Synthesis of 1,4-enamino ketones by [3,3]-rearrangements of dialkenylhydroxylamines

Article abstract of DOI:10.1021/ol501230e

The synthesis of 1,4-enamino ketones has been achieved through the [3,3]-rearrangement of dialkenylhydroxylamines generated from the addition of N-alkenylnitrones to electron-deficient allenes. The mild conditions required for this reaction, and the simultaneous installation of a fluorenyl imine N-protecting group as a consequence of the rearrangement, avoid spontaneous cyclization of the 1,4-enamino ketones to form the corresponding pyrroles and allow for the isolation and controlled divergent functionalization of these reactive intermediates. The optimization, scope, and tolerance of the new method are discussed with demonstrations of the utility of the products for the synthesis of pyrroles, 1,4-diones, and furans.

Full text of DOI:10.1021/ol501230e

Letter
pubs.acs.org/OrgLett
Synthesis of 1,4-Enamino Ketones by [3,3]-Rearrangements of
Dialkenylhydroxylamines
Wiktoria H. Pecak, Jongwoo Son, Amy J. Burnstine, and Laura L. Anderson*
Department of Chemistry, University of Illinois at Chicago, Chicago, Illinois 60607, United States
S
* Supporting Information
ABSTRACT: The synthesis of 1,4-enamino ketones has been
achieved through the [3,3]-rearrangement of dialkenylhydrox-
ylamines generated from the addition of N-alkenylnitrones to
electron-deficient allenes. The mild conditions required for
this reaction, and the simultaneous installation of a fluorenyl
imine N-protecting group as a consequence of the rearrange-
ment, avoid spontaneous cyclization of the 1,4-enamino ketones to form the corresponding pyrroles and allow for the isolation
and controlled divergent functionalization of these reactive intermediates. The optimization, scope, and tolerance of the new
method are discussed with demonstrations of the utility of the products for the synthesis of pyrroles, 1,4-diones, and furans.
subsequent spontaneous [3,3]-rearrangement to give 1,4-
enamino ketones 4 (Scheme 1b). Isolation of these compounds
with a fluorenone imine protecting group, installed as a
consequence of the [3,3]-rearrangement, provided the oppor-
tunity for their straightforward conversion to tetrasubstituted
pyrroles, 1,4-diones, and tetrasubstituted furans. Considered in
sequence with our reported N-alkenylnitrone synthesis, this two-
step procedure can be described as an oxime-mediated oxidative
coupling of alkenyl boronic acids and allenes to form 1,4-diones
and 1,4-dione derivatives.
The synthesis of 1,4-enamino ketone 4a was initially observed
when N-cyclohexenylnitrone 1a was treated with allenoate 2a in
toluene at 40 °C. A solvent screen showed that the preparation of
4a was most efficient in 1,2-dichloroethane (DCE) but also
occurred in dioxane, acetonitrile, DMF, and t-BuOH (Table 1,
entries 1−6). Decomposition of the reaction mixture was
observed at higher temperatures, but isolation of 4a was possible
in attenuated yields when the reaction was run at 25 °C (Table 1,
entries 7−9). In addition to solvent and temperature, several
acidic and basic additives were also tested to determine their
effect on the synthesis of 4a, but none improved the yield of the
desired product.10 The conditions described in Table 1, entry 5,
were determined to be optimal conditions for the synthesis of 4a
and were used for further exploration of the scope of the
method.11
[3,3]-Rearrangements of dialkenylhydrazines and dialkenylhy-
droxylamines are important transformations that are employed
as the key C−C bond forming steps in the Piloty−Robinson and
Trofimov pyrrole syntheses.1−3 Unfortunately, the conditions
required to generate these intermediates and to achieve these
transformations limit their scope and generality.4−6 We surmised
that dialkenylhydroxylamines could alternatively be accessed
through the addition of an N-alkenylnitrone to an allene.7,8 This
route could then be used to circumvent limitations of the pyrrole
syntheses mentioned above as well as provide access to isolable
[3,3]-rearrangement products for divergent functionalization
prior to heterocycle formation. Our recent discovery that N-
alkenyl fluorenone oximes can be prepared by a copper-mediated
C−N bond-forming reaction between fluorenone oxime and
alkenyl boronic acids facilitated our study (Scheme 1a).9 Herein,
we describe the generation of dialkenylhydroxylamines 3 by the
addition of N-alkenylnitrones 1 to activated allenes 2 and a
Scheme 1. [3,3]-Rearrangement of Dialkenylhydroxylamines
Generated from N-Alkenylnitrones
Several N-alkenylnitrones were tested under the optimized
reaction conditions to determine the scope of the transformation
(Table 2). Cycloalkenylnitrone substituents were discovered to
be particularly amenable to the preparation of imine-protected
1,4-enamino ketones 4, and cyclohexenyl, cycloheptenyl, and
cyclooctenyl groups were well-tolerated by the transformation
(Table 2, entries 1−3). N-Cyclopentenylnitrones were also
efficient substrates, but enamino ketone 4d was sensitive to
Received: April 29, 2014
Published: June 25, 2014
© 2014 American Chemical Society
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Letter
enamino ketones 4e−i (Table 2, entries 5−9). Monosubstituted
enamino ketones 4g−i were isolated as 1:1 mixtures of
diastereomers. Gratifyingly, nitrones with heterocyclic substitu-
ents such as 1j and 1k were also well-tolerated (Table 2, entries
10 and 11), and nitrone 1l with a linear alkenyl group gave the
corresponding product 4l in good yield. These examples describe
the generality of the method for the synthesis of imino-protected,
1,4-enamino ketones and offer an alternative route to enamine
displacements of α-halogenated ketones or oxidative couplings of
enamines and silyl enol ethers for the preparation of
monoenamino-functionalized 1,4-diones.12−14
Table 1. Optimization of the Addition of N-Alkenylnitrone 1a
to Allenoate 2a and Rearrangement to 4a
a
entry
solvent
temp (°C)
yield (%)
1
2
3
4
5
6
7
8
9
PhMe
dioxane
MeCN
DMF
40
40
40
40
40
40
80
60
25
63
65
80
54
89
72
dec
56
66
In addition to the nitrones discussed above, the scope of the
allene component of the transformation was tested to determine
the range of the method for installing the ketone fragment of the
products. As shown in Table 3, when methyl allenoates with
DCE
t-BuOH
DCE
Table 3. Scope of Allene Reagent
DCE
DCE
a
1
Determined by H NMR spectroscopy using CH2Br2 as a reference:
1a (1 equiv), 2a (3−4 equiv), 0.1 M, 18 h.
Table 2. Scope of N-Alkenylnitrone Reagent
a
Percent isolated yield. Conditions: 1a (1 equiv), 2 (3−4 equiv), 0.1
M in DCE, 40 °C, 18−24 h.
isopropyl, butyl, and benzyl substituents were treated with
nitrone 1a, enamino ketones 4m−o were isolated in good yield
(Table 3, entries 1−3). These results suggest that the cascade
rearrangement is tolerant of various substitution patterns at this
position. Several different allenoates, including phenyl, styrenyl,
allyl, and propargyl esters, smoothly underwent addition and
rearrangement with 1a (Table 3, entries 4−7). In addition,
allenes with alternative electron-withdrawing groups, such as
sulfonyl and Weinreb amide functionalities, were equally
effective substrates for the preparation of functionalized 1,4-
enamino ketones (Table 3, entries 8 and 9).
A proposed mechanism for the conversion of mixtures of N-
alkenylnitrones and allenes to 1,4-enamino ketones is illustrated
in Scheme 2a. Addition of nitrone 1a to electron-deficient allene
2a could form intermediate 3a, which could then undergo a
[3,3]-rearrangement to form azallenium 5a and a subsequent
proton transfer to form 4a.15 Alternatively, a [3 + 2]-
cycloaddition to form exomethylene isoxazoline 6a could also
predicate a [3,3]-rearrangement to form azepine 7a (Scheme
2b). A subsequent retro-Mannich reaction could then cleave the
azepine to form 4a.16 The pathway illustrated in Scheme 2b,
a
Percent isolated yield. Conditions: 1 (1 equiv), allenoate 2a (3−4
equiv), 0.1 M in DCE, 40 °C, 18−24 h.
purification on silica gel (Table 2, entry 4). Substituted
cyclohexenylnitrones with alkyl, ester, and ketal substituents
smoothly underwent the addition and rearrangement to give
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process with the addition and rearrangement reaction providing
direct conversion of N-alkenylnitrone 1a to tetrasubstituted
pyrrole 8a in good yield. Pyrroles with 2-CH2CO2R groups have
previously been prepared by the treatment of α-aminated
ketones with β-ketoesters.19 The transformation described above
provides a simple, alternative route to these compounds through
an oxime-mediated coupling of an alkenyl boronic acid and an
electron-deficient allene.
Scheme 2. Proposed Mechanism
To further pursue the use of imino-protected 1,4-enamino
ketones 4 as synthetic intermediates, we also screened conditions
for chemoselective reductions. As shown in Scheme 4,
Scheme 4. Synthetic Diversification of Isolated 1,4-Enamino
Ketones by Selective Reduction Methods
however, seems less likely than the pathway illustrated in Scheme
2a due to the sterically hindered and electronically deactivated
fluorenyl imine which would be unlikely to undergo a [3 + 2]-
cycloaddition.17
With several 1,4-enamino ketone products in hand, we decided
to investigate the reactivity of these unusual imino-protected
intermediates. Hydrolysis conditions were tested to remove the
fluorenone imine and assess the use of these compounds for the
preparation of highly substituted pyrroles. A mixture of p-
toluenesulfonic acid (TsOH) and H2O in ether was determined
to be optimal for removal of the fluorenone imine from 4a and
the synthesis of tetrasubstituted pyrrole 8a (Scheme 3). These
conditions were tolerated by a variety of 1,4-enamino ketones 4
and provided tetrasubstituted pyrroles with cyclohexyl,
−CH2CO2R, and Weinreb amide functional groups.18 The
hydrolysis of 4a can also be performed as a two-step, single-flask
hydrogenation of fluorenone imine 4a with Pd/C gave a
fluorenyl amine which cyclized to the corresponding N-
fluorenylpyrrole 9a. In contrast, reduction of 4a with NaBH4
gave δ-hydroxyenamine 10a. To our delight, a NaCNBH3
reduction of 4a in acetic acid gave 1,4-dione 11a, which could
also be subsequently converted to tetrasubstituted furan 12a.20
These experiments imply that [3,3]-rearrangements of dialke-
nylhydroxylamines, triggered by the addition of N-alkenylni-
trones to allenes, can provide rapid access to 1,4-diones and their
derivatives. These transformations provide alternative routes to
oxidative enolate couplings and Stetter reactions to access these
challenging fragments.21,22
Scheme 3. Hydrolysis of Imine-Protecting Group To Give
Tetrasubstituted Pyrroles
In summary, we have discovered a new method for the
generation of dialkenylhydroxylamines through the addition of
N-alkenylnitrones to electron-deficient allenes and the synthesis
of 1,4-enamino ketones by a subsequent spontaneous [3,3]-
rearrangement. This new route to dialkenylhydroxylamines has a
broader scope than the Trofimov reaction, and the mild reaction
conditions allow for the isolation of a novel fluorenylimine-
protected 1,4-enamino ketone intermediate. Simple functional-
ization methods have been shown to be effective for the
conversion of these compounds to pyrroles, 1,4-diones, and
furans. Ongoing work in our laboratory is focused on controlling
the stereochemistry of these rearrangements and further
exploring the synthetic utility of the imino-protected enamino
ketone rearrangement products.
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures and compound characterization data.
This material is available free of charge via the Internet at http://
pubs.acs.org.
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Letter
(11) Preparation of 4a can be achieved in attenuated yield (40 − 50%)
from the corresponding oxime through a two-step, single-flask, Chan−
Lam coupling followed by the addition of 2a.
AUTHOR INFORMATION
■
Corresponding Author
(12) For examples of the preparation of azabutadienes by addition/
elimination and isomerization, see: (a) Barluenga, J.; Joglar, J.; Fustero,
S.; Gotor, V.; Krueger, C.; Romao, M. J. Chem. Ber. 1985, 118, 3652.
(b) Grigg, R.; Stevenson, P. J. Synthesis 1983, 1009.
*E-mail: lauralin@uic.edu.
Notes
The authors declare no competing financial interest.
(13) For examples of the preparation of 1,4-enamino ketones by
enamine additions to α-halogenated ketones, α,β-unsaturated ketones,
and 1,2-diones, see: (a) Lopez-Alvarado, P.; Garcia-Granda, S.; Alvarez-
Rua, C.; Avendano, C. Eur. J. Org. Chem. 2002, 1702. (b) Schank, K.;
Leider, R.; Lick, C.; Glock, R. Helv. Chim. Acta 2004, 87, 869.
(c) Koulouri, S.; Malamidou-Xenikaki, E.; Spyroudis, S.;
Tsanakopoulou, M. J. Org. Chem. 2005, 70, 8780. (d) Li, W.-D. Z.;
Ma, B.-C. J. Org. Chem. 2005, 70, 3277. (e) Bremner, J. B.; Samosorn, S.
Aust. J. Chem. 2003, 56, 871. (f) Shaw, K. J.; Luly, J. R.; Rapoport, H. J.
Org. Chem. 1985, 50, 4515.
ACKNOWLEDGMENTS
■
We acknowledge generous funding from ACS-PRF (DNI-
50491), NSF (NSF-CHE 1212895), and the University of
Illinois at Chicago. We also thank Prof. T. Driver (UIC) for
insightful discussions and Mr. Furong Sun (UIUC) for mass
spectrometry data.
(14) For examples of oxidative couplings of enamines and silyl enol
ethers, see: (a) Narasaka, K.; Okauchi, T.; Tanaka, K.; Murikami, M.
Chem. Lett. 1992, 2099. (b) Jang, H.-Y.; Hong, J.-B.; MacMillan, D. W.
C. J. Am. Chem. Soc. 2007, 129, 7004. (c) Li, Q.; Fan, A.; Lu, Z.; Cui, Y.;
Lin, W.; Jia, Y. Org. Lett. 2010, 12, 4066.
(15) For examples of fluorenone-substituted azaallenium salts, see:
(a) Frey, H.; Mehlhorn, A.; Ruehlmann, K. Tetrahedron 1987, 43, 2945.
(b) Al-Talib, M.; Jibril, I.; Jochims, J. C.; Huttner, G. Tetrahedron 1985,
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Org. Chem. 1988, 53, 955. (b) Padwa, A.; Bullock, W. H.; Kline, D. N.;
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