Copper-catalyzed olefin aminoacetoxylation

Article abstract of DOI:10.1021/ol101702w

A new catalyst system for intramolecular olefin aminoacetoxylation is described. In contrast to previously reported palladium- and copper-catalyzed systems, the conditions outlined in this communication favor piperdine formation with terminal olefin subst

Full text of DOI:10.1021/ol101702w

ORGANIC
LETTERS
2010
Vol. 12, No. 18
4110-4113
Copper-Catalyzed Olefin
Aminoacetoxylation
Danny E. Mancheno, Aaron R. Thornton, Armin H. Stoll, Aidi Kong, and
Simon B. Blakey*
Department of Chemistry, Emory UniVersity, Atlanta, Georgia 30322
sblakey@emory.edu
Received July 21, 2010
ABSTRACT
A new catalyst system for intramolecular olefin aminoacetoxylation is described. In contrast to previously reported palladium- and copper-
catalyzed systems, the conditions outlined in this communication favor piperdine formation with terminal olefin substrates and induce cyclization
with traditionally less reactive disubstituted olefins.
Vicinal amino alcohols are present in a wide variety of
medicinally important compounds, perhaps most famously
exemplified by the Taxol side chain. Although there are many
conceivable approaches to this important chemical motif,
including the Mannich reaction and epoxide or aziridine
opening reactions, one of the most attractive strategies for
1,2-amino alcohol synthesis remains the direct aminohy-
droxylation of an olefin. Following its discovery in 1996,
Sharpless’ osmium-catalyzed asymmetric aminohydroxyla-
tion rapidly rose in prominence to become the premier
reaction for 1,2-amino alcohol synthesis.1 Despite more than
a decade of development, issues with regioselectivity as well
as catalyst toxicity, combined with the prominence of the
1,2-amino alcohol motif, have ensured that olefin aminohy-
droxylation remains a high-profile problem for the synthetic
community. Recent advances in this area include the Lewis
acid promoted addition of oxaziridines to olefins developed
by Yoon and co-workers2 and the hypervalent iodine-induced
palladium-catalyzed amino-oxygenation reactions reported
by Sorensen,3 Stahl,4 and Sanford.5 Additionally, the Chem-
ler group recently reported a copper-catalyzed enantioselec-
tive amino-oxygenation reaction.6 While these recent meth-
odologies represent important advances in the field, the
palladium- and copper-catalyzed reactions outlined above are
generally limited to monosubstituted terminal olefins7
and, in intramolecular cases, show a preference for 5-exo-
cyclization, leading to pyrrolidine formation.
Recently, both Michael and Wardrop reported metal-free
intramolecular oxy-amination reactions that provide access
to the complementary 6-endo cyclization products.8 In both
cases, acidic media are required to accelerate the reaction
and provide useful levels of conversion (typically TFA is
utilized as both an additive and an oxygen source in the
amino-oxygenation reaction).
(3) Alexanian, E. J.; Lee, C.; Sorensen, E. J. J. Am. Chem. Soc. 2005,
127, 7690.
(4) Liu, G.; Stahl, S. S. J. Am. Chem. Soc. 2006, 128, 7179.
(5) Desai, L. V.; Sanford, M. S. Angew. Chem., Int. Ed. 2007, 46, 5737.
(6) (a) Fuller, P. H.; Kim, J.-W.; Chemler, S. R. J. Am. Chem. Soc.
2008, 130, 17638. (b) Paderes, M. C.; Chemler, S. R. Org. Lett. 2009, 11,
1915.
(7) Although one example of a cis-1,2-disubstituted olefin is provided
by Liu and Stahl (ref 4), they state that “in general, internal olefins appear
to be ineffective substrates”.
(1) (a) Li, G.; Chang, H.-T.; Sharpless, K. B. Angew. Chem., Int. Ed.
Engl. 1996, 35, 451. (b) Nilov, D.; Reiser, O. AdV. Synth. Catal. 2002,
344, 1169. (c) Muniz, K. Chem. Soc. ReV. 2004, 33, 166.
(8) (a) Lovick, H. M.; Michael, F. M. J. Am. Chem. Soc. 2010, 132,
1249. (b) Wardrop, D. J.; Bowen, E. G.; Forslund, R. E.; Sussman, A. D.;
Weerasekera, S. L. J. Am. Chem. Soc. 2010, 132, 1188. (c) For a copper-
promoted 6-endo cylization, see: Sherman, E. S.; Chemler, S. R. AdV. Synth.
Catal. 2009, 351, 467. (d) For metal-free 5-exo-selective olefin oxy-
amination, see: Correa, A.; Tellitu, I.; Dom´ınguez, E.; SanMartin, R. J.
Org. Chem. 2006, 71, 8316.
(2) (a) Michaelis, D. J.; Shaffer, C. J.; Yoon, T. P. J. Am. Chem. Soc.
2007, 129, 1866. (b) Michaelis, D. J.; Ischay, M. A.; Yoon, T. P. J. Am.
Chem. Soc. 2008, 130, 6610. (c) Michaelis, D. J.; Williamson, K. S.; Yoon,
T. P. Tetrahedron 2009, 65, 5118. (d) Benkovics, T.; Du, J.; Guzei, I. A.;
Yoon, T. P. J. Org. Chem. 2009, 74, 5545.
10.1021/ol101702w  2010 American Chemical Society
Published on Web 08/24/2010

As part of our research program investigating alternative
catalysts for metallonitrene/alkyne cascade processes,9 we
discovered that the cationic copper(I) complex Cu(CH3CN)4PF6
could catalyze the regio- and diastereoselective olefin ami-
nooxygenation of sulfamate ester 1, providing 3-pivaloylpip-
eridine 2 (Scheme 1).
During this study, we quickly established that the
Cu(CH3CN)4PF6-catalyzed olefin amino-oxygenation reaction
was indeed selective for piperidine formation. Activation of
the nitrogen atom with a nosyl substituent was important
for reaction efficiency, with tosyl, acyl, and carbamoyl
alternatives all observed to be less effective (entries 1-4).
The nature of the carboxylate in the hypervalent iodine
oxidant did not significantly effect the reaction outcome, with
acetate, pivaloate, and dimethylphenyl acetate all effectively
incorporated into the product (entries 1, 5, and 6). The nature
of the solvent had a profound effect both on reaction yield
and regioselectivity, with dichloromethane and trifluorotolu-
ene observed to be the most effective media for efficient
3-acetoxypiperidine fomation (entries 1, 7-11).
Scheme 1
.
Copper-Catalyzed Olefin Aminooxygenation Favors
Piperidine Ring Formation
Carbonate bases (entries 1 and 13) were found to be more
effective than soluble tetrabutylammonium acetate (entry 12)
or stronger alkoxide alternatives (entry 14).
Under the optimized conditions (Table 1, entry 1) a variety of
monosubstituted γ-aminoolefins could be cyclized, and a preference
for 3-acetoxypiperidine formation was observed (Table 2). How-
Relative stereochemistry assigned by X-ray crystallography; see the
Supporting Information for details.
The exclusive formation of the piperidine ring system
stood in stark contrast to the previously reported metal-
catalyzed olefin aminooxygenation reactions, and the mod-
erately basic reaction conditions offered a useful complement
to the metal-free olefin oxamidation protocols.
Table 2. Intramolecular Aminoacetoxylation of Terminal
Olefinsa
However, it was not apparent whether this unusual
outcome arose from the rigid nature of the starting material
or was a more general feature associated with the reaction
conditions. Thus, a small number of simple 5-aminopentene
derivatives were prepared to assess these reaction conditions
in an unbiased system (Table 1).
Table 1. Optimization of a Simple Copper-Catalyzed Olefin
Amino-Oxygenation Protocol
entry
R
R′
base
solvent % yieldb endo/exo
1
2
3
4
5
6
7
8
Ns Me
Ts Me
Ac Me
Boc Me
Ns t-Bu
Ns C(Me)2Ph K2CO3
Ns Me
Ns Me
Ns Me
Ns Me
Ns Me
Ns Me
Ns Me
Ns Me
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
88
47
0
9:1
8:2
-
0
-
73
70
0
29
72
18
6
34
72
43
9:1
9:1
-
95:5
92:8
70:30
-
9:1
9:1
9:1
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Bu4NOAc CH2Cl2
CsCO3
KOtBu
C6H6
9
CF3C6H5
CH3C6H5
MeCN
10
11
12
13
14
CH2Cl2
CH2Cl2
a Reaction conditions: 10 mol % of Cu(CH3CN)4PF6, 1.5 equiv of
PhI(OAc)2, 1.0 equiv K2CO3, rt, CH2Cl2. b Isolated yield. In cases where
two regioisomers were obtained, the combined yield is reported with product
ratio in parentheses (determined by 1H NMR analysis of the crude reaction
mixture). c Reaction conducted in trifluorotoluene at 70 °C.
a CuI, CuOTf, and Cu(OTf)2 were also investigated but were found to
be significantly less effective catalysts. b Yield and ratio determined by 1H
NMR assay using 1,3,5-trimethoxybenzene as an internal standard.
Org. Lett., Vol. 12, No. 18, 2010
4111

ever, significant steric congestion adjacent to the olefin
reduced the reaction rate (it was necessary to conduct this
reaction at 70 °C for efficient cyclization) and led to a
reversal in the regioselectivity (entry 3).
We also observed a loss of regioselectivity in the cycliza-
tion of the aromatic substrate N-nosyl-2-allylaniline (entry
4). For the bicyclic sulfamate ester substrates outlined in
entries 5 and 6, cylization proceeded both regio- and
diastereoselectivly to provide the piperidine products in good
yields as single diastereomers.
provide the pyrrolidine products, with only cis-N-nosyl-1-
amino-4-hexene providing significant quantites of the pip-
eridine product (entry 2). For 1,2-dialkylolefins, we observe
an anti addition of the nitrogen and acetate across the double
bond, regardless of the regiochemical outcome of the reaction
(entries 1, 2, and 6). This outcome is in contrast to the
previously reported metal free system, in which 5-exo
cyclizations gave syn addition products and 6-endo cycliza-
tions exhibited anti selectivity.8a For the phenyl-substituted
olefins (entries 3 and 4), both olefin isomers converge on a
single product diastereomer, corresponding to antiaminoac-
etoxylation across the trans-olefin. In the case of the
isopropyl-substituted olefin (entry 5), an unusual 1,3-ami-
noacetoxylated product was obtained.
Additionally we have investigated the aminoacetoxyla-
tion of 1,2-disubstituted olefins (Table 3). Importantly, the
These reaction outcomes are consistent with a mechanism
in which the copper catalyst and the N-nosylamine combine
under the oxidative conditions to form an electrophilic
copper(III) amido species (Scheme 2).10,11
Table 3. Intramolecular Aminoacetoxylation of 1,2-Disubstituted
Olefinsa
Scheme 2. Proposed Catalytic Cycle Accounting for Observed
Regio- and Diastereoselectivity: (i) Initial Oxidation to Cu(III)
Amide; (ii) Nucleophile Attacks Carbon Most Able To Stabilize
a Positive Charge Resulting in Anti Addition of the Nucleophile
and Copper Across the Olefin; (iii) Reductive Elimination
Coordination of the tethered olefin to the Cu(III) center
activates the double bond for anti attack by an external
acetate, with the nucelophile attacking at the position most
able to stabilize a positive charge. Thus, in the case of
monosubstituted olefins, acetate attack occurs at the internal
position, leading to the observed endo cyclization.12 If the
(10) For exaples of well-defined oganometallic Cu(III) complexes, see:
(a) Willert-Porada, M. A.; Burton, D. J.; Baenziger, N. C. J. Chem. Soc.,
Chem. Commun. 1989, 1633. (b) Naumann, D.; Roy, T.; Tebbe, K.-F.;
Crump, W. Angew. Chem., Int. Ed. Engl. 1993, 32, 1482. (c) Furuta, H.;
Maeda, H.; Osuka, A. J. Am. Chem. Soc. 2000, 122, 803. (d) Ribas, X.;
Jackson, D. A.; Donnadieu, B.; Mah´ıa, J.; Parella, T.; Xifra, R.; Hedman,
B.; Hodgson, K. O.; Llobet, A.; Stack, T. D. P. Angew. Chem., Int. Ed.
2002, 41, 2991. (e) Santo, R.; Miyamoto, R.; Tanaka, R.; Nishioka, T.;
Sato, K.; Toyota, K.; Obata, M.; Yano, S.; Kinoshita, I.; Ichimura, A.; Takui,
a Reaction conditions: 10 mol % of Cu(CH3CN)4PF6, 1.5 equiv of
PhI(OAc)2, 1.0 equiv of K2CO3, rt, CH2Cl2. b Isolated yield. In cases where
two regioisomers were obtained, the combined yield is reported with the
product ratio in parentheses. c The stereochemistry was determined by X-ray
crystallography; see the Supporting Information for details. d The stereo-
chemistry was determined by NOE experiments; see the Supporting
Information for details.
T. Angew. Chem., Int. Ed. 2006, 45, 7611
.
(11) For C-N bond formation from Cu(III) coumpounds, see: (a)
Huffman, L. M.; Stahl, S. S. J. Am. Chem. Soc. 2008, 130, 9196. (b) Casitas,
A.; King, A. E.; Parella, T.; Costas, M.; Stahl, S. S.; Ribas, X. Chem. Sci.
standard reaction conditions provide cyclic aminoacetoxyl-
ation products in good to excellent yields. In most cases,
we observe a significant preference for 5-exo cyclization to
2010, DOI: 10.1039/c0sc00245c
.
(12) For related anti nucleometalations, see: (a) Åkermark, B.; Ba¨ckvall,
J. E.; Siirala-Hanse´n, K.; Sjo¨berg, K.; Zetterberg, K. Tetrahedron Lett. 1974,
15, 1363. (b) Åkermark, B.; Ba¨ckvall, J. E.; Hegedus, L. S.; Zetterberg,
K.; Siirala-Hanse´n, K.; Sjo¨berg, K. J. Organomet. Chem. 1974, 72, 127.
(c) Hegedus, L. S.; Allen, G. F.; Waterman, E. L. J. Am. Chem. Soc. 1976,
98, 2674. (d) Ba¨ckvall, J. E. Acc. Chem. Res. 1983, 16, 335.
(9) (a) Thornton, A. R.; Blakey, S. B. J. Am. Chem. Soc. 2008, 130,
5020. (b) Thornton, A. R.; Martin, V. I.; Blakey, S. B. J. Am. Chem. Soc.
2009, 131, 2434.
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Org. Lett., Vol. 12, No. 18, 2010

internal position is significantly hindered (e.g., Table 2, entry
3), then these steric factors may overide the electronic bias
leading the nucleophile to preferentially attack the primary
carbon. The preference for acetate attack on the carbon most
able to stablilize positive charge is also observed in the
reaction of the styrenal substrates (Table 3, entries 3 and 4).
The convergence of both olefin isomers to a single product
diastereomer suggests that in these cases the olefins them-
selves may isomerize under the reaction conditions. In the
case of 1,2-dialkyl-substituted olefins, there is no significant
electronic bias, so the regiochemical outcome of the reaction
is most likely dictated by subtle geometric factors, leading
in some cases to selective reactions (e.g., Table 3, entry 1)
and in other cases to mixtures of regioisomeric products
(Table 3, entry 2). Such a mechanism would also explain
the formation of the 1,3-aminoacetoxylated product observed
in the reaction of the isopropyl-substituted olefin (Table 3,
entry 5).
Based on our proposed mechanism, we predicted that
alternative nucleophiles included in the reaction mixture
could be used to trap the activated olefin complex. Accord-
ingly, the use of Koser’s salt in place of the bisacetoxyiodo-
benzene oxidant led to the incorporation of the tosylate into
the product 6 (Scheme 4).13
Scheme 4. Alternative Oxidant for Olefin Aminotosylation
In conclusion, we have developed a new aminoacetoxyl-
ation protocol that provides complementary regioselectivity
to previously reported palladium- and copper-catalyzed
reactions. The new reaction proceeds under complementary
pH conditions to recently reported metal free reactions,
allowing for the selective formation of 3-acetoxy piperidine
products from γ-aminoolefins. Experiments based on our
mechanistic hypothesis demonstrated that alternative nucleo-
philes can also be incorporated into the product under similar
reaction conditions.
In this case, a 1,2-hydride shift in the activated olefin
complex 3 would provide stable tertiary cation 4 prior to
external acetate attack, accounting for the observed
product 5 (Scheme 3). In all cases, a reductive elimination
step would complete the reaction and regenerate the Cu(I)
catalyst.
Acknowledgment. We are grateful for financial support
from the NSF (NSF CHE 0847258). We thank Kenneth
Hardcastle, Rui Cao, and Sheri Lense for assistance with
X-ray crystallography (Emory University, Department of
Chemistry, X-ray crystallography center).
Scheme 3
.
A 1,2-Hydride Shift Leads to the Formation of
1,3-Aminoacetoxylation Product 5
Supporting Information Available: Experimental pro-
cedures, structural proofs, and analytical data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL101702W
(13) A related metal-free olefin amino-oxytosylation was reported in a
review article, but no experimental details were provided. See: Moriarty,
R. M.; Vaid, R. K.; Koser, G. F. Synlett 1990, 365.
Org. Lett., Vol. 12, No. 18, 2010
4113