Selective Synthesis of Unsymmetrical Aliphatic Acyloins through Oxidation of Iridium Enolates

Article abstract of DOI:10.1002/chem.201803117

The first method to access unsymmetrical aliphatic acyloins is presented. The method relies on a fast 1,3-hydride shift mediated by an Ir^III complex in allylic alcohols followed by oxidation with TEMPO⁺. The direct conversion of allylic alcohols into acyloins is achieved in a one-pot procedure. Further functionalization of the Cα′ of the α-amino-oxylated ketone products gives access to highly functionalized unsymmetrical aliphatic ketones, which further highlights the utility of this transformation.

Full text of DOI:10.1002/chem.201803117

A Journal of
Accepted Article
Title: Selective Synthesis of Unsymmetrical Aliphatic Acyloins through
Oxidation of Iridium Enolates
Authors: Amparo Sanz-Marco, Samuel Martinez Erro, and Belén
Martín-Matute
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To be cited as: Chem. Eur. J. 10.1002/chem.201803117
Link to VoR: http://dx.doi.org/10.1002/chem.201803117
Supported by

10.1002/chem.201803117
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Selective Synthesis of Unsymmetrical Aliphatic Acyloins through
Oxidation of Iridium Enolates
Amparo Sanz-Marco,[a] Samuel Martinez-Erro,[a] and Belén Martín-Matute*[a]
Abstract: The first method to access unsymmetrical aliphatic
acyloins is presented. The method relies on a fast 1,3-hydride shift
mediated by an Ir(III) complex in allylic alcohols followed by
oxidation with TEMPO+. The direct conversion of allylic alcohols into
acyloins is achieved in a one-pot procedure. Further functionalization
of the Ca´ of the a-aminooxy ketone products gives access to highly
functionalized unsymmetrical aliphatic ketones, which further
highlights the utility of this transformation.
Scheme 1. Synthesis of a-oxidized carbonyl compounds.
The selective synthesis of a-oxygenated carbonyl compounds is
of paramount importance in organic chemistry.[1,2] These motifs
methods involving formation of transient transition-metal
enolates.[ 19 ] These species are produced from allylic alcohol
are commonly found in biologically active molecules, and they
moieties through an internal 1,3-hydrogen shift mediated by Ru,
are versatile building blocks in organic synthesis. Through direct
Rh, or Ir catalysts.[20,21] Allylic alcohols are readily available, and
by selecting the appropriate allylic alcohol precursor, this
versatile approach enables the synthesis of carbonyl
compounds functionalized selectively and exclusively at the
desired a-carbon in excellent yields. The method has been used
in particular for the construction of C-halogen bonds. Our
preliminary attempts to apply this strategy to the synthesis of a-
oxygenated carbonyl compounds were hampered by oxidative
side-reactions of the transition-metal catalysts and the allylic
alcohols under the oxidative reaction conditions.[22] After
extensive investigations, in this paper we present a versatile
strategy that overrides inherent ketone biases, and uses allylic
alcohols as synthetic equivalents of enolates for the synthesis of
a-oxygenated carbonyl compounds as single constitutional
isomers.
oxidation, a-hydroxy aldehydes,[
a-hydroxy-b-dicarbonyl
3
]
compounds,[
oxazolidinones,[
a-hydroxy esters,[
a-hydroxy N-acyl
4
]
5
]
and a-hydroxy carboxylic acids[
can be
6
]
7 ]
accessed (Scheme 1a). In a recent contribution, Maulide
reported an excellent method for the selective a-oxidation of
amides by using triflic anhydride to activate the amide
functionality.[8] Similarly, the synthesis of a-hydroxy ketones can
be accomplished through the reaction of the parent ketones with
different oxidants. [9] However, their selective synthesis (i.e., the
formation of single constitutional isomers) is still a rather
challenging task. Good results can be obtained when prepared
through the oxidation of silyl enol ethers and enolates derived
from ketones that i) are symmetrical, ii) have a single enolizable
Ca (e.g., R1 = aryl), or iii) have sterically and/or electronically
biased enolizable Ca.[10] Oxidizing agents that have successfully
been used include peroxyacids,[
metal oxides,[
N-
11
]
12 ]
Initially, we studied the reaction of allylic alcohol 1a with
TEMPO. We observed that decomposition occurred, and allylic
alcohol 1a was only recovered in 33% yield. When 2,2,6,6-
sulfonyloxaziridines,[ 13 ] and molecular oxygen.[ 14 ] Additionally,
hypervalent iodine reagents have been used to introduce a-
OH , -OAc, or -OTs functionalities.[ 15 ] With oxidants such as
tetramethylpiperidine-1-oxoammonium
tetrafluoroborate
nitrosobenzene[
(TEMPO) or its derivatives,[
or 2,2,6,6-tetramethylpiperidin-1-oxyl
16
]
-
(TEMPO+ BF4 , 2) was used, enone 4 was formed in 58% yield
17
]
(See SI, Table S1). This is not surprising, as TEMPO+ has been
described as an excellent oxidant for alcohols.
the corresponding a-
[22]
aminooxylated ketones are obtained. These are precursors to
the hydroxy ketones upon reduction of the N-O bond. Moreover,
they are themselves important as radical initiators in
polymerization reactions.[17a,18]
Despite these precedents, a method for the selective
synthesis of a-oxygenated carbonyl compounds formally derived
from unsymmetrical ketones with unbiased substituents has not
been reported. Furthermore, a method that can be used to
introduce the a-hydroxy ketone functional group selectively into
a molecule with additional carbonyl moieties or acidic hydrogens
is still an unresolved challenge.
Thus, it is
necessary to use a catalytic system that would mediate the 1,3-
hydride shift faster than the background TEMPO-mediated
oxidation reaction of the allylic alcohol. Our previous
investigations demonstrated that the 1,3-hydride shift can be
mediated by complexes of the general formula [Cp*Ir(III)] having
at least one halide ligand.[23] The commercially available complex
[Cp*IrCl2]2 was therefore chosen, and allylic alcohol 1a as the
model substrate. Initial experiments were carried out with
TEMPO, aiming to promote its disproportionation[23] into the
hydroxylamine (TEMPOH) and TEMPO+ under the inherently
acidic reaction conditions used for the Ir-catalyzed isomerization
of allylic alcohols.[y]a-Aminooxylated ketone 3a was obtained in
a potentially promising 12% yield when TEMPO (2.2 equiv.) was
stirred for 30 min before the addition of allylic alcohol 1a.
During the last few years, our group has developed catalytic
[a]
Dr. A. Sanz-Marco, S. Martinez-Erro, Prof. B. Martín-Matute
Department of Organic Chemistry
Stockholm University
Different single-electron oxidants were evaluated to promote
the oxidation of TEMPO, and they gave similar results (see
Supporting Information). Satisfactory yields (65%) were obtained
Stockholm 10691, Sweden
E-mail: belen.martin.matute@su.se
[24]
when TEMPO (2.2 equiv.) was stirred with HBF4 for 30 min
Supporting information for this article is given via a link at the end of
the document.
before the addition of 1a and the catalyst. It can therefore be
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concluded that to obtained a-oxidized ketone 3a, the efficient
generation of TEMPO+ is necessary. It is important to note that
in all these instances, 3a was produced as a single constitutional
isomer. This complete selectivity can only be attributed to the
oxidation of an enolate intermediate.[19]
To study the scope of the reaction we mainly chose
substrates that would give a-aminooxylated ketones 3 that
would be not obtained selectively if synthesized from the
corresponding sterically and electronically biased ketone
precursors (Scheme 2). Allylic alcohols bearing terminal alkenes
provided 3a-3j in high yields. Even allylic alcohols with sterically
hindered aliphatic chains (1d-1e) reacted in yields up to 86%.
Remarkably, the reaction conditions were compatible with
several functional groups, including ethers (1f), alkenes (1g-1h),
sec-alcohols (1i), and carbonyl groups (1j). The presence of
some of these functionalities means that some of the substrates
have aliphatic methylene groups bearing acidic protons, and
even hydroxy functionalities. Nevertheless, this mild, base-free
methodology yields complete chemoselectivity and only the
allylic alcohol moiety was transformed. The reaction was carried
out on allylic alcohols bearing 1,2-disubstituted alkenes (1k-1p).
Here, the Ir-catalyzed 1,3-hydride shift took place more slowly
than for terminal allylic alcohols, resulting in the formation of
enone by-products. However, when the reactants were added
slowly at 45 °C, satisfactory results were obtained (3k-3o).
Table 1. 1,3-Hydride shift / aminooxylation of 1a.[a]
O
BF4
O
N
Ph
Ph
OH
[IrCp*Cl2]2 (2.5 mol%)
4
Ph
N
O
2
Ph
Solvent/H2O (1:2)
30 min
O
O
1a
3a
5
Solvent /
H2O
Entry
T (°C)
Yield [%][b]
4
5
3a
57
1
2
20
35
45
35
35
35
35
35
35
35
35
THF
THF
7
6
5
4
-
-
5
2
2
11
3
8
-
78
63
30
60
51
53
76
82
79
53
3
THF
4
Dioxane
Dioxolane
Acetone
Et2O
5
6
6
4
2
4
7
5
7
8[c]
9[d]
10[e]
11[f]
THF
THF
-
THF
-
THF
-
[a] 1a (0.1 mmol, 0.2 M) and 2 (1.2 equiv.) under air. [b] Determined by 1H
NMR spectroscopy using an internal standard. [c] 0.1 M. [d] 0.3 M. [e] Under
an atmosphere of argon. [f] 1 M.
The alternative pathway, involving isomerization to the ketone
followed by oxidation, would result in the formation of a mixture
of isomeric products (i.e., oxidation at Ca and at Ca’). An
optimization of the reaction conditions using oxoammonium
tetrafluoroborate 2 was then carried out (Table 1). The reaction
of 1a with 2 catalyzed by [Cp*IrCl2]2 (2.5 mol%) in THF / H2O
o
(1:2) at 20 C gave 3a in 57% yield (Table 1, entry 1), together
with 7% of enone 4. At higher temperatures, the yield of 3a
increased to 78% at 35 °C (entry 2) after only 15 min. Higher
temperatures (45 °C, entry 3) favored the decomposition of
allylic alcohol 1a, resulting in a lower yield of 63% (entry 3). The
replacement of THF by other organic solvents proved
unsuccessful (entries 4-7). Further tuning of the concentration of
the reactants in aqueous THF (entries 8-11) resulted in
increased yields (82% at 0.3 M, entry 9). All reactions were run
under an atmosphere of air. Similar results were obtained when
the reaction was performed under inert atmosphere and with
degassed solvents (entry 10). At 1 M (entry 11), the yield was
again compromised. Based on these results, the conditions in
entry 9 were chosen to study the scope of the reaction. It should
be noted that just 1.2 equivalents of oxidant 2 was enough to
achieve high yields in a very fast and robust reaction, under an
atmosphere of air.
Scheme 2. Isomerization / aminooxylation of allylic alcohols. Yields by 1H
NMR spectroscopy (isolated yields in parentheses). [a] By slow addition of the
reactants at 45 °C. [b] By slow addition of the reactants.
When the allylic system was conjugated, as in 1p, the oxidation
of the alcohol moiety was faster than the isomerization /
aminooxylation process, resulting in a low yield of 27%. Primary
allylic alcohols were also transformed into the corresponding a-
aminooxylated aldehydes (3q-3r) in good yields.
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a-Aminooxylated ketones 3 can easily be converted into
acyloins 6 by reductive cleavage of the N–O bond. Current
available methods rely on isolating the a-aminooxylated ketones
and carrying out the reduction in a separate step.[5,25] One-pot
reactions have numerous benefits, including decreasing the
amounts of solvent, effort, and energy used, and the amount of
waste produced.[26] The tandem 1,3-hydride shift / aminoxylation
reaction reported here takes place under essentially neutral and
additive-free conditions, thus we decided to investigate the
synthesis of acyloins 6 from allylic alcohols in a one-pot
procedure. The reduction step was carried out with zinc metal in
AcOH at rt.[25] After a short optimization of the one-pot procedure
(see Supporting Information), the optimal conditions were
applied to several allylic alcohols (Scheme 3).
migratory insertion / b-hydride/deuteride elimination pathway (iia
and iib). The latter (iib) is responsible for the introduction of D at
Ca. Upon reaction of the resulting enolate with oxoammonium
tetrafluoroborate salt 2, the corresponding acyloin is obtained
(Scheme 4).
[D Ir]
[Ir]
R
O
OH
CH3
1l-[D1] (92% D)
[R = CH3-(CH2)3]
O
O
i
R
[Ir]cat
2
D
CH3
OTMP
-[Ir]cat
CH3
R
D/H
R
CH3
1,4-D Addition
D/H
D/H
H/D
3l-[D1] (85% D)
(77% D at Cβ;
8% D at Cα)
ii
O
R
O
iia
CH3
Migratory
Insertion
[Ir]
D
R
CH3
[R = CH3-(CH2)3]
[Ir D]
O
iib
R
CH3
H
[Ir]
D
Scheme 4. Proposed mechanism for the iridium-catalyzed isomerization /
aminooxylation / reduction of allylic alcohols
To further demonstrate the synthetic importance of our
method, the remaining Ca´ of 3a was functionalized following a
method developed by Romea and Urpí.[27] Thus, a Ti-enolate was
formed upon coordination to 3a (Scheme 5). Subsequent
addition of benzaldehyde, N-chlorosuccinimide (NCS) or N-
bromosuccinimide (NBS) gave selectively functionalized ketones
7a, 7b, and 7c.
Scheme 3. One-pot synthesis of unsymmetric acyloins from allylic alcohols.
Yields by 1H NMR spectroscopy (isolated yields in parentheses).
Scheme 5. Synthesis of carbonyl compounds with both Ca and Ca’
selectively functionalized. Isolated yields.
A wide range of allylic alcohols with terminal alkenes 1a-1i
were successfully transformed into the corresponding a-hydroxy
ketones in good to moderate isolated yields. Even allylic
alcohols with internal alkenes 1k-1o were converted into the
desired acyloins with complete selectivity and in satisfactory
isolated yields. The yields of the one-pot reactions were
comparable to those obtained for the synthesis of a-
aminooxylated ketones 3, indicating full conversion in the
reduction process. Notably, functional groups sensitive to
oxidation are tolerated in the reaction, and a-hydroxy ketones
6g-6i and 6m were synthesized with complete chemoselectivity.
In conclusion, the first method for the synthesis of aliphatic
unsymmetrical acyloins as single constitutional isomers is
reported. The method relies on fast Ir(III)-catalyzed 1,3-hydride
shift in allylic alcohols in the presence of the oxidant. Only when
a fast hydride shift takes place are unwanted oxidative side-
reactions avoided. A wide range of allylic alcohols bearing
several functional groups were successfully transformed. Also,
in a one-pot procedure, allylic alcohols could be directly
transformed into acyloins. As the conditions are base-free, acidic
functionalities or enolizable methylenes are tolerated. The
synthetic utility of this selective method was further
demonstrated through selective further functionalization at the
a’-carbon.
The reaction of 1l-[D1] (92% D) (Scheme 4) afforded a-
aminooxylated ketone 3l-[D1] (85% D) with
a deuterium
distribution of 77% D at Cb and 8% D at Ca . The deuterium
distribution in the oxidized ketone agrees well with our previous
investigation. [23] Thus, the 1,3-H(D) shift occurs via formation of
enone intermediates,[19,20,23] which then undergo reduction of the
double bond via a 1,4-hydride/deuteride addition (path i) or a
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10.1002/chem.201803117
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Acknowledgements
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This project was supported by the Swedish Research Council
through Vetenskapsrådet and Formas, and by the Knut and
Alice Wallenberg Foundation. A. S.-M. thanks Universitat de
València, the Generalitat Valenciana and the European Social
Fund for a post-doctoral grant.
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Keywords: oxidation • iridium • hydride shift • a-hydroxy
ketones • allylic alcohols
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Notes
y HCl is formed in catalytic amounts in the 1,3-H shift by
[Cp*IrCl2]2.
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10.1002/chem.201803117
Chemistry - A European Journal
COMMUNICATION
COMMUNICATION
Selective Oxidation. A selective
method to synthesize unsymmetrical
acyloins as single constitutional
isomers is presented. From allylic
alcohols, a fast iridium-catalyzed 1,3-
hydride followed by an oxidation
affords a-hydroxy carbonyls with
outstanding selectivity.
Amparo Sanz-Marco, Samuel Martinez-
Erro, Belén Martín-Matute*
Page No. – Page No.
Selective Synthesis of Unsymmetrical
Aliphatic Acyloins through Oxidation
of Iridium Enolates
This article is protected by copyright. All rights reserved.