Regio- and Enantioselective Rhodium-Catalyzed Addition of 1,3-Diketones to Allenes: Construction of Asymmetric Tertiary and Quaternary All Carbon Centers

Article abstract of DOI:10.1002/anie.201610577

An unprecedented highly regio- and enantioselective rhodium-catalyzed addition of 1,3-diketones to terminal and 1,1-disubstituted allenes furnishing asymmetric tertiary and quaternary all-carbon centers is reported. By applying a Rh^I/phosphoramidite/TFA catalytic system under mild conditions, the desired chiral branched α-allylated 1,3-diketones could be obtained in good to excellent yields, with perfect regioselectivity and in high enantioselectivity. The reaction shows a broad functional-group tolerance on both reaction partners highlighting its synthetic potential.

Full text of DOI:10.1002/anie.201610577

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201610577
German Edition: DOI: 10.1002/ange.201610577
Asymmetric Catalysis
Regio- and Enantioselective Rhodium-Catalyzed Addition of
1,3-Diketones to Allenes: Construction of Asymmetric Tertiary and
Quaternary All Carbon Centers
Thorsten M. Beck and Bernhard Breit*
Abstract: An unprecedented highly regio- and enantioselective
rhodium-catalyzed addition of 1,3-diketones to terminal and
1,1-disubstituted allenes furnishing asymmetric tertiary and
quaternary all-carbon centers is reported. By applying a RhI/
phosphoramidite/TFA catalytic system under mild conditions,
the desired chiral branched a-allylated 1,3-diketones could be
obtained in good to excellent yields, with perfect regioselectiv-
ity and in high enantioselectivity. The reaction shows a broad
functional-group tolerance on both reaction partners high-
lighting its synthetic potential.
Scheme 2. Strategies for rhodium-catalyzed construction of a-allylated
1,3-dicarbonyl compounds and b-chiral g,d-unsaturated ketones.
O
ver the past decades enormous progress has been made in
À
À
the field of allylic C heteroatom and C C bond formation.
Of particular synthetic value is the transition-metal-catalyzed
allylic substitution reaction[1–5] and allylic C H oxidation
unsaturated ketones, either after in situ decarboxylation or
after basic saponification. g,d-Unsaturated ketones are
important building blocks in organic synthesis and are
known to have diverse biological properties.[14] However,
[6,7]
À
allowing the construction of complex structures in high
chemo-, regio- and stereoselectivity. However, drawbacks of
these methods are associated with the requirement of pre-
installed leaving groups or the need of stoichiometric amount
of oxidant resulting in a lack of atom-economy.[8]
As an atom-economic alternative, we recently reported on
the rhodium-catalyzed addition of a series of pronucleophiles
to allenes and alkynes furnishing branched allylic products
À
the formation of allylic C C bonds through addition to
allenes or alkynes with control of the absolute stereochem-
istry has been challenging so far.[15]
We herein report on an unprecedented highly regio- and
enantioselective rhodium-catalyzed addition of 1,3-diketones,
which can be viewed as a methyl ketone equivalent, to
terminal and 1,1-disubstituted allenes under mild conditions
to construct tertiary and quaternary all-carbon stereocenters
(Scheme 2, lower part). Furthermore, follow-up chemistry
allows through deacetylation, the synthesis of g,d-unsaturated
ketones, cyclization to a-acetyl-b-vinyl cycloalkanones as well
as the entry into heterocycle synthesis furnishing products in
high enantiopurity, highlighting the synthetic utility of this
method.
À
À
À
À
through C O, C S, C N and C C bond formation
(Scheme 1).[9] Mechanistic studies have revealed that these
Scheme 1. Rhodium-catalyzed addition of pronucleophiles to terminal
and internal alkynes and allenes.
Initial reactions were conducted with 3-phenylpropyl
allene (1) and acetylacetone (2) as model substrates. After
first reactivity assays we were pleased to identify
[Rh(COD)Cl]2 (1.0 mol%) and phosphoramidite ligand (S)-
L1 (3.0 mol%) in presence of TFA (20 mol%) as an acidic co-
catalyst to furnish the desired branched addition product 3a
in 76% yield with remarkable enantioselectivity of 91% ee
(Table 1, entry 1). Notably, diolefin and phosphine-olefin
ligands have recently gained great attention in asymmetric
catalysis.[17,18]
transformations pass a p- and/or s-allyl intermediate which is
subsequently trapped by the corresponding nucleophile.[10]
The first successfully applied class of substrates in our
À
hands to form allylic C C bonds were 1,3-dicarbonyl com-
pounds, such as b-keto acids,[11] b-keto esters and amids[12] and
1,3-diketones[13] using allenes and readily accessible alkynes
(Scheme 2, upper part). All three methods provide g,d-
For a more detailed understanding of the binding mode of
the used phosphoramidite ligand a derivative without olefin
moiety (S)-L2 was prepared and tested (entry 2). By employ-
ing this ligand only 7% yield but still 80% ee were observed,
which suggests the importance of a coordination of the
alkenic moiety in (S)-L1 (entry 2). By varying the ortho/ortho’
substituents on the BINOL skeleton or by semi-hydrogena-
[*] T. M. Beck, Prof. Dr. B. Breit
Institut fꢀr Organische Chemie, Albert-Ludwigs-Universitꢁt Freiburg
Albertstraße 21, 79104 Freiburg (Germany)
E-mail: bernhard.breit@chemie.uni-freiburg.de
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under http://dx.doi.org/10.
1002/anie.201610577.
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Table 1: Ligand screening and optimization of reaction conditions[16]
Table 2: Scope of terminal and 1,1-disubstituted allenes with acetylace-
tone (2) for the formation of tertiary and quaternary carbon centers.
Entry
Ligand
Yield [%][a]
ee [%][b]
1
2
3
4
(S)-L1
(S)-L2
(S)-L3
(S)-L4
(S)-L5
(R)-L6
(R)-L1
76
7
10
41
traces
65
94
91
80
79
82
–
5
6
89
95
7[c]
[a] Isolated yield of the branched product 3a. [b] The enantiomeric excess
(ee) was determined by chiral HPLC. [c] Reaction performed in CH2Cl2 at
room temperature. TFA=trifluoroacetic acid, DME=dimethoxyethane.
tion, neither yield nor enantioselectivity could be further
improved (entries 3–6). Since the solvent had a remarkable
effect on the addition of other 1,3-dicarbonyl compound to
alkynes a solvent screening was carried out.[13,16]
Dichloromethane was identified to work best providing
product 3a in 94% yield with an excellent ee of 95%
concomitant with lowering the reaction temperature to room
temperature for even milder reaction conditions (entry 7). In
all cases the branched allylic addition product was the only
regioisomer that could be detected.
[a] All yields are isolated yields. [b] The enantiomeric excess (ee) was
determined by chiral HPLC. [c] This reaction was performed over 40 h.
[d] This reaction was performed using 1.2 equiv of allene over 4 h.
[e] This reaction was performed over 66 h.
With these optimized mild conditions in hand we first
explored the scope of terminal allenes. Terminal allenes were
rapidly prepared in one or two steps from commercially
available starting materials.[19] The desired branched allylic
nary carbon centers (Table 2, lower part).[20] Remarkable
yields and good to excellent enantioselectivities were
observed for this difficult transformation (3t–3w).
À
C C coupling products were the only observed regioisomers
and could be obtained in mostly good to excellent yields and
enantioselectivity (Table 2).
Next we switched focus on the scope of 1,3-diketones
using 1 as the privileged allene substrate (Table 3). The
reaction of heptane-1,3-dione with allene 1 led to the
branched product 4 with an excellent yield of 89% and
92% ee (Table 3), although yields and ee values dropped for
sterically more congested derivatives (5, 6). The addition of
the symmetric bisbenzoyl methane led to 7 in 90% yield and
88% ee. With non-symmetric benzoyl acetones excellent yield
and ee of 8 (91%, 92% ee, 1:1.1 d.r.) were obtained. Reaction
using a-branched 1,3-diketones provided 9 and 10 with
excellent ee but lower yields. Varying the pattern of functional
groups on the aryl moiety of bisbenzoyl methane was possible
and furnished the desired addition products in mostly good to
excellent yields and enantioselectivity. A methyl substituent
on the aryl moiety is well tolerated in ortho-, meta- and para-
position (11–13). Furthermore, other tolerated functional
groups in para-positions were halogens (F, Cl and Br) as well
as electron-donating (OMe) and electron-withdrawing (CF3)
substituents. At this point, the assignment of the absolute
3-Phenylpropyl-, phenyl- and linear alkyl-substituted
allenes were suitable substrates in the addition reaction
furnishing the corresponding allylic products in excellent
yields and enantioselectivity (Table 2). An exception was
phenyl allene with an only moderate enantioselectivity (3b).
A number of functional groups were well-tolarated such as
nitrile (3h), phthalimidoyl (3i), ester (3i), sulfonyl (3k) and
phenyl ether (3l). Also, substrates with standard protecting
groups for hydroxy functions such as a benzyl ether (3m),
PMB ether (3n), silyl ether (3o) and benzoate (3p) behaved
well. To our delight even allenes containing alkyl chloride and
alkyl bromide side chains reacted smoothly furnishing the
allylation products 3q–3s in high yields and enantioselectiv-
ities.
Even allylation of 1,1-disubstituted allenes could be
achieved allowing for the construction of challenging quater-
2
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Table 3: Scope of 1,3-diketones with allene 1.
Table 4: One pot synthesis of rhodium-catalyzed addition and basic
deacetylation to form g,d-unsaturated ketones.
[a] All yields are isolated yields. [b] The enantiomeric excess (ee) was
determined by chiral HPLC.
[a] All yields are isolated yields. [b] The enantiomeric excess (ee) was
determined by chiral HPLC. [c] This reaction was performed over 66 h.
[d] The diastereomeric ratio (d.r.) was determined by 1H NMR analysis.
configuration could be accomplished by an X-ray crystallo-
graphic analysis of 18.[21] Finally, heterocyclic bisthiophenoyl
propane-1,3-dione and an unsymmetrically substituted bis-
benzoyl methane could be applied to the addition reaction to
yield 19 and 20 in good yield and enantioselectivity.
Subjection of the branched a-allylated 1,3-diketones to an
ethanolic solution of potassium hydroxide, initiated a hydrox-
ide-mediated deacetylation to furnish synthetically valuable
g,d-unsaturated ketones in a one-pot synthesis (Table 4). This
methodology represents an enantioselective synthetic alter-
native to methyl ketone enolate allylation reaction or Claisen/
Carroll-type rearrangement furnishing g,d-unsaturated
ketones with tertiary and quaternary all-carbon stereocenters
in good to high enantiopurity.[22]
The branched a-allylated 1,3-diketones are useful starting
materials for heterocycle synthesis (Scheme 3, upper part).
Condensation with hydroxylamine and hydazines led to the
corresponding oxazole 27 and pyrazoles 28–30 in good to
excellent yields and enantioselectivity. Both, oxazoles and
pyrazoles are of enormous medicinal interest.[23,24]
The intramolecular cyclization of a-allylated 1,3-dike-
tones via enolate alkylation under mild conditions led to the
cycloalkanes 31 and 32 in high yields and enantiopurity
Scheme 3. Application in heterocyclic synthesis and cyclizations:
a) from 3a: NH2OH·HCl (1.5 equiv), HClconc (cat.), EtOH, 808C, 18 h;
b) from 3a: N2H4·HCl (1.5 equiv), HClconc (cat.), EtOH, 808C, 18 h;
c) from 3a: MeN2H3 (1.5 equiv), HClconc (cat.), EtOH, 808C, 18 h;
d) from 3a: PhN2H3 (1.5 equiv), HClconc (cat.), EtOH, 808C, 18 h;
e) from 3r or 3s: Cs2CO3 (3.0 equiv), acetone, 608C, 60 min; f) from
3o: R’=Me: Et2O:TFA (10:1), 408C, 90 min; g) from 3o: R’=Ph:
THF:TFA (10:1), 808C, 2.5 h.
(Scheme 3, lower part). Furthermore, treatment of silylether-
functionalized substrates under acidic conditions led to the
formation of the dihydropyranes 33 and 34 in 90% and 86%
yield under preservation of enantiopurity.[25]
To conclude, we have developed the first atom-economic,
regio- and enantioselective rhodium-catalyzed addition of
1,3-diketones to terminal and 1,1-disubstituted allenes. This
method allows the construction of tertiary and quaternary all-
carbon stereocenters under mild conditions in good to
excellent yields, perfect regioselectivity and high enantiose-
lectivity. Underlining the utility of the obtained products, one-
step transformations to oxazoles and pyrazoles, systems of
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Acknowledgements
This work was supported by the DFG and the Fonds of the
Chemical Industry. We thank Umicore, BASFand Wacker for
generous gifts of chemicals, Dr. Daniel Kratzert for X-ray
crystal structure analysis, Anne Aßmann (University Frei-
burg) for her motivated and skillful technical assistance, and
Jan Wçssner and Johannes Eckert for their help during their
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Conflict of interest
The authors declare no conflict of interest.
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Keywords: 1,3-diketones · allenes · asymmetric catalysis ·
rhodium · g,d-unsaturated ketones
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Manuscript received: October 28, 2016
Final Article published: && &&, &&&&
Angew. Chem. Int. Ed. 2017, 56, 1 – 6
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Asymmetric Catalysis
T. M. Beck, B. Breit*
&&& — &&&
Regio- and Enantioselective Rhodium-
Catalyzed Addition of 1,3-Diketones to
Allenes: Construction of Asymmetric
Tertiary and Quaternary All Carbon
Centers
Rh-Catalysis: A regio- and enantioselec-
tive atom-economic catalytic addition of
1,3-diketones to allenes is reported fur-
nishing tertiary and quaternary all-carbon
stereocenters under mild reaction condi-
tions. The reaction shows a broad func-
tional-group tolerance and numerous
variations on both reaction partners
highlight its synthetic utility.
6
www.angewandte.org
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2017, 56, 1 – 6
These are not the final page numbers!