Tethered aminohydroxylation (TA) reaction of amides

Article abstract of DOI:10.1021/ol900631y

The first examples of amide-tethered aminohydroxylation reactions, catalyzed by osmium, showing that the use of N-O-based reoxidants are essential for success, are reported. The system that is described is compatible with a variety of different alkene sub

Full text of DOI:10.1021/ol900631y

ORGANIC
LETTERS
2009
Vol. 11, No. 11
2305-2307
Tethered Aminohydroxylation (TA)
Reaction of Amides
Timothy J. Donohoe,* Cedric K. A. Callens, and Amber L. Thompson†
Department of Chemistry, UniVersity of Oxford, Chemistry Research Laboratory,
Mansfield Road, Oxford OX1 3TA, U.K.
timothy.donohoe@chem.ox.ac.uk
Received March 26, 2009
ABSTRACT
The first examples of amide-tethered aminohydroxylation reactions, catalyzed by osmium, showing that the use of N-O-based reoxidants are
essential for success, are reported. The system that is described is compatible with a variety of different alkene substitution patterns and ring
sizes and works with low loadings in both cyclic and acyclic systems. The levels of diastereoselectivity that were observed for substituents
at both the allylic and homallylic position bode well for the use of stereoselective TA reactions in organic synthesis.
The osmium-catalyzed aminohydroxylation reaction has
proven to be a valuable method for the introduction of two
Scheme 1
adjacent heteroatoms by the (stereospecific-syn) oxidation
of an alkene.1 In the intermolecular reaction, Sharpless has
shown that both carbamates and amides are suitable nitrogen
sources for the asymmetric aminohydroxylation (AA) when
they are used as their corresponding N-halo derivative (which
acts as the reoxidant in the catalytic cycle). For carbamate-
based aminohydroxylation, chlorination of the parent
(ROCONH2) carbamate can be carried out in situ by the use
of tBuOCl.2 However, for AA reactions involving amides,
the in situ generation of an N-halo amide (bromo derivatives
are required) is not yet achievable, and these must be
tended the aminohydroxylation reaction of carbamates to
generated in a prior step from the amide (RCONH2) and DBI
proceed in an intramolecular fashion to access synthetically
(dibromoisocyanuric acid) (Scheme 1).3 We recently ex-
useful amino diol units in both cyclic and acyclic systems.4
However, we had no success in performing an intramolecular
TA of an N-bromo amide onto a pendant alkene. The
problems that we encountered stemmed from unwanted
† Author to whom correspondence regarding X-ray crystallography should
be addressed.
(1) (a) Kolb, H. C.; Sharpless, K. B. Transition Met. Org. Synth. 1998,
2, 243. While other useful aminohydroxylation reactions based on metals
such as copper and palladium have emerged, it is fair to say that none can
match the stereospecificity and functional group tolerance offered by
osmium. (b) Alexanian, E. J.; Lee, C.; Sorensen, E. J. J. Am. Chem. Soc.
2005, 127, 7690. (c) Liu, G.; Stahl, S. S. J. Am. Chem. Soc. 2006, 128,
7179. (d) Michaelis, D. J.; Shaffer, C. J.; Yoon, T. P. J. Am. Chem. Soc.
2007, 129, 1866. (e) Fuller, P. H.; Kim, J.; Chemler, S. R. J. Am. Chem.
Soc. 2008, 130, 17638.
(3) (a) Bruncko, M.; Schlingloff, G.; Sharpless, K. B. Angew. Chem.,
Int. Ed. 1997, 36, 1483. (b) Demko, Z. P.; Bartsch, M.; Sharpless, K. B.
Org. Lett. 2000, 2, 2221.
(4) (a) Donohoe, T. J.; Helliwell, M.; Johnson, P. D.; Keenan, M. Chem.
Commun. 2001, 2078. (b) Donohoe, T. J.; Johnson, P. D.; Cowley, A.;
Keenan, M. J. Am. Chem. Soc. 2002, 124, 12934. (c) Donohoe, T. J.;
Johnson, P. D.; Pye, R. J. Org. Biomol. Chem. 2003, 1, 2025. (d) Donohoe,
T. J.; Johnson, P. D.; Pye, R. J.; Keenan, M. Org. Lett. 2004, 6, 2583.
(2) Li, G.; Angert, H. H.; Sharpless, K. B. Angew. Chem., Int. Ed. 1997,
35, 2813.
10.1021/ol900631y CCC: $40.75
Published on Web 05/06/2009
 2009 American Chemical Society

oxidation of the alkene by DBI which was necessary to form
the N-bromo amide prior to the TA reaction. Herein, we
report a solution to this problem using N-O reoxidants
derived from amides.
Scheme 3
Recently, we have reported an improvement of our original
TA reaction that allowed N-OCOAr based substrates to act
as the reoxidant for the reaction, thus removing the need for
chlorine-based reagents in the reaction (see 1 f 2).5 This
protocol was very successful for carbamates and allowed TA
reactions to become higher yielding, cleaner, and compatible
with low catalyst loadings. In this paper, we examine the
viability of perfoming TA reactions of amides that have been
preactivated as RCONHOCOAr derivatives so as to circum-
vent the problems of alkene bromination that were previously
encountered.
In each case, our synthesis of the requisite N-OCOAr
amides began with the corresponding acid which was
converted into the hydroxamic acid in one pot (oxalyl
chloride then NH2OH), followed by reaction with trimethy-
benzoyl chloride. In our hands, this was the best aryl
derivative, and acylation using pentafluorobenzoyl chloride
gave decomposition products that appeared to originate from
the Lossen rearrangement.5b This sequence proved to be
reliable and high yielding across a wide range of substrates
Scheme 2.
Scheme 2
predicted, vide infra.7 The oxidation of substrate 14 was
followed by in situ lactonisation of the newly installed
hydroxyl group to form the lactam/lactone 15 which is the
basis of several natural products.8 Finally, oxidation of 1,1-
disubstituted alkenes revealed the potential of this TA to
provide highly substituted lactams.
We next examined the idea of diasteroselective cyclization
reactions on chiral substrates; therefore, a series of chiral
acids were converted into the oxidation precursors and then
subjected to the TA reaction in a search for stereoselectivity,
Scheme 4. Early studies showed that even a Me group
adjacent to the carbonyl gave decent levels of diastereose-
lectivity for the cis-1,3-disubstituted pyrrolidinones 22 and
trans-piperidinones 23.9 Moving the stereodirecting methyl
group to an allylic position was not as successful and
compounds 25 and 26 were formed with little selectivity.
However, introducing a larger (Ph) group at this position
did impart significant levels of diastereoselectivity upon the
TA reaction (27 f 28), and this process should have
application in natural product synthesis.10
With the requisite O-aryloyl hydroxamic acids in hand,
we examined their reaction with catalytic osmium(VI) in the
form of potassium osmate, in a mixture of tert-butyl alcohol
and aqueous MeCN, Scheme 3 (Ar ) Me3C6H3).
Bearing in mind that the substrate itself is the reoxidant
for Os(VI) to Os(VIII) then no other additives were required
and these are very clean reactions. The results shown in
Scheme 3 reveal that the tethered aminohydroxylation
reaction of amides is an efficient process capable of forming
ꢀ-lactams (n ) 0), pyrrolidinones (n ) 1), and piperidinones
(n ) 2) in good yields and with low catalyst loadings (1%
in some cases, with the remaining mass being recovered
starting material).6 Moreover, the results of oxidation of 7
and 11 show that the reaction is stereospecific for the syn-
addition of the two heteroatoms across the alkene, as
Finally, we examined this TA sequence on cyclic alkenes
in order to assess the full scope of the methodology, Scheme
(5) (a) Donohoe, T. J.; Chughtai, M. J.; Klauber, D. J.; Griffin, D.;
Campbell, A. D. J. Am. Chem. Soc. 2006, 128, 2514. (b) Donohoe, T. J.;
Bataille, C. J. R.; Gattrell, W.; Kloesges, J.; Rossignol, E. Org. Lett. 2007,
9, 1725. see also. (c) Lebel, H.; Huard, K.; Lectard, S. J. Am. Chem. Soc.
2005, 127, 14198. (d) Lebel, H.; Lectard, S.; Parmentier, M. Org. Lett.
2007, 9, 4797.
(7) The stereochemistry of 8-10, 12, 13, 17, 20, 28, 30, 32, and 35
was determined by X-ray analysis and of 15, 25, and 34 by analogy. The
stereochemistry of 22 and 23 was assigned by NMR experiments.
(8) Pilli, R. A.; Ferreira de Oliveira, M. C. Nat. Prod. Rep. 2000, 17,
117.
(9) Knapp, S.; Levorse, A. T. J. Org. Chem. 1988, 53, 4006.
(10) See, for example, the epiclausinamides: Wu, Y.; Liu, L.; Wei, H.;
Liu, G. Acta Pharmacol. Sin 2006, 27, 1024.
(6) The TA reaction to form 7- and 8-membered lactam rings was
unsuccessful.
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Org. Lett., Vol. 11, No. 11, 2009

Scheme 4
Scheme 6
was characterized by X-ray crystallography and lends
considerable weight to the proposed mechanism). The X-ray
structure of 35 is significant because it is the first time that
we have been able to observe an azaglycolate osmate ester
derived from an amide, rather than a carbamate. As expected,
35 was transformed into genuine product 30 in a separate
hydrolysis experiment.
5. The results show that a variety of stereoselective syn
addition reactions are possible giving access to useful cyclic
amino alcohols.
To conclude, we have reported the first examples of amide
tethered aminohydroxylation reactions and shown that the
use of N-O-based reoxidants are essential. The system is
compatible with a variety of different alkene substitution
patterns and ring sizes (4, 5, 6) and works with low loadings
in both cyclic and acyclic systems. The levels of diastereo-
selectivity that we observed bode well for the use of
stereoselective TA reactions in synthesis.12
Scheme 5
Acknowledgment. We thank the EPSRC for funding this
project.
Supporting Information Available: Experimental pro-
cedures and spectroscopic/X-ray data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL900631Y
(11) Griffith, W. P.; Pawson, D. J. Chem. Soc., Dalton Trans. 1973,
12, 1315.
We propose the following mechanism for this reaction,
Scheme 6. Indeed, we were able to trap out an Os(VI)
intermediate11 generated in a model stoichiometric oxidation
of 29 using TMEDA as a stabilizing ligand (compound 35
(12) For example: (a) Donohoe, T. J.; Johnson, P. D.; Pye, R. J.; Keenan,
M. Org. Lett. 2005, 7, 1275–1277. (b) Kenworthy, M. N.; McAllister, G. D.;
Taylor, R. J. K. Tetrahedron Lett. 2004, 45, 6661–6664. (c) Cohen, J. L.;
Chamberlin, A. R. Tetrahedron Lett. 2007, 48, 2533–2536.
Org. Lett., Vol. 11, No. 11, 2009
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