CpTiCl2-Catalyzed Cross-Coupling between Internal Alkynes and Ketones: A Novel Concept in the Synthesis of Halogenated, Conjugated Dienes

Article abstract of DOI:10.1002/chem.202001023

A novel concept for the synthesis of halogenated, conjugated dienes is disclosed: the CpTiCl₂-catalyzed coupling of keto-alkynes, in the presence of Me₃SiBr/Et₃N?HBr. This reaction provided five-, six-, and seven-membered

Full text of DOI:10.1002/chem.202001023

A Journal of
Accepted Article
Title: CpTiCl2-Catalyzed Cross-Coupling between Internal Alkynes
and Ketones: a Novel Concept in the Synthesis of Halogenated,
Conjugated Dienes.
Authors: Esther Roldan-Molina, Maria M. Nievas, Jorge A. R. Navarro,
and Juan Enrique Oltra
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To be cited as: Chem. Eur. J. 10.1002/chem.202001023
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CpTiCl2-Catalyzed Cross-Coupling between Internal Alkynes and
Ketones: a Novel Concept in the Synthesis of Halogenated,
Conjugated Dienes.
Esther Roldan-Molina,[a] Maria M. Nievas,[a] Jorge A. R. Navarro,*[b] and J. Enrique Oltra*[a]
[a]
Dr. Esther Roldan-Molina, Maria M. Nievas and Prof. J. Enrique Oltra.
Department of Organic Chemistry
Faculty of Sciences, University of Granada
Campus Fuentenueva s/n, E-18071, Granada, Spain
E-mail: joltra@ugr.es
[b]
Prof. Jorge A. R. Navarro.
Department of Inorganic Chemistry
Campus Fuentenueva s/n, E-18071, Granada, Spain
E-mail: jarn@ugr.es
Supporting information for this article is given via a link at the end of the document.
Abstract: A novel concept for the synthesis of halogenated,
conjugated dienes is disclosed: the CpTiCl2-catalyzed coupling of
keto-alkynes, in the presence of Me3SiBr/Et3N·HBr. This reaction
provided five-, six- and seven-membered carbocycles, nitrogenated
heterocycles, as well as six-membered oxygenated heterocycles
leading to a brominated conjugate diene. These products showed
highly reactivity in Diels-Alder, Suzuki and Sonogashira reactions,
giving complex chemical structures in only three steps from the
corresponding acyclic keto-alkyne. We believe that this strategy
paves the way towards the synthesis of bioactive natural products
and new materials.
complex CpTiCl2,9 which constitutes a novel concept for the
straightforward synthesis of halogenated, conjugated dienes.
This procedure gives conjugated dienes on carbocycles and
heterocycles of five, six and seven-membered rings with good
yields. In addition, we also confirm the synthetic utility of this
kind of compounds in Diels-Alder cycloadditions, Suzuki and
Sonogashira cross-coupling reactions.
Results and Discussion
Model keto-alkyne 1 was chosen to optimize the reaction
conditions.10 Thus, treatment of 1 with a substoichiometric
amount of CpTiIIICl2 (10 mol%, generated in situ by stirring
commercial CpTiIVCl3 with Mn dust under inert atmosphere) and
the combination Me3SiBr/Et3N·HBr, gave an 85% yield of the
brominated conjugated diene 2 (Scheme 1).
Introduction
Conjugated dienes are fundamental building blocks in organic
synthesis. In front of dienophiles they undergo the venerable
Diels-Alder cycloaddition,1 one of the most powerful reactions for
the synthesis of complex molecules, including bioactive natural
products,2 such as (-)-vinigrol,3 (±)-pestalachloride C,4 (+)-
dimericbiscognienyne A5 and bolivianine (Figure 1). 2f,6
Scheme 1. CpTiCl2-catalyzed cyclization of keto-alkyne 1.
Under the same conditions, ketones 3-12 generate brominated
conjugated dienes 2, 13-21 (Table 1). Results summarized in
entries 1-5 (Table 1) confirmed the usefulness of the method for
the synthesis of brominated conjugated dienes on carbocycles
with five-, six- and seven-membered rings in yields ranging from
52% to 84%. The synthesis of conjugated cycloheptene 16 is
noteworthy, despite of the moderate yield, due to that seven-
membered rings are not generally favoured by thermodynamic
factors.11
Conjugated pyrroline 17 and tetrahydropyridine 18 were
obtained with 75% and 80% yields respectively (Table 1, entries
6-7). Afterwards, CpTiCl2-catalyzed cyclization of keto-alkyne 10
gave tetrahydroazepine 19 (Table 1, entry 8), confirming that the
method is capable to generate halogenated, conjugated dienes
on nitrogenated heterocycles.
Figure 1. Chemical structure of (-)-vinigrol, (±)-pestalachloride C, (+)-
dimericbiscognienyne A and bolivianine.
Moreover, halogenated conjugated dienes may be even more
useful in organic synthesis because they can undergo efficient
C-C bond forming reactions, such as Suzuki cross-coupling
reaction (awarded with the Nobel Prize in Chemistry 2010),7
Sonogashira-type reactions and others. Nevertheless, these
conjugated dienes are, in general, not easy to obtain by other
procedures8 and, therefore, the development of new methods for
preparing them is desirable.
Finally, cyclization of keto-alkynes 11 and 12 provided
conjugated dihydropirane 20 and benzopirane 21, whose
In this report, we present the intramolecular cross-coupling
between alkynes and ketones catalyzed by the half-sandwich
1
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chemical structure is closely related to coumarins with a pendant
conjugated double bond (Table 1, entries 9-10). It should be
noted that in all cases only brominated, conjugated dienes were
obtained, regardless of the halogen atom on the starting keto-
alkyne.
Mechanistic Studies.
Once we were confident on the utility of this unprecedented
reaction, we wonder about the potential mechanism allowing the
direct generation of brominated, conjugated dienes from keto-
alkynes, catalyzed by CpTiCl2. To explore this mechanism, the
cyclization of keto-alkyne 4 by a stoichiometric amount of
CpTiCl2 was carried out in order to simplify the mechanistic
study (Scheme 2).
Table 1. Cyclizations of keto-alkynes 3-12 catalyzed by CpTiCl2.[a]
Scheme 2. Synthesis of α-hydroxyallene 22 using stoichiometric amounts of
CpTiCl2.
Surprisingly, under the experimental conditions summarized in
Scheme 2, the α-hydroxyallene 22 was obtained instead of any
conjugated diene. This result suggested that α-hydroxyallenes
might be intermediates in the way towards halogenated,
conjugated dienes.
To check this possibility, 22 was treated with Me3SiBr, Et3N·HBr
and the combination of Me3SiBr/Et3N·HBr. Results in Table 2
indicated that only the combination Me3SiBr/Et3N·HBr was able
to provide the expected conjugated diene 13, supporting that
conjugated dienes proceed from α-hydroxyallenes intermediates.
Table 2. Conversion of α-hydroxyallene 22 in the diene 13 under different
conditions.[a]
Entry
Reagent
Me3SiBr (3 equiv)
Results[%][b]
13 [trace]
1
2
3
Et3N·HBr (2 equiv)
22 [100%]
13 [90%]
Me3SiBr (3 equiv)/ Et3N·HBr (2 equiv)
[a] Experimental conditions: CH2Cl2 as solvent for 6 h under Ar atmosphere at
room temperature. [b] Yields determined by 1H-NMR spectroscopy.
CpTiCl2-catalyzed intermolecular cross-coupling between
ketones and alkynes was previously reported.9d This process
generated homopropargylic alcohols and the role of Me3SiBr as
the titanocene-regenerating agent was proved. Taking into
account this precedent and results summarized in Table 2, the
following hypothetical catalytic cycle is proposed to explain the
formation of brominated, conjugated dienes (Scheme 3).
CpTiIIICl2 is generated in situ by stirring commercial CpTiIVCl3
with Mn dust. Then, CpTiIIICl2 abstracts the halogen atom from
keto-alkyne I generating the propargyl-TiIV complex II.12 The
intramolecular nucleophilic attack to the carbonyl group gives
alcoxy-TiIV intermediate III, forming a new C-C bond which
closes the ring depicted in III. Me3SiBr regenerates the
CpTiIVBrCl2 species and originates the silylated allene IV.
Afterwards, IV undergo a nucleophilic attack by the Br− of the
triethylammonium bromide (Et3N·HBr) present in the medium.
This attack promotes the electronic rearrangement that, finally,
originates the brominated conjugated diene V. This hypothetical
mechanism explains not only the presence of the halogen on the
[a] Experimental conditions: CpTiCl3 (10 mol%), Mn dust (2 equiv), Et3N·HBr (2
equiv), Me3SiBr (3 equiv), THF as solvent, 12 h under Ar atmosphere at room
temperature. [b] Yields determined by 1H-NMR spectroscopy.
2
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disubstituted double bond but it would also justify the reason
why it is always a brominated product regardless of the type of
substrate employed, because Et3N·HBr is the source of the
halogen atom in the final product V.
Table 3. Diels-Alder cycloaddition of conjugated dienes 2,13,16-19.[a]
Scheme 3. Hypothetical catalytic cycle for CpTiCl2-catalyzed cyclization of
keto-alkynes.
The proposed mechanism in Scheme 3 takes as starting point
the transformation of keto-alkyne 4 in α-hydroxyallene 22
promoted by stoichiometric amounts of CpTiCl2 (Scheme 2).
Nevertheless, catalytic conditions are not the same that
stoichiometric ones. Therefore, keto-alkyne 23 was chosen as
substrate on the basis of the Bredt´s rule, which prevents
formation of a conjugated diene with a double bond placed at
the bridgehead position of a bridged bicyclic system (Scheme
4).13
[a] Experimental conditions: diene (1 equiv), 25 (2 equiv), xylene as solvent for
12 h at reflux under Ar atmosphere. [b] Yields determined by 1H-NMR
spectroscopy. [c] Isolated yield.
Diels-Alder cycloaddition between conjugated diene 2 and
dienophile 25 provided a good 82% yield of cycloadduct 26
(Table 3, entry 1), confirming the usefulness of this process for
the synthesis of bicyclic systems constituted by five- and six-
membered fused rings.
It should be noted that cyanides can be easily transformed into
other functional groups, such as amines, ketones, carboxylic
acids and others.14 Cycloadditions of 13 and 16 with 25 (Table 3,
entries 2-3) gave products 27 (80%) and 28 (81%), extending
the procedure to the synthesis of bicyclic carbocycles containing
six- or six- and seven-membered fused rings.
Scheme 4. Synthesis of the α-hydroxyallene 24.
As expected, treatment of 23 with a catalytic amounts of CpTiCl2
and the combination Me3SiBr/Et3N·HBr gave α-hydroxyallene 24
and no any conjugated diene was detected. This result strongly
supports the catalytic cycle propose in Scheme 3.
Diels-Alder Cycloadditions.
Despite of the Diels-Alder cycloaddition is a well-known process,
the behavior of conjugated dienes supporting a halogen atom
(electron withdrawing group) is not so well-documented. So the
Diels-Alder reaction on halogenated, conjugated dienes 2, 13,
16-19 was explored. The results obtained are summarized in
Table 3.
Synthesis of pyrrolidine 29 (84%), piperidine 30 (75%) and
azepane 31 (81%) from nitrogenated, conjugated dienes 17-19
(Table 3, entries 4-6) suggested that this method could be
employed in the synthesis of some alkaloids.
3
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Suzuki cross-coupling reactions.
of the corresponding products (Table 4, entry 3-4). Treatment of
the six-membered bromodiene 13 with 32 and 33 gave cross-
Suzuki cross-coupling between boronic acids and organohalides, coupling products 40 and 41 with 81% and 66% yields
catalyzed by palladium(0) complexes, generally generates a
new C(sp2)-C(sp2) bond.15 Thus, Suzuki-type reactions between
brominated conjugated dienes 2, 13 and 18 with boronic acids
32-35 gave coupling products 36-42 with yields ranging from
55% to 85% (Table 4).
respectively (Table 4, entries 5-6). Finally, the synthesis of
tetrahydropyridine 42 (80%) demonstrated this method can be
extended to relatively complex nitrogenated rings incorporating
functionalized conjugated dienes (Table 4, entry 7).
Table 4. Suzuki cross-coupling reaction of conjugated dienes 2, 13 and 18
with 32-35.[a]
Scheme 5. Diels-Alder cycloaddition of Suzuki cross-coupling product 40.
Remarkably, coupling products 36-42 conserve the conjugated
diene motif in their structure and, therefore are potential
substrates for the Diels-Alder cycloaddition. In this way,
treatment of Suzuki coupling product 40 with 25 generated the
tricyclic product 43 (81%) (Scheme 5), with a substantial
increase of molecular complexity in only three steps from the
acyclic keto-alkyne 4.
Table 5. Sonogashira cross-coupling reaction of conjugated dienes 2, 13 and
18.[a]
[a] Experimental conditions: diene (1 equiv), terminal alkyne (1.1 equiv),
Pd(PPh3)4 (10 mol%), CuI (0.1 equiv) and a mixture of Et2NH/Et3N (8:1) as
solvent for 12 h, under Ar atmosphere. [b] Yields determined by 1H-NMR
spectroscopy. [c] For double Sonogashira cross-coupling: conjugated diene (1
equiv) and terminal alkyne (2.2 equiv).
[a] Experimental conditions: diene (1 equiv), boronic acid (1.1 equiv),
Pd(PPh3)4 (10 mol%), EtOH, Na2CO3 and benzene as solvent for 6 h at reflux,
under Ar atmosphere and protected from light. [b] Yields determined by 1H-
NMR spectroscopy.
Sonogashira cross-coupling reactions.
As expected, treatment of the five-membered bromodiene 2 with
boronic acids 32-35 provided cross-coupling products 36-39 with
good yields (Table 4, entries 1-4). It should be noted that the
steric hindrance of boronic acids 34 and 35 did not affect yields
The Sonogashira cross-coupling reaction allows the
straightforward formation of a C(sp2)-C(sp) bond.16 This cross-
4
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coupling reaction was assayed under the experimental
conditions summarized in Table 5, using brominated conjugates
dienes 2, 13 and 18 and different terminal alkynes 44-47.
Conflict of interest
The authors declare no conflict of interest.
Keywords: titanium • ketones • alkynes • cross-coupling •
cyclizations
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Figure 2. Chemical structure of Sonogashira cross-coupling products 49-52.
Reaction
between
brominated
diene
13
with
trimethylsilylacetylene (44) furnished silylated, conjugated
dienyne 48 with a 63% yield (Table 5, entry 1). Deprotection of
48, gave terminal alkyne 45 which reacted with 2 to generate the
polyconjugated product 49. Moreover, 45 also reacted with
nitrogenated bromodiene 18 to give product 50 (Table 5, entries
2-3, Figure 2), supporting that the method could be able to
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Sonogashira coupling between 13 and aryldiyne 47 provided
highly conjugated compound 52.
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Conclusion
In summary, CpTiCl2, in the presence of the combination
Me3SiBr/Et3N·HBr, catalyzes the cyclization of keto-alkynes
giving five-, six- and seven-membered carbocycles, nitrogenated
heterocycles, as well as six-membered oxygenated heterocycles
leading a brominated, conjugated diene in their structure. These
brominated dienes have shown highly reactivity in Diels-Alder,
Suzuki and Sonogashira reactions, providing complex chemical
structures in only three steps from the corresponding acyclic
keto-alkyne. This represents a novel concept in the synthesis of
halogenated, conjugated dienes, which might be incorporated in
new synthetic routes towards biologically active molecules and
supramolecular materials. At the moment, we are assaying the
Suzuki and Sonogashira cross-coupling reactions on the
brominated cycloadducts obtained in the present work. The
results will be reported in due date.
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Acknowledgements
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The authors acknowledge the Spanish Government (Project
CTQ2015-70724-R) for financial support. E. R-M also thanks
the Spanish Government for her FPU grant (FPU14/01472).
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Entry for the Table of Contents
Insert graphic for Table of Contents here.
Synthesis of bicyclic product III, from acyclic keto-alkyne I, catalyzed by CpTiIIICl2, followed by a Diels-Alder cycloaddition provided III
in an acceptable overall yield. Ten CpTiIIICl2-catalyzed cyclizations and seven Diels-Alder reactions are reported. Moreover, seven
and five examples of the Suzuki and Sonogashira cross-couplings with halogenated dienes obtained from above cyclizations have
been also described.
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