Rhodium-catalyzed chemo- and regioselective decarboxylative addition of β-ketoacids to alkynes

Article abstract of DOI:10.1039/c6cc02272c

A highly efficient rhodium-catalyzed chemo- and regioselective addition of β-ketoacids to alkynes is reported. Applying a Rh(i)/(S,S)-DIOP catalyst system, γ,δ-unsaturated ketones were prepared with exclusively branched selectivity under mild conditions. This demonstrates that readily available alkynes can be an alternative entry to allyl electrophiles in transition-metal catalyzed allylic alkylation reactions.

Full text of DOI:10.1039/c6cc02272c

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Rhodium-Catalyzed Chemo- and Regioselective Decarboxylative
Addition of β-Ketoacids to Alkynes
Received 00th January 20xx,
Accepted 00th January 20xx
a
a
a
Changkun Li, Christian P. Grugel and Bernhard Breit *
DOI: 10.1039/x0xx00000x
A highly efficient rhodium-catalyzed chemo- and regioselective addition of β-ketoacids to alkynes is reported. Applying a
Rh(I)/(S,S)-DIOP catalyst system, δ, γ-unsaturated ketones were prepared with exclusively branched selectivity under mild
conditions. This demonstrates that readily available alkynes can be an alternative entry to allyl electrophiles in transition-
metal catalyzed allylic alkylation reactions.
www.rsc.org/
Transition-metal catalyzed allylic substitution reactions (Tsuji-Trost transition metal catalyzed allylic alkylation chemistry have
reaction) have proven of fundamental importance in the emerged. Starting with linear or branched allylic electrophiles and
construction of complex target molecules, since they allow the enolates, high regio- and enantioselectivities could be obtained
4
simultaneous construction of new stereocenters and a versatile under milder conditions (Scheme 1, eq 1). The careful selection of
alkene function enabling further skeleton expanding operations. leaving groups and bases is generally crucial for the outcome of the
Numerous useful organic building blocks could be synthesized in a allylic substitutions, and in this respect different additives have to
highly chemo-, regio-, diastereo- and enantioselective be used and inorganic salt waste is generated during the course of
1
5
manner. δ, γ−Unsaturated ketones are important intermediates for this process. From the viewpoint of atom economy, greener
2
the synthesis of many biologically active molecules. The alternatives to allylic substitutions are still very desirable.
preparation of this type of compounds can be achieved from
Recently, we reported a series of rhodium-catalyzed addition
thermal Claisen rearrangement of vinyl allyl ethers, which are reactions of several pronucleophiles to allenes, furnishing branched
3
usually not easy to access. Recently, alternative methods based on
allylic products in an atom-economic manner, which can be
6
regarded as atom-economic alternatives to the allylic substitution.
7
Transition-Metal Catalyzed Allylic Substitutions
Inspired by the biosynthesis of polyketides and fatty acids, we
R'
developed a decarboxylative addition of β-ketoacids to allenes as
an efficient method to construct tertiary and quaternary carbon
centers under mild and neutral reaction conditions (Scheme 1, eq
LG
OM
TM (Pd, Ir, Ru, Rh)
R
LG or
+
O
eq 1
R
R'
-
MLG
R
8
Our previous work:
Decarboxlative addition to terminal allenes
2). Although allenes are excellent substrates in these reactions, the
use of alkynes as alternative substrates is much more attractive
R3
R2
[Rh(cod)Cl]
2
DPPF
O
O
because of the ease of availability. Herin, we report a rhodium-
O
R1
+
R3
CO
2
eq 2
9
+
catalyzed chemo- and regioselective decarboxylative addition of β-
HO
R1
R2
DCE, rt
10
ketoacids to alkynes (Scheme 1, eq 3) furnishing valuable γ,δ-
R1 = aryl, alkyl; R2 = alkyl, H
unsaturated ketones.
This work:
The conversion of terminal alkynes by rhodium to branched allylic
products via an intermediate allene developed in our group usually
requires the help of a substoichiometric amount of a carboxylic acid
as cocatalyst, to allow the coupling of stronger nucleophiles under
Decarboxlative addition to alkynes
R2
[
(
Rh(cod)Cl]
2
S,S)-DIOP
Me
O
O
+
O
+
eq 3
R1
R2
CO
2
HO
Toluene, rt
R1
11
acidic condition. On the other hand, internal methyl alkynes can
1
2
Scheme 1. Transition-metal-catalysed construction of γ, δ
unsaturated ketone
-
be converted to terminal allenes with the help of a metal-hydride.
Especially for the Pd- and Rh-catalyzed processes reported by
Yamamoto and Dong, the presence of carboxylic acids is
1
2a-e, I, j
mandatory.
We expected that β-ketoacids might be capable
of fulfilling two roles. First they may act as carboxylic acids to
enable the generation of a metal hydride species that allows the
conversion of internal and terminal alkynes to allenes (Scheme 2).
Secondly, they may act as a source for carbon nucleophiles, needed
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for the desired C-C bond formation. The rhodium/diphosphine both, the catalyst loading (entry 5) as well as the amount of
catalyst would have to be efficient and selective for both of the alkyne substrate was lowered (entry 6). Gratifyingly, no
isomerization and addition steps, suppressing
a
premature decrease of yield was observed when less alkyne was
decarboxylative decomposition of the less stable β-ketoacid.
subjected to the reaction (entry 7). Further reactivity assays,
applying different ligands to the indicated reaction conditions
revealed a high sensitivity concerning the bite angle of the
diphosphine ligand. Smaller angled DPPP gave much lower
yield of the product (entry 8). Even though a similar backbone
was applied, DPPB showed different reactivity (entry 9).
Furthermore, when DPPF, which is the best ligand in the
8
reported addition to allenes, was used in this reaction, only
moderate yield was obtained (39 %, entry 10). This results in
the assumption, that DPPF is not efficient in the isomerization
step in this dual catalysis. To our delight, in all cases the
Scheme 2. Alkynes as atom-economic allyl source in carbon-
carbon bond formation
We started the investigation with 1-phenyl-1-propyne 1a reaction exhibited high chemo- and regioselectivities, without
and benzoylacetic acid 2a as model substrates (Table 1). In the formation of any allyl benzoylacetate and linear
presence of 5.0 mol % of [Rh(cod)Cl] and 10.0 mol % DPEphos unsaturated ketone.
ligand in dichloroethane at 35 C, 35 % of the desired
With the optimized conditions in hand, we examined the
branched -unsaturated ketone 3aa was isolated as the only scope of
-ketoacids in this decarboxylative addition reaction
δ,γ-
2
o
δ,
γ
β
1
3
regioisomer (entry 1). When (S,S)-DIOP was used as the (Table 2). Benchmarking the results with 1-phenyl-1-propyne
ligand, the yield increased to 61 % (entry 2). Cooling down to 1a, a wide range of different functional groups on the acid side
room temperature gave a similar conversion and yield (59 %, are tolerated. Aromatic substituted
β-ketoacids bearing
entry 3). Switching the solvent from dichloroethane to electron-donating groups and halogen at ortho- and meta-
toluene, dramatically increased the yield to 84 % (entry 4), positions respectively, reacted smoothly in good yields (3ab
probably due to the lower solubility of 2a in less polar toluene, and 3ac). Bulkier naphthyl and 2-thiophenyl substituents (3ad
which decreases the rate of premature decarboxylation of
β
-
and 3ae) as well as β-ketoacids bearing primary, secondary
and tertiary aliphatic groups also behaved well in this reaction,
ketoacid 2a. The same level of reactivity was obtained when
and afforded the desired products in good yields (3af to 3ah).
a
Table 1. Optimization of the reaction conditions
Even more challenging substrates such as a highly
benzyl group may be incorporated into the corresponding
unsaturated ketones (3ai). Notably, even alkenyl substituents
are well-tolerated furnishing - and -double unsaturated
ketones, being suitable for ring closing metathesis reactions
α-acidic
γ,δ-
α
,
β
γ,δ
4
g,14
leading to cyclopentenones (3aj).
A limitation is an alkynyl
substitutent adjacent to the ketone function. To our surprise,
Table 2. The scope of β-ketoacids in the rhodium-catalyzed
decarboxylative addition to alkynes
a
d
entry
ligand
DPEphos
(S,S)-DIOP
(S,S)-DIOP
(S,S)-DIOP
(S,S)-DIOP
(S,S)-DIOP
(S,S)-DIOP
DPPP
solvent
DCE
X : Y
2 : 1
yield (%)
35
b,c
1
b,c
2
DCE
2 : 1
61
c
3
DCE
2 : 1
59
c
4
toluene
toluene
toluene
toluene
toluene
toluene
toluene
2 : 1
84
5
6
7
8
9
2 : 1
81
1.5 : 1
1 : 1.5
1.5 : 1
1.5 : 1
1.5 : 1
83
82
25
DPPB
43
1
0
DPPF
39
a
b
0
.5 mmol scale reactions were carried out in 1.0 ml of solvent.
o
c
The reaction was carried out at 35 C. 5 mol% [Rh(cod)Cl]
mol% ligand were used. Isolated yield.
2
and 10
d
a
0
.5 mmol scale reactions were carried out in 1.0 ml of solvent.
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only trace amount of 3ak was detected, giving rise for the benzoic acid is necessary to accelerate this isomerization. Benzoyl
assumption that competing coordination of two different alkynes and p-methoxybenzyl protected hydroxyl function as well as a
suppress the reaction.
phthalimide function were installed into the γ, δ−unsaturated
ketone in high yields (3na to 3pa).
Next, we investigated the scope of the alkyne coupling partner
(Table 3). Halogenated 1-phenyl-1-propynes 1b to 1d reacted with
To this end the (S,S)-DIOP exhibited the highest reactivity in this
benzoylacetic acid 2a to afford the corresponding γ, δ-unsaturated rhodium-catalyzed decarboxylative allylation reaction, but the
1
6
ketones 3ba to 3da in high yields. Lower yield was obtained for the enantioselectivity being rather low. Subjecting (R,R)-DTBM-DIOP
iodo-substituted alkyne 1e, perhaps due to the fact that aryl iodide to the indicated reaction conditions resulted in first promising
is easier to undergo an oxidative addition with the rhodium catalyst. results to conduct this reaction in an asymmetric fashion, furnishing
1
7
Electron-donating groups are also tolerated in this reaction (3fa and the desired γ, δ-unsaturated ketone in promising 64% ee.
ga), although electron-withdrawing groups seem to accelerate the
3
reaction leading to a higher yield (3ha). meta-Methylphenyl and 2-
naphthyl have no influence on the reactivities of the coupling Conclusions
reaction (3ia and 3ja). However, a chloro substituent in ortho-
position of the phenyl ring slows down the reaction significantly. To
our delight, subjecting 1.0 equiv of benzoic acid to the reaction was In conclusion, we have developed a highly regioselective
beneficial and resulted in good yields for 3ka. This suggests, that decarboxylative addition of
-ketoacids to alkynes under very
β
the role of the additional benzoic acid presumably is the mild reaction condition employing a commercially available
acceleration of the alkyne/allene isomerization step. Besides aryl rhodium catalyst, thus extending the rhodium-catalyzed
groups, alkenyl substituents (1-cyclohexenyl and cinnamyl) may also addition of pronucleophiles to a new C-C bond forming
be introduced at the β position of the γ, δ-unsaturated ketones (3la reaction. Readily available alkynes were used as an alternative
and 3ma), although for the latter case, a 1: 0.9 mixture of entry to allyl electrophiles, releasing CO2 as the only
1
5
regioisomers could be isolated. The aliphatic methyl alkynes are byproduct, and furnishing valuable γ, δ-unsaturated ketones
generally less reactive than the aromatic counterparts and extra
building blocks. Further efforts on the ligand design and
synthesis for an asymmetric version of this reaction as well as
the extension to other C-C, C-N, C-S and C-O bond forming
reactions are under investigation in our laboratory.
Table 3. The scope of alkynes in rhodium-catalyzed
a
decarboxylative additions
Acknowledgements
This work was supported by the DFG. C.L. thanks the Alexander
von Humboldt Foundation for a postdoctoral fellowship.
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