α-Amination of keto-nitrones via Multihetero-Cope rearrangement employing an imidoyl chloride reagent

Article abstract of DOI:10.1039/c2cc33401a

α-Aminations of ketone-derived nitrones have been developed via [3,3]-rearrangement of the intermediates generated upon condensation with imidoyl chlorides. Careful reagent selection provides synthetically attractive amino protecting groups. The enediamide or α′-carbamoyl enamide products can be hydrolyzed to the desired carbonyl, or exposed to electrophiles for further α-functionalization.

Full text of DOI:10.1039/c2cc33401a

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COMMUNICATION
a-Amination of keto-nitrones via Multihetero-Cope rearrangement
employing an imidoyl chloride reagentw
Justin T. Malinowski, Ericka J. Malow and Jeffrey S. Johnson*
Received 10th May 2012, Accepted 6th June 2012
DOI: 10.1039/c2cc33401a
a-Aminations of ketone-derived nitrones have been developed
via [3,3]-rearrangement of the intermediates generated upon
condensation with imidoyl chlorides. Careful reagent selection
provides synthetically attractive amino protecting groups. The
enediamide or a0-carbamoyl enamide products can be hydrolyzed
to the desired carbonyl, or exposed to electrophiles for further
a-functionalization.
Extension of this strategy to achieve a-amination has been
scarcely pursued. The use of an imidoyl chloride rather than an
acyl chloride in the condensation with a keto-nitrone afforded
a-amido ketone products in two preliminary investigations.7
The imidoyl electrophiles used (Y, Z = Ph or Y = Ph, Z = Me
(Scheme 1)) provided N-Ph/Me-benzoylamino products that
would be difficult to convert to the free a-amino ketones.
a-Amino carbonyls are ubiquitous in organic chemistry. Creation
of this functional group via Ca–N bond construction is a central
challenge in organic synthesis that has received considerable
attention in the literature.1 The electrophilic a-amination of
enolates and their equivalents is in principle a direct, efficient
method for a-amino carbonyl synthesis and significant work on
this problem has been reported. Azodicarboxylates are especially
prominent N(+)-sources that have been widely and effectively
applied to this reaction, including asymmetric variants,2 but come
with several drawbacks. Atom inefficiency, explosion hazard,3 and
typically harsh or multistep deprotection protocols to reveal the
amine somewhat counterbalance the favourable reactivity profile.
Thus, an argument can be made that an important but often-
overlooked component of the electrophilic a-amination problem
lies in the ‘‘packaging’’ of the amine product. Previous studies by
our group made use of a weak N–O bond for electrophilic
amination methodology,4 and we questioned whether this tactic
could be harnessed to provide convenient nitrogen protecting
groups (e.g. Boc, Fmoc, Cbz) concomitantly upon a-amination.
The purpose of this communication is to report a [3,3]-rearrange-
ment of imidoyl nitrones providing a-amination products with
synthetically-attractive amino protecting groups.
ð1Þ
In formulating a reaction design for an a-amination that
proceeds with concurrent generation of synthetically-attractive
protecting groups, we envisioned that a [3,3]-rearrangement
involving an appropriately functionalized imidoyl chloride reagent
could be useful (Scheme 1). Herein, we disclose an a-amination
protocol for keto-nitrone substrates via [3,3]-rearrangement. The
a-amino products obtained are conveniently configured as benzyl
carbamates (NH–Cbz). An unexpected deprotonation event
occurs with acyl migration to furnish enediamide or a0-carbamoyl
enamide products dependent on the a-proton availability on the
nitrone substrate (vide infra).
The requisite keto-nitrones were prepared via hydroxylamine/
ketone condensation.8 A variety of enolizable ketones were
employed with aryl, alkyl, and cyclic substrates providing varied
yields (13–88%) of nitrone product.9 These compounds are stable
to SiO2 chromatography and can be stored in a freezer indefinitely.
The Cbz-protected trifluoromethyl imidoyl chloride 1 was
synthesized via the published two step route.10
[3,3]-Sigmatropic rearrangements are important reactions for the
reliable introduction of various functionality in complex settings.5
Multihetero-[3,3]-rearrangements, such as those of N-alkyl-N-
acetoxyenamines, are an important subclass.6 Coates and
Cummins were the first to develop this rearrangement as a
method for a-functionalization: treatment of N-tBu nitrones
with acyl chlorides provide a-acyloxy carbonyls (eqn (1)).6b
Department of Chemistry, University of North Carolina at Chapel Hill,
Chapel Hill, North Carolina 27599-3290, United States.
E-mail: jsj@unc.edu
w Electronic supplementary information (ESI) available: Experimental
details and characterization data for new compounds. See DOI:
10.1039/c2cc33401a
Scheme 1 a-Amination via multiheteroatom [3,3]-rearrangement.
c
7568 Chem. Commun., 2012, 48, 7568–7570
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Table 1 Aryl nitrone scopea,b,c
Scheme 2 Initial result and proposed mechanism.
The reaction of cyclopentanone-derived nitrone 2 and the
imidoyl chloride 1 in the presence of Et3N at 0 1C led to rapid
and complete reagent consumption. Analysis of the crude
reaction mixture showed formation of an a0-carbamoyl enamide
product (3), rather than the anticipated a-amino imine or ketone
(Scheme 2). This was rationalized ex post facto by a 1,4-trifluoro-
acetyl migration/proton transfer6a of the initial [3,3]-imine
product (5 - 3, Scheme 2). At this time it is unclear whether
the system is under kinetic or thermodynamic control, although
the formation of a0-carbamoyl enamide products (deprotona-
tion at the less-hindered site) suggests a kinetic scenario.
Equimolar quantities of nitrone and reagent 1 treated with
2.0 equiv. triethylamine provided the optimal results for this
transformation when run in CH2Cl2 at 0 1C. The reaction was
usually complete within 30 min.
a
b
All reactions: [1]0 = 0.1 M. Yields of isolated products. See
c
Supporting Information for more details.
Table 2 Cyclic/alkyl nitrone scopea,b,c
A divergence in reactivity was observed when acetophenone-
derived nitrone 6 was subjected to identical conditions. In the
absence of an a0-enolizable proton, terminal deprotonation
occurred at the a-site furnishing the enediamide product (9 - 7,
Scheme 3).
With optimized conditions in hand and two product classes
identified, we explored the scope of the [3,3]-rearrangement/
a-amination. Nitrones derived from acetophenone derivatives
provided moderate yields ranging from 49–66% (7, 10–12,
Table 1). The enediamide moiety was formed exclusively in the
(Z)-configuration. When a propiophenone-derived nitrone was
used, the product geometry was reversed (12), presumably due
to increased A1,3-strain introduced by the methyl substituent
(vs. ꢀH). Cyclic nitrones also performed well in the [3,3]-rearrange-
ment (Table 2). Cyclopentyl and cyclohexyl substrates provided
a0-carbamoyl enamides in 64–78% yields (3, 13–16). The use
of a 4-tBu-cyclohexanone derived nitrone decreased the yield
and provided minimal diastereoselectivity (17).
a
b
All reactions: [1]0 = 0.1 M. Yields of isolated products; dr
determined by 1H NMR spectroscopy. See Supporting Information
for more details.
c
The nitrone N-benzyl protecting group was varied, using
the cyclopentyl core as a model. Several substituted benzyl
nitrones were examined, with the tolyl group providing the
highest yield (14). A chiral nitrone derived from (S)-a-methyl
Scheme 3 Divergent reactivity with aryl nitrone.
c
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hydrolysis, carbonyl functionality may be revealed providing a
new method for carbonyl a-amination. Ongoing studies in our
laboratory are focused on extending this method to aldo-nitrones
and development of an asymmetric variant.
Notes and references
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Stereoselective Synthesis, ed. G. Helmchen, R. W. Hoffmann,
J. Mulzer and E. Schaumann, Thieme, Stuttgart, 1996, vol. 9,
pp. 5133–5157; (b) C. Greck and J. P. Genet, Synlett, 1997, 741;
(c) E. Ciganek, Org. React., 2009, 1–36; (d) J. P. Genet, C. Greck
and D. Lavergne, in Modern Amination Methods, ed. A. Ricci,
Wiley-VCH, Weinheim, Germany, 2000, ch. 3; (e) J. M. Janey,
Angew. Chem., 2005, 117, 4364 (Angew. Chem., Int. Ed., 2005,
44, 4292).
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(Angew. Chem., Int. Ed., 2002, 41, 1790); (e) Y. Hayashi,
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Scheme 4 Secondary transformations.
benzylamine was synthesized and tested,11 but chirality transfer
was poor (18).
The acetone-derived nitrone provided the enediamide 19
rather than the isomeric a0-carbamoyl enamide. In this case
and other examples reported with diminished yields, competing
reactions producing unknown byproducts account for the mass
balance. The cyclohexenone-derived nitrone displayed unique
reactivity wherein the chloride byproduct was incorporated
yielding cis-b0-chloro-a0-carbamoyl enamide 20.
Both the enediamide and a0-carbamoyl enamide products
are resistant to hydrolysis and survive acidic or basic aqueous
workup; however, after extensive screening of conditions,
basic hydrolysis was realized upon treatment with freshly
prepared sodium benzylthiolate in MeOH. Subjecting the
enamide 3 to these conditions cleanly provided the Cbz-protected
a-amino ketone 21 in 85% yield (A, Scheme 4). Enediamide
product 7 was also hydrolyzed upon thiolate exposure and
subsequent acidic workup. In this case, partial tranesterification
occurred providing the methoxy-carbamyl protected a-amino
ketone as a minor product (B, Scheme 4). A one-pot procedure
taking nitrone starting material directly to the Cbz-protected
a-amino ketone 21 was also realized by treating the crude
reaction product from the [3,3]-a-amination with NaSBn/
MeOH. This sequence resulted in a yield of 69%, significantly
higher than the analogous two-step process (C, Scheme 4).
The enamide in both product classes provides opportunities
for further a-functionalization. Exposure of enamide 3 to Br2
provided hemiaminal oxazolidinone 23 from bromination-
debenzylation (D, Scheme 4).
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In conclusion, we have developed an a-amination of keto-
nitrones via multiheteroatom-[3,3]-rearrangement. This reaction
provides enediamide or a0-carbamoyl enamide products based
on the enolizable sites on the substrates employed. Upon basic
c
7570 Chem. Commun., 2012, 48, 7568–7570
This journal is The Royal Society of Chemistry 2012