Copper catalyzed enantioselective intramolecular aminooxygenation of alkenes

Full text of DOI:10.1021/ja806585m

Published on Web 12/02/2008
Copper Catalyzed Enantioselective Intramolecular Aminooxygenation of
Alkenes
Peter H. Fuller, Jin-Woo Kim, and Sherry R. Chemler*
Department of Chemistry, UniVersity at Buffalo, The State UniVersity of New York, Buffalo, New York 14260
Received August 24, 2008; E-mail: schemler@buffalo.edu
Table 1. Oxidant and N-Substituent Screena
The catalytic asymmetric aminooxygenation of olefins is a very
important process due to the significance of the products as building
blocks in the synthesis of drugs and natural products.1 The
enantioselective intermolecular osmium-catalyzed aminohydroxy-
lation developed by Sharpless and co-workers has proven to be an
extremely useful method, as exemplified by its use in numerous
entry
R
oxidant
yieldb (%)
%eec
syntheses of biologically active compounds.2 Surprisingly, an
enantioselective intramolecular olefin aminooxygenation, which
would result in the direct synthesis of chiral nitrogen heterocycles,
has not previously been reported. While regio- and diastereoselec-
tive intramolecular osmium-3 and palladium-catalyzed4 olefin
aminooxygenation reactions have been reported, no successful
ligand-based asymmetric variants have been disclosed.5 Herein we
report a novel and mechanistically distinct copper-catalyzed enan-
tioselective intramolecular aminooxygenation of olefins.5f This
method allows for the synthesis of chiral indolines and pyrrolidines,
common components in biologically active molecules.
1
2
3
4
5
6
1a, R ) Ts
1a
MnO2 (3 equiv)
O2 (1 atm)
71
96
97
NR
NR
NR
72
81
83
-
-
-
1a
-
-
-
-
1b, R ) SO2Me
1c, R ) Bz
1d, R ) Cbz
a Conditions: Cu(OTf)2 (0.2 equiv) and ligand (0.2 equiv) were
combined, dissolved in PhCF3 (0.07 M w/r to 1) and heated at 50 °C for
2 h. Substrate 1 (1 equiv), oxidant, TEMPO (3 equiv), and K2CO3 (1
equiv) were added. The reaction was heated at 110 °C for 24 h. b Yield
refers to amount of isolated 2 after purification by flash chromatography
on SiO2. c Enantiomeric excesses were determined by chiral HPLC
analysis [Chiralcel (S,S) Whelk]. NR ) No reaction.
We recently reported an enantioselective copper-catalyzed in-
tramolecular carboamination of olefins which results in the synthesis
of chiral sultams.6 Mechanistic analysis of the racemic, copper-
promoted version of this reaction indicated the presence of a primary
carbon radical species that was trapped with tetramethylaminopy-
ridyl radical (TEMPO) in excellent yield (cf. 1 f 2).7 This process,
signifying a net aminooxygenation reaction, inspired us to ascertain
whether a catalytic enantioselective variant could be achieved.
Our study commenced by adding TEMPO (3 equiv) to the
optimal catalytic enantioselective carboamination reaction condi-
tions, which use MnO2 as a stoichiometric oxidant (Table 1, entry
1). Upon further examination we found that TEMPO alone could
be used for copper turnover [Cu(I) to Cu(II)]. As shown in Table
1, the yield and enantioselectivity both increased upon removal of
additional oxidants (entry 3). A variety of other nitrogen protecting
groups were also surveyed (Table 1, entries 4-6). The tosyl group
proved superior to the unreactive methyl sulfonamide, benzamide,
and carbamate.
Our next objective was to identify an optimal ligand for
asymmetric induction (Table 2). An early screen of commercially
available bisoxazoline ligands revealed that the 5-phenyl substitution
pattern is essential. Other aryl substituents such as 2-naphthalene,8
as well as cis and trans 4,5-disubstituted phenyl bisoxazoline
derivatives9 were also examined. When used in slight excess, both
antipodes of the 4,5-cis-diphenyl bisoxazoline ligand were optimal
(entries 5 and 6).
Table 2. Chiral Ligand Screena
entry
ligand(equiv)
yieldb (%)
%ee (config)c
1
2
3
4
5
6
R ) (S,S)-Phbox (0.2)
97%
47%
97%
97%
97%
97%
83% (R)
43% (R)
77% (S)
88% (S)
88% (R)
90% (S)
R ) (S,S)-2-Napthbox (0.2)
R ) (4R,5R)-Bis-Phbox (0.2)
R ) (4R,5S)-Bis-Phbox (0.2)
R ) (4S,5R)-Bis-Phbox (0.25)
R ) (4R,5S)-Bis-Phbox (0.25)
a Conditions: Cu(OTf)2 (0.2 equiv) and ligand were combined,
dissolved in PhCF3 (0.07 M w/r to 1a) and heated at 50 °C for 2 h.
Substrate 1a (1 equiv), TEMPO (3 equiv) and K2CO3 (1 equiv) were
added. The reaction was heated at 110 °C for 24 h. b Same as footnote b
for Table 1. c Same as footnote c for Table 1
entries 1, 8, and 9). Note ortho substituted aniline derivatives (R
) OMe, Cl) were unreactive.
The generality of the reaction was examined as shown in Table
3. N-Sulfonyl-2-allyl aniline substrates 1 cyclized in 57-97% yield
providing indolines 2 in 50-91% ee. A variety of functional groups
on the aniline were tolerated with the exception being a slight
decrease in ee for the electron-withdrawing nitrile 1i.
The nature of the sulfonamide significantly effects the enantio-
selectivity where the tosyl was superior to the mesyl substrate 1b
(Table 1, entry 4) and the nosyl substrate 1k (Table 3, compare
The 4-pentenylamine substrates 3 cyclized in 74-97% yield
providing pyrrolidines 4 in 75-92% ee (entries 10-16).10 O2 (1
atm) as a co-oxidant was necessary to drive these reactions to
completion. The unsubstituted aliphatic substrate 3e, nosylate 3f,
and the 1,1-disubstituted olefin substrate 5 all required higher
catalyst loading to obtain an appreciable yield and ee (Table 3,
9
17638 J. AM. CHEM. SOC. 2008, 130, 17638–17639
10.1021/ja806585m CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
Table 3. Scope of Enantioselective Aminooxygenation with
(4R,5S)-Bis-Phbox Liganda
Scheme 1. Transition State Model and TEMPO Functionalization
This aminooxygenation method provides efficient access to a
variety of chiral pyrrolidines and indolines of interest to synthetic
organic and medicinal chemists. Its further optimization and
application toward the syntheses of such compounds are underway.
Acknowledgment. Financial Support from the National Insti-
tutes of Health/NIGMS RO1 GM078383 is gratefully acknowledged.
Note Added after ASAP Publication. After this paper was
published ASAP December 2, 2008, some of the ligand stereochemical
assignments were corrected in Tables 2 and 3 and several schemes in
the Supporting Information, and a reagent was changed in Scheme 1.
The corrected versions were published ASAP December 4, 2008.
Supporting Information Available: Experimental procedures and
compound characterization. This material is available free of charge
via the Internet at http://pubs.acs.org.
References
(1) Bergmeier, S. C. Tetrahedron 2000, 56, 2561.
(2) Reviews of enantioselective aminohydroxylation processes: (a) O’Brien,
P. Angew. Chem., Int. Ed. 1999, 38, 326. (b) Bolm, C.; Hildebrand, J. P.;
Muniz, K. Catalytic Asymmetric Synthesis, 2nd ed.; Ojima, I., Ed.; Wiley-
VCH: 2000; pp 412-424. (c) Schlingloff, G.; Sharpless, B. K. Asymmetric
Oxidation Reactions; Katsuki, T., Ed.; Oxford University Press: 2001; pp
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(e) Bodkin, J. K.; McLeod, M. D. J. Chem. Soc., Perkin Trans. 1 2002,
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L. V.; Sanford, M. S. Angew. Chem., Int. Ed. 2007, 46, 5737.
(5) For other intramolecular aminooxygenation reactions, see: (a) Noack, M.;
Gottlich, R. Chem. Commun. 2002, 536. (b) Chikkanna, D.; Han, H. Synlett
2004, 2311. (c) Correa, A.; Tellitu, I.; Dominguez, E.; SanMartin, R. J.
Org. Chem. 2006, 71, 8316. (d) Cochran, B. M.; Michael, F. E. Org. Lett.
2008, 10, 5093. (e) Mahoney, J. M.; Smith, C. R.; Johnston, J. N. J. Am.
Chem. Soc. 2005, 127, 1354. (f) For recent Cu- and Pd-catalyzed
intermolecular aminooxygenation reactions, see Supporting Information.
(6) Zeng, W.; Chemler, S. R. J. Am. Chem. Soc. 2007, 129, 12948.
(7) Sherman, E. S.; Fuller, P. H.; Kasi, D.; Chemler, S. R. J. Org. Chem. 2007,
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(8) vanLingen, H. L.; vanDelft, L. F.; Storcken, R. P. M.; Hekking, K. F. W.;
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Eur. J. Org. Chem. 2005, n/a, 2975.
(9) Desimoni, G.; Faita, G.; Mella, M. Tetrahedron 1996, n/a, 13649.
(10) N-Tosyl-2-allyl-benzylamine did not provide the corresponding six-
membered ring aminooxygenation product.
(11) Kan, T.; Fukuyama, T. Chem. Commun. 2004, n/a, 353.
(12) A discussion of the C-O bond forming mechanism is provided in the
Supporting Information.
(13) Sheldrake, H. M.; Wallace, T. M. Tetrahedron Lett. 2007, 48, 4407.
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(15) Compound 9, an intermediate en route to a chiral ligand, was previously
synthesized in a more lengthy sequence from L-glutamic acid: Nagaoka,
Y.; Tomioka, K.; Nakagawa, Y.; Kanai, M. Tetrahedron 1998, 54, 10295.
a Conditions: Cu(OTf)2 (0.2 equiv) and ligand (0.25 equiv) were
combined, dissolved in PhCF3 (0.07 M w/r to substrate) and heated at
50 °C for 2 h. Substrate (1 equiv), TEMPO (3 equiv), and K2CO3 (1
equiv) were added. The reaction was heated at 110 °C for 24 h.
b Reaction was run at 120 °C under O2 (1 atm). c 0.4 equiv of Cu(OTf)2
and 0.5 equiv of ligand were used. d Yield refers to amount of isolated
product after purification by flash chromatography on SiO2.
e Enantiomeric excess were determined by chiral HPLC analysis. Each
reaction was run at least 2 times. f A range of 86-90% ee was obtained.
entries 14-16). In the latter case, chiral tertiary amine 6 is formed
in good enantioselectivity. The reaction of the nosylate 3f (86%
yield, 89% ee) is notable since this sulfonyl group is easier to
remove than the corresponding tosylate.11
The absolute configuration was assigned by conversion of 2a
and 4e to their corresponding known chiral N-tosyl amino alcohols
(see Supporting Information). The absolute configuration of the rest
of the aminooxygenation products were assigned by analogy. The
observed stereochemistry is consistent with a proposed transition
state model where the substrate’s N-substituent is trans to the
nearest oxazoline’s phenyl groups (Scheme 1).6,12 The TEMPO
adduct 4a was converted to the aminoalcohol13 7 and oxidized to
aldehyde14 8 without diminished enantioselectivity (Scheme 1).
Furthermore, removal of the tosyl group followed by TEMPO
reduction provided the known chiral amino alcohol 9, thereby
assigning the absolute configuration of 4a.15
JA806585M
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J. AM. CHEM. SOC. VOL. 130, NO. 52, 2008 17639