Regioselective Rhodium-Catalyzed Addition of 1,3-Dicarbonyl Compounds to Terminal Alkynes

Article abstract of DOI:10.1021/acs.orglett.5b03391

A new method for the rhodium-catalyzed regioselective C-C bond formation using terminal alkynes and 1,3-dicarbonyl compounds to achieve valuable branched α-allylated 1,3-dicarbonyl products is reported. With a Rh(I)/DPEphos/p-CF₃-benzoic acid as the catalyst system, the desired products can be obtained in good to excellent yields and with perfect regioselectivity. A broad range of functional groups were tolerated, and first experimental insights of a plausible reaction mechanism were obtained.

Full text of DOI:10.1021/acs.orglett.5b03391

Letter
pubs.acs.org/OrgLett
Regioselective Rhodium-Catalyzed Addition of 1,3-Dicarbonyl
Compounds to Terminal Alkynes
Thorsten M. Beck and Bernhard Breit*
̈
̈
Institut fur Organische Chemie, Albert-Ludwigs-Universitat Freiburg, Albertstr. 21, 79104 Freiburg im Breisgau, Germany
*
S Supporting Information
ABSTRACT: A new method for the rhodium-catalyzed regioselective C−C bond formation using terminal alkynes and 1,3-
dicarbonyl compounds to achieve valuable branched α-allylated 1,3-dicarbonyl products is reported. With a Rh(I)/DPEphos/
p‑CF -benzoic acid as the catalyst system, the desired products can be obtained in good to excellent yields and with perfect
3
regioselectivity. A broad range of functional groups were tolerated, and first experimental insights of a plausible reaction
mechanism were obtained.
ecently, we reported on a series of rhodium-catalyzed
Scheme 1. Proposed Pathway for Carbon−Carbon Bond
1
R
addition of different pronucleophiles to allenes and
Formation from Terminal Alkynes
2
terminal alkynes, which can be regarded as an atom economic
alternative to the transition metal-catalyzed allylic substitu-
3
−7
8,9
tion and the palladium-catalyzed allylic oxidation. Although
1
0
terminal allenes displayed in many cases higher reactivity, the
11
isomeric terminal alkynes are much easier accessible substrates
and thus synthetically more appealing starting materials.
Unfortunately, the reactivity of terminal alkynes is so far
restricted to the additions of carboxylic acids furnishing allylic
Table 1. Ligand Screening and Optimizations
2a,c
esters (C−O bond formation) as well as to the addition of
sulfonylhydrazides furnishing allylic sulfones (C−S bond
2
b
formation).
However, the addition of carbon nucleophiles would be
synthetically very attractive since this allows for further carbon
skeleton extension. Mechanistic investigations indicated that the
reaction of terminal alkynes and carboxylic acids proceed via a
σ‑allyl rhodium complex as the resting state. We speculated
that a suitable carbon nucleophile such as a 1,3-dicarbonyl
species could serve to trap this σ-allyl complex by a C−C bond
formation.
We herein report on the successful realization of this concept
achieving a regioselective rhodium-catalyzed addition of 1,3-
dicarbonyl compounds to terminal alkynes as an efficient method
for the formation of valuable branched α-allylated 1,3-dicarbonyl
compounds (Scheme 1).
a
entry
Ar
x (mol %)
yield (%)
12
1
2
3
Ph
Ph
100
0
64
traces
93
p-CF C H
4
100
3
6
b
4
p-CF C H
4
50
97
3
6
a
b
Isolated yield of the branched product 4. Reaction performed in
DCE/EtOH (5:1).
8
1
0 °C led to the desired branched product 4 in 64% yield (Table
, entry 1). In the absence of benzoic acid, only traces of product
could be observed (entry 2) demonstrating its importance for the
title reaction. Studying different para substituted benzoic acid
Our studies emanated by employing 1-dodecyne (1, 2.0 equiv)
1
3
and acetylacetone (2, 1.0 equiv) as model system (Table 1).
14
After first reactivity assays we were pleased to find that applying
Rh(COD)Cl] (2.5 mol %) and DPEphos (3, 7.5 mol %) as
[
Received: November 26, 2015
2
catalyst and benzoic acid (100 mol %) as an additive in DCE at
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b03391
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
derivatives revealed that p-CF C H CO H was most effective,
Scheme 3. Scope of 1,3-Dicarbonyl Compounds with 1-
3
6
4
2
leading to 93% yield of 4 (entry 3). Also the solvent plays an
important role in this reaction. An optimized solvent mixture of
DCE and ethanol (5:1) allowed to reduce the amount of p-
CF C H CO H to 50 mol %, still providing the highest yield
Dodecyne (1)
3
6
4
2
(
entry 4). In all cases the branched allylic addition product was
the only regioisomer that could be observed.
With these optimized conditions in hand we next explored the
scope of alkynes. A large number of commercially available or
easily accessible terminal alkynes were suitable substrates for the
reaction and afforded exclusively branched products in good to
excellent yields (Scheme 2). Additionally, linear alkyl-, aliphatic
Scheme 2. Scope of Alkynes with Acetylacetone (2)
a
b
Reaction was carried out over 66 h. The diastereomeric ratio (dr)
1
was determined by H NMR analysis.
methane led to 8 in 92% yield. Also, with benzoyl acetone, high
yields of 9 (97%, 1:1.2 dr) were obtained.
Varying the pattern of functional groups on the aryl moiety of
bisbenzoyl methane was possible and furnished the desired
addition products in mostly good yields. Furthermore, the
heterocyclic bisthiophenoyl propane-1,3-dione could be applied
to yield 19 in 96% yield.
The resulting α-allylated 1,3-dicarbonyl compounds are useful
starting materials for heterocycle synthesis of medicinal
15,16
interest.
Hence, reaction of 4a with hydroxylamine led to
the oxazole 20. Correspondingly, reaction with hydrazine and
phenylhydrazine furnished the pyrazoles 21 and 22, respectively,
in good to excellent yields (Scheme 4). Pyrazoles are suitable
substrates for a further functionalization by rhodium-catalyzed
a
This reaction was additionally performed in a 5 mmol scale and gave
a in 95% isolated yield. All yields are isolated yields.
b
4
1
j
N-allylation with allenes developed in our laboratories.
Subjection of the α-allylated 1,3-dicarbonyl compounds to
ethanolic potassium hydroxide solution initiated a deacetylation
resulting in the formation of γ,δ-unsaturated ketones in
quantitative yield (Scheme 4). This facile access to γ,δ‑unsatu-
rated methyl ketones represents a synthetic alternative to an
enolate allylation reaction or a Claisen/Carroll-type rearrange-
cyclic-, phenyl-, and linear ω-substituted alkynes were applicable.
To our delight even prehalogenated alkynes were tolerated well
(
4j, 4k), and additionally, several other functional groups such as
a cyano substituent (4l), a phthalimidoyl function (4m), and a
thioether function(4n) were compatible. Also substrates with
protecting groups for hydroxy functions, including silyl ether
17
ment.
Furthermore, treatment of either chlorine or silylether
functionalized substrates 4j and 4r under basic or acidic
conditions, respectively, led to the formation of the dihydropyran
(
4q−4s), trityl ether (4t), benzyl ether (4u), and benzoate
functions (4v) behaved well. Even the presence of a hydroxy
18
group was well tolerated (4w).
system 24 in good yields (Scheme 4).
Next, the reaction could be applied to a variety of 1,3-
diketones (Scheme 3). The reaction of heptane-3,5-dione with 1-
dodecyne (1) led to the branched product 5 with an excellent
yield of 98% (Scheme 3), albeit yields dropped for sterically more
congested derivatives. The addition of the symmetric bisbenzoyl
In order to attain first insights into the reaction mechanism,
the following control experiments were performed. Subjecting
the allylic benzoic ester 25 to the reaction conditions furnished
4a, the product of an allylic substitution reaction. This indicates
that 25 might be an intermediate during the course of this
B
DOI: 10.1021/acs.orglett.5b03391
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 4. Applications in the Synthesis of Trisubstituted
Oxazoles, Tri- or Tetra-Substituted Pyrazoles, Deacetylation,
and Cyclization
Scheme 6. Proposed Catalytic Cycle
the allylic ester B. Anion exchange of C with acetylacetone would
provide allyl complex D. Reductive elimination from D would
release the allylic addition product E.
To conclude, starting from simple terminal alkynes and
,3‑dicarbonyls we have developed a highly regioselective
1
rhodium-catalyzed C−C bond forming reaction furnishing
valuable branched α-allylated 1,3-dicarbonyl compounds in
good to excellent yields. The utility of the obtained products
was demonstrated through one step transformations to
heterocyclic systems of medicinal interest. Furthermore,
hydroxide mediated deacetylation provided products of a formal
methylketone enolate allylation or Claisen/Carroll-type rear-
rangement. Further attempts regarding extensions of this
method to the formation of quaternary centers, other
reaction (Scheme 5). However, from our previous mechanistic
studies on the rhodium-catalyzed addition of benzoic acid to
Scheme 5. Control Experiments
(
carbon-) nucleophiles as well as the development of an
asymmetric variant are ongoing in our laboratories.
ASSOCIATED CONTENT
Supporting Information
■
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.5b03391.
Experimental procedures and analytical data for synthe-
sized alkynes, diarylpropane-1,3-diones, and α-allylated
1
13
1
,3-dicarbonyl compounds, including H NMR and C
NMR (PDF)
AUTHOR INFORMATION
Corresponding Author
terminal alkynes furnishing branched allylic benzoates, it is
known that allylic esters can undergo reaction with the rhodium
catalyst to furnish σ-allyl rhodium complex 26, which has been
isolated previously representing the resting state of the catalyst.
Hence, to clarify whether the σ-allyl rhodium complex 26 is an
intermediate in the reaction with acetylacetone as a nucleophile,
a stoichiometric reaction with the preformed rhodium complex
■
*E-mail: bernhard.breit@chemie.uni-freiburg.de.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
2
6 was monitored in an NMR experiment. Indeed, formation of
We thank DFG (Deutsche Forschungsgemeinschaft) for
generous support of our program. Anne Aßmann (University
Freiburg) is acknowledged for technical support.
the allylic addition product 4a could be observed suggesting the
rhodium complex 26 to be an intermediate of the catalytic cycle.
Additionally, isotope-labeling experiments with deuterated
substrate showed deuterium incorporation in all positions of
REFERENCES
19
■
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DOI: 10.1021/acs.orglett.5b03391
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DOI: 10.1021/acs.orglett.5b03391
Org. Lett. XXXX, XXX, XXX−XXX