Fe-Catalyzed Direct α C-H Amination of Carbonyl Compounds

Article abstract of DOI:10.1021/acs.orglett.5b00710

A direct Fe-catalyzed α-amination of 1,3-dicarbonyl compounds has been accomplished using arylhydroxylamines as aminating agents. This novel protocol allows convenient access to α-amino carbonyl derivatives without the need for any postreaction manipulations. This is an operationally simple procedure that works at low temperatures in shorter reaction times and produces high yields with excellent N-selectivity. (Figure Presented).

Full text of DOI:10.1021/acs.orglett.5b00710

Letter
pubs.acs.org/OrgLett
Fe-Catalyzed Direct α C−H Amination of Carbonyl Compounds
Siva Murru,*,† Charles Seth Lott,† Frank R. Fronczek,‡ and Radhey S. Srivastava*,†
†Department of Chemistry, University of Louisiana at Lafayette, Lafayette, Louisiana 70504, United States
‡Department of Chemistry, Louisiana State University, Baton Rouge, Louisiana 70803, United States
S
* Supporting Information
ABSTRACT: A direct Fe-catalyzed α-amination of 1,3-
dicarbonyl compounds has been accomplished using arylhy-
droxylamines as aminating agents. This novel protocol allows
convenient access to α-amino carbonyl derivatives without the
need for any postreaction manipulations. This is an opera-
tionally simple procedure that works at low temperatures in shorter reaction times and produces high yields with excellent N-
selectivity.
arbonyl compounds bearing α-amino substitution are
widely represented among pharmaceutically active com-
use of two different catalysts: one for carbonyl activation (Lewis
acid catalysis) and the other for nitroso compounds generation
(Scheme 2). The most recent report by Luo et al. discloses the
C
pounds, peptides and proteins, and complex natural products.1
Development of a direct synthetic strategy toward this high-
value synthon is a longstanding goal in organic synthesis, with
many research groups greatly contributing to α-amination.
Transition metal catalyzed α-aminations, through the reactions
of suitable nucleophiles and their electrophilic partners, have
been reported.2 For instance, the catalytic α-amination of
enolate derivatives such as ketones, β-ketoesters, and aldehydes
often involves the use of 2π-electrophile aza-substrates to
deliver α-hydrazinyl or α-hydroxy-amino products, two
structural classes that must undergo drastic reductive
conditions to cleave N−N and N−O bonds in order to access
the corresponding amines3 (Scheme 1).
Scheme 2. Previously Reported N-Hydroxy α-Amination and
Nitroso-Aldol vs Our Direct α-Amination
Scheme 1. Postreaction Modifications (N−X Bond
Cleavage) To Make α-Amino Carbonyl Compounds
preparation of N-hydroxy amine products using N-hydroxy
carbamates.5d Maruoka et al. reported a metal-free hydrox-
yamination process using a combination of TEMPO and BPO
as the oxidant.6 A few other organocatalytic hydroxyamination
methods were developed starting from nitrosobenzene.7
However, the end products in all of these reactions are N-
hydroxyl amines which require an additional reduction step to
make corresponding amines. Most importantly the use of
additional oxidants, precious metal catalysts, and/or other
additives makes these methods more expensive. Indeed, the
development of direct amination of carbonyl compounds,
without the need for any postreaction manipulations, still
remains challenging.
Similarly, the direct coupling of carbonyls and nucleophilic
amines is appealing and a more straightforward strategy for the
synthesis of α-amino carbonyls. Mechanistically, such a
coupling of two nucleophiles would require high temperatures
and judicious selection of oxidative conditions using a terminal
oxidant. Recently, MacMillan et al. reported a direct α-
amination reaction with nucleophilic amines under aerobic
conditions in which an electrophilic α-bromocarbonyl was
generated in situ through an aerobic oxidation-coupled
process.4 However, the method is only good for strong
nucleophilic secondary amines.
Other research groups of Yamamoto,5a Selig,5b and Alaniz5c
have independently reported in situ generation of nitroso-
carbonyls for aminoxylation (i.e., nitroso-aldol) and hydrox-
yamination reactions of β-ketoesters through the simultaneous
Received: March 10, 2015
Published: April 13, 2015
© 2015 American Chemical Society
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DOI: 10.1021/acs.orglett.5b00710
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Organic Letters
Letter
Compared to other transition metals, iron is one of the most
abundant in the universe, inexpensive, environmentally benign,
and relatively nontoxic.8 Over the past few decades iron
catalysts have been extensively applied to various reactions,
such as oxidation, epoxidation, addition, cyclization, etc.9
However, the iron-catalyzed C−N bond-forming reactions are
underdeveloped and have become an important goal for
synthetic chemists. In our continuation of extensive research on
catalytic amination chemistry, here we present a direct Fe-
catalyzed α C−H amination process that could deliver the final
products as amines utilizing hydroxylamines as aminating
agents (Scheme 2). This method possesses several advantages
such as (1) only a single catalyst for both electrophile
generation and nucleophile activation, (2) an inexpensive and
nontoxic Fe-catalyst, (3) no requirement of any oxidants or
additives, (4) high N-selectivity, and (5) no requirement of any
postreaction manipulation (reduction step).
Scheme 4. Direct α-Amination of 1,3-Dicarbonyl
Compounds Using Phenylhydroxylamine
a b
,
Previously we reported transition metal catalyzed allylic C−
H amination of simple olefins, 1,3-dienes, and α,β-unsaturated
carbonyls using hydroxylamines as aminating agents.10 We have
isolated metal(Fe and Cu)-nitroso complexes {Fe[ArN(O)N-
(O)Ar]3}2+2FeCl4 and {[Cu(ArNO)3]+PF6 } and implicated
them as reactive intermediates in allylic C−H amination
reactions.10b,c,f,g The crystal structure of the Fe-azodioxide
complex10b,c indicates the presence of both Fe(II) and Fe(III)
ionic species which is an advantageous feature for bimetallic
catalysis.11 Considering these unique features, we envisioned
that the Fe-catalyst would serve a dual purpose in the α-
amination of 1,3-dicarbonyl compounds where Fe(II) generates
active nitroso intermediates (electrophiles) and Fe(III) acts as a
Lewis acid catalyst to activate the 1,3-dicarbonyl derivatives
(nucleophiles).
−
−
In initial reaction development, we tested a set of known iron
catalysts12 and copper catalysts13 for the reaction of 2-methyl
ethyl acetoacetate (a) with phenyl hydroxylamine (1) in 1,4-
dioxane solvent at 70 °C (Scheme 3). A few Fe-catalysts, i.e.
a
All reactions were performed at 50 °C with a 1:1.2 substrate ratio
b
(PhNHOH: substrate). Isolated yields.
Scheme 3. Optimization of Conditions for the Reaction of
Phenyl Hydroxylamine with 2-Methyl Ethylacetoacetate
(3−7) worked fairly well (isolated up to 95%) when compared
to unsubstituted (1) and methyl substituted hydroxylamines
(2). Reactions of arylhydroxylamines bearing ortho-substitu-
tions (8a, 9a) are also efficient, and the desired products were
isolated in very good yields. In order to extend the reaction
scope we integrated other carbonyl derivatives such as 3-
methyl-2,4-pentanedione (b), ethyl-2-oxocyclopentanecarbox-
ylate (c), and α-acetyl butyrolactone (d) to afford the desired
amination products (1b−1d) in good yields. There appears to
be no substantial steric restrictions in the case of 2-acyl cyclic
carbonyl substrates c and d. Surprisingly, there was no reaction
when we employed 2-methyl-1,3-cyclopentadienone (e) in
which both the carbonyl groups are part of the strained cyclic
ring. This is probably due to the steric effects of two carbonyls
and the C-2 methyl group. Interestingly, 2-methyl cyclo-
hexanone (f), a monocarbonyl derivative, afforded the
amination product (1f) in relatively low yield (54%) unlike
other 1,3-dicarbonyls. This observation indirectly supports the
strong activation of 1,3-dicarbonyl derivatives when compared
to monocarbonyl substrates.
anh FeCl2, anh FeCl3, FeCl2·4H2O, and FeCl3·6H2O, were
found to be superior to other catalysts in terms of higher yields
and shorter reaction times (3−4 h). Further screening of
different solvents and a range of temperatures led us to
consider p-dioxane as a suitable solvent and 50 °C as the
optimum temperature.14
When a series of aryl hydroxylamines (1−10) with 2-methyl
ethylacetoacetate (a) were subjected to optimized reaction
conditions (5 mol % FeCl2, p-dioxane, 50 °C), the
corresponding α-amination products (1a−10a) were produced
in good to excellent yields as shown in Scheme 4. p-Substituted
arylhydroxylamines containing electron-withdrawing groups
1
All amination products were characterized by GC-MS, H
and 13C NMR, and IR-analysis. In most cases GC-MS analyses
of reactions indicate only single amination products. However,
a small amount (up to 5%) of azoxybenzene, a common side
product in amination reactions, was also detected in a few
cases.15 The structure of the amination product (1d) from the
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Organic Letters
Letter
α-acetyl butyrolactone (d) was confirmed by X-ray crystallo-
graphic analysis for the first time (Figure 1).16
reactions to deduce the reaction mechanism. Previously
reported α-amination reactions utilize two different catalysts
to serve different purposes,5 whereas the current method
utilizes only a single catalyst.
In conclusion, we have developed an Fe-catalyzed direct α-
C−H amination of 1,3-dicarbonyl compounds using arylhy-
droxylamines. This approach is highly N-selective and produced
important classes of α-amino carbonyl compounds in excellent
yields. Various carbonyl compounds have been implicated for
amination including β-ketoesters, 1,3-diketones, ethyl-2-oxocy-
clopentane carboxylate, and 3-methyl-2-oxindole. The amina-
tion product of α-acetyl butyrolactone was also confirmed by X-
ray crystallographic analysis. Further investigations and studies
are being directed toward understanding the reaction
mechanism and developing the direct asymmetric amination
of carbonyl compounds.
Figure 1. An ORTEP view with atomic numbering scheme of
amination product 1d.
Encouraged by these results, and considering the biological
significance of oxindoles containing a 3,3-disubstituted
quaternary carbon, we intended to perform an α-amination
on 3-methyl-2-oxindole (g). In fact, 3,3-disubstituted oxindoles
are widely present in natural products and bioactive molecules
such as the vasopressin VIb receptor antagonist SSR-14945, the
gastrin/CCK-B receptor antagonist AG-041R, and the anti-
inflammatory agent BMS-561392.17 In particular, 3-substituted
oxindoles bearing a heteroatom on a quaternary carbon are
extremely important in medicinal chemistry, and thus their
synthesis has been a topic of interest in recent years.18
Gratifyingly, α-amination of 3-methyl-2-oxindole afforded the
desired amination product in 76% yield (Scheme 5).
ASSOCIATED CONTENT
■
S
* Supporting Information
Details of experimental procedure, characterization data, copies
of H and 13C NMR spectra for all isolated compounds, HR-
1
MS spectra for 6a and 1g. This material available for free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: rss1805@louisiana.edu.
*E-mail: sxm2239@louisiana.edu.
Notes
Scheme 5. Fe-Catalyzed α-Amination of 3-Methyl-2-oxindole
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are thankful for the financial support of the Louisiana Board
of Regents [LEQSF(2013-16)-RD-B-06].
As discussed earlier, we hypothesize that the Fe-catalyst plays
a dual role in generating the activated nitroso intermediate
(i)10b,c as well as in activating the dicarbonyl compound (ii),
ultimately resulting in both intermediates reacting together to
produce the desired amination product (Scheme 6). This type
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