-alkyl oxaziridine toward sulfoxidation using a
stoichiometric zinc(II) additive has been reported: Schoumacker, S.;
Hamelin, O.; Teti, S.; Pecaut, J.; Fontecave, M. J. Org. Chem. 2005, 70,
301-308.
(
6) Davis, F. A.; Abdul-Malik, N. F.; Awad, S. B.; Harakal, M. E. Tetrahedron
Lett. 1981, 22, 917-920.
(
2
7) The use of Cu(OTf) as a catalyst leads to higher diastereoselectivities,
presumably by Lewis acid-catalyzed epimerization of the aminal stereo-
center, albeit with diminished yields.
(
8) Among additives screened, HMPA provided the fastest rates of reaction,
but less toxic ligands can be used instead. For example, aminohydrox-
ylation of styrene proceeds in 81% and 89% yield using 5 mol % of DMPU
and pyridine, respectively (see Supporting Information).
(9) The benzylidene aminal of 2 is readily hydrolyzed using TFA in dioxane/
O (4 h, 80 °C, 95% yield; see Supporting Information).
H
2
(
10) Mithani, S.; Drew, D. M.; Rydberg, E. H.; Taylor, N. J.; Mooibroek, S.;
Dmitrienko, G. I. J. Am. Chem. Soc. 1997, 119, 1159-1160.
(
11) We have not observed regioisomeric aminal products in the aminohy-
droxylations of any styrenic olefins investigated to date.
(12) Krasik, P.; Bohemier-Bernard, M.; Yu, Q. Synlett 2005, 854-856.
(
13) Aub e´ , J. Chem. Soc. ReV. 1997, 26, 269-277.
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