One-Pot Alkynylation of Azaaryl Aldehydes and Spontaneous Base-Free Rearrangement into Enone Esters: an Autoinductive Mechanism

Article abstract of DOI:10.1002/ejoc.201701566

A direct synthesis of γ-oxo-α,β-unsaturated esters has been developed. When heteroaromatic aldehydes are reacted with deprotonated ethyl propiolate, in the presence of Me₂Zn or BuLi, the newly formed propargylic alcohol rearranged spontaneously to give the corresponding unsaturated keto ester. Isotope labeling, allenol intermediate trapping and crossover experiments provided insight into the reactive sequence and suggest an autocatalytic mechanism.

Full text of DOI:10.1002/ejoc.201701566

A Journal of
Accepted Article
Title: One-pot Alkynylation of Azaaryl Aldehydes and Spontaneous
Base free Rearrangement into Enone Esters: an Autoinductive
Mechanism
Authors: Bora Sieng, Matias Funes-Maldonado, Carlo Romagnoli, and
Mohamed Amedjkouh
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201701566
Link to VoR: http://dx.doi.org/10.1002/ejoc.201701566
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10.1002/ejoc.201701566
European Journal of Organic Chemistry
COMMUNICATION
One-pot Alkynylation of Azaaryl Aldehydes and Spontaneous
Base free Rearrangement into Enone Esters: an Autoinductive
Mechanism
Bora Sieng, Matias Funes Maldonado, Carlo Romagnoli and Mohamed Amedjkouh*[a]
Abstract: A direct synthesis of γ-oxo-α,β-unsaturated esters has
been developed. When heteroaromatic aldehydes are reacted with
deprotonated ethyl propiolate, in the presence of Me2Zn or BuLi, the
newly formed propargylic alcohol rearranged spontaneously to give
the corresponding unsaturated keto-ester. Isotope labeling, allenol
intermediate trapping and crossover experiments provided insight
into the reactive sequence and suggest an autocatalytic mechanism.
The same rearrangement has been observed on propargylic
alcohols bearing a CF3 group on the alkyne.[27-28] Many other
methods involving the use of transition metals such as Pd, Ru,
Rh, Ir have been developed for the isomerization of propargylic
alcohols to enones.[29-33] All these methods require first forming
and isolating the propargylic alcohol and then submitting it to the
rearrangement conditions. However, in 2006, Wang et al.
developed
a one pot alkynylation-isomerization-alkynylation
sequence for coupling aldehydes and alkynes without
a
transition metal catalyst for the synthesis of 1-en-4-yn-3-ols.[34]
The reaction was promoted by KOtBu and provided a rapid
access to (E)-1-en-4-yn-3-ol and (Z)-2-en-4-yn-1-ol compounds.
However, the reaction was limited to substituted phenyl
acetylenes. Moreover, the synthesis of heterocyclic chalcones
Introduction
Chiral propargylic alcohols are important and versatile synthetic
intermediates. They can be converted to a wide variety of
chemical functions.[1-7] Sato reported the first synthesis of
enantiopure alkynyl alcohol by adding lithium trimethylsilyl
acetylene in the presence of a chiral amino-alcohol.[8] Later, Soai
described the use of zinc-alkynyl complexes to access
enantioenriched propargylic alcohols.[9] Thereafter, several
has
been
accomplished
from
pyridine-2-carbaldehyde
derivatives, secondary amines, and alkynes with CuNPs/C as
catalyst.[35-36]
ligands have been used successfully for this reaction.[2-3,
10-15]
O
O
CO2Et
O
N
N
N
OH
Me2Zn
N
The presence of different functional groups allows rapid
diversification and large libraries of compounds can be prepared
from this type of intermediates. They can also undergo
cycloadditions with various substrates to yield complex
structures.[[16-17]] Propargylic alcohols can undergo isomerization
to provide α,β-unsaturated carbonyl compounds. Such
compounds represent a valuable and versatile class of synthetic
intermediates in organic synthesis.
+
CO2Et
CO2Et
H
+
E-1
Z-1
1 : 2.2
30%
Scheme 1. Spontaneous redox isomerization.
We have recently reported on the use of the Soai’s autocatalyst
in the asymmetric alkynylation of azaaryl aldehydes with various
zinc acetylinides.[37-39] During our investigations, an interesting
rearrangement was observed with electron deficient alkynes
under the same reaction conditions, which gave rise to
The isomerization process can occur through the Meyer-
Schuster and Rupe rearrangement, in which a 1,3- or 1,2-shift of
the hydroxyl group of the propargylic alcohol takes place, which
usually require harsh acidic conditions.[18-19] Secondary
propargylic alcohols, in particular, can also isomerize into α,β-
unsaturated carbonyl compounds through a redox isomerization.
The first example of such an isomerization was reported by
Nineham and Raphael in 1949, at high temperatures in the
presence of Et3N.[20] Since then, other bases such as DABCO,
KOH or NaHCO3 have also been used in this reaction, promoting
the rearrangement of secondary propargylic alcohols into
enones.[21-26] It is assumed that such rearrangement occurs via
an allene intermediate.
heteroaromatic
enone.
Such
isomerization
occurred
spontaneously in situ without the addition of any base or
transition metal. Herein, we report our preliminary mechanistic
study of the direct formation of γ-oxo-α,β-unsaturated ester from
heteroaromatic aldehydes.
Results and Discussion
When pyridine-2-carboxaldehyde was treated with the zinc anion
of ethyl propiolate in the presence of an amino-alcohol, the
expected propargylic alcohol was not obtained. Instead, the γ-
oxo-α,β-unsaturated ester 1 was isolated in 30% yield (Scheme
1). Notably, both Me2Zn and n-BuLi can be used for the
generation of the acetylinides. In some cases, this operation is
simplified by n-BuLi providing cleaner reactions and shorter
reaction times. However, in contrast to previously reported
examples we noticed that in our case the use of a base was not
[a]
Prof. Dr. M. Amedjkouh, Dr. B. Sieng, M. Funes Maldonado, Carlo
Romagnoli
Department of Chemistry
University of Oslo
Postboks 1033 Blindern 0315 OSLO Norge
Fax: (+)
E-mail: mamou@kjemi.uio.no
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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10.1002/ejoc.201701566
European Journal of Organic Chemistry
COMMUNICATION
required, although a catalytic amount of aminoalcohol is used to
activate Me2Zn, but only for the alkynylation step. Thus, various
azaaryl aldehydes were considered to explore the scope of this
rearrangement (Table 1).
reaction with smaller size ring suggests that the presence of an
available lone pair on the nitrogen atom, acting as a base, is
crucial for the rearrangement. Indeed, pyrrole derivative turned
the rearrangement off (entry 3). While 1-methyl-1H-imidazole-2-
carboxaldehyde generated only the rearranged product 5,
although in low yield, no alkynol was observed (entry 4). The
isomerization did not proceed with thiazole-5-carboxaldehyde,
and stopped at the propargylic alcohol (entry 6), whereas the
reaction with its regio-isomer thiazole-2-carboxaldehyde gave
the keto-ester 6 (entry 5). Again, in absence of a nitrogen, no
rearrangement was observed with thiophene-2-carboxaldehyde
(entry 7). All together these observations confirm the role of the
nature of aldehyde, but also the position of the nitrogen atom in
the azaaryl ring (table 1, entries 1 and 6). Among other
aldehydes with N-substituent, in the reaction of electron-poor 4-
nitrobenzaldehyde rearrangement product 9 was isolated in 28%
yield (entry 8), alongside unidentified by-products. The reaction
with electron-rich 4-dimethylamino-benzaldehyde, showed no
sign of rearrangement (entry 9). While the reduced availability of
the lone pair for NMe2, delocalized in the benzene ring, may
account for the absence of isomerization, the strong withdrawing
NO2 may lead to increased acidity of the propargylic C-H, prone
for isomerisation.
Table 1. Scope of direct alkynylation-isomerization.
OH
O
n-BuLi
+
R
CHO
or
CO2Et
R
R
CO2Et
THF, -78 o
C
CO2Et
Entry Aldehyde
Product
Yield
%
[a]
OH
N
1
68
53
85
CO2Et
2
O
CO2Et
2
3
4
5
6
7
N
3
OH
N
CO2Et
4
Table 2. Effect of alkyne structure on direct isomerization of alkynols.
O
CO2Et
Entry
1
Aldehyde
Alkyne
Product Yield %
N
17
N
OH
5
O
CO2Et
N
Ph
S
S
S
11, 89%
17[b]
N
OH
6
TMS
2
3
OH
N
TMS
12, 73%
53
N
CO2Et
O
7
OTHP
OTHP
OH
N
13, 71%
63
CO2Et
8
Other alkynes were examined under the standard conditions
with pyridine-4-carboxaldehyde, which gave cleaner reactions
than the 2-pyridine aldehyde (Table 2). No rearrangement was
observed using phenyl acetylene and TMS-acetylene. However,
compound 11 was unstable and decomposed after a few hours
into unidentified compounds. Remarkably, the THP-protected
propargyl alcohol rearranged in-situ into the corresponding
enone 13.
O
CO2Et
8
9
28
83
O2N
9
OH
Work up conditions were also an important factor. Acccording to
literature the rearrangement is Z-selective and hardly detectable
by NMR analysis. The Z-isomer is prone to rapid isomerization
CO2Et
Me2N
10
[a] Isolated yields. [b] NMR yield.
into
a
thermodynamically favored E-isomer at elevated
temperature in presence of base. We anticipated that keeping a
basic environment during the work-up would trap the kinetic
product, the first formed isomer (Table 3). Under a mild alkaline
environment (entry 1) the Z-enone was isolated as the major
isomer. However, work up at lower pH favored the E-enone up
When pyridine-3-carboxaldehyde was subjected to the reaction
conditions, the propargylic alcohol 2 was the only product
isolated (entry 1). The pyridine-4-carboxaldehyde gave the
unsaturated keto-ester 3 as the sole product (entry 2). The
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10.1002/ejoc.201701566
European Journal of Organic Chemistry
COMMUNICATION
to 2:1 ratio, suggesting an isomerization of Z to E under acidic
conditions.
was added. The only product isolated was identified as the b-
diketone 20, which can only be attributed to the aldol reaction
between the allenolate intermediate 18 and the pyridine-2-
carboxaldehyde in excess as second portion. Aldol adduct 19
was not isolated suggesting subsequent rearrangement
immediately after the addition of the allenolate onto the aldehyde.
We should also point that the trapping experiment was
unsuccesfull with benzaldehyde.
Table 3. Effect of acid/base media on the Z:E ratio of the formed product.
OZnMe
O
N
N
OH
N
H
CO2Et
+
CO2Et
O
Me2ZN, toluene
quench
O
CO2Et
N
N
CO2Et
+
E-1
Z-1
OH
O
O
O
O
Me2N
ZnMe2
N
N
N
H(D)
CO2Et
+
toluene
N
CO2Et
Entry
Proton source
Sat. NaHCO3 aq.
H2O
Z:E Ratioa
82/18
then
20 (39%)
D(H)
1
2
3
4
50/50
O
(D)H
OZnMe
C
O
O
OH
N
N
N
N
1N HClaq.
35/65
N
H(D)
(D)H
4N HCl in dioxane
33/67
CO2Et
CO2Et
84 %
40 %
(D)H
CO2Et
(D)H
22
18
19 (H) Not observed
21(D) unstable
a NMR ratio on crude mixture
Scheme 2. Evidence of a zinc allenoate and Deuterium-labelling experiment.
Two different mechanisms have been proposed for this
reaction. Isomerization of the propargylic alcohol 14, through a
1,3-hydride shift leading to an allenol, has been invoked to
account for this transformation. (Figure 1, a).[34] Later the same
year, Koide proposed another mechanism which starts with the
deprotonation of alcohol 15 (Figure 1, b).[22,23] The cumulene
intermediate can be formed by resonance and is reprotonated at
the terminal site to give the allene. Subsequently, a final allenol-
enone tautomer exchange gives the unsaturated keto-ester 17.
To gain further insight into the mechanism of this sequence
of rearrangements, the same reaction was implemented starting
from deuterated aldehyde. The D-pyridine-2-carboxaldehyde
was prepared in two steps from ethyl picolinate and subjected to
identical reaction conditions. The corresponding aldol adduct 21
was formed with different degrees of deuterium incorporation at
the α and β positions with respect to the aldol group. Gratefully,
the presence of the deuterium retarded the second
rearrangement by virtue of a primary isotope effect, and we were
able to isolate the product of the aldol reaction 21, after flash
chromatography, before rearranging into labeled b-diketone 22
(Scheme 2). Finally, compound 20 was isolated.
OH
O
H
HO
R1
C
a)
b)
Ph
H
R1
R1
Ph
Ph
16
14
R
O
H
Base
OMe
H
Base
H
HO
R1
H
O
H
O
HO
R1
OMe
C
R1
C
C
Base
CO2Et
R1
O
(D)H Base
OM
CO2Me
MO
OM
D
3
17
15
O
3
N
N
N
2
4
C
C
D
C
OEt
OEt
C
2
2
1
CO2Et
25
Figure 1. Mechanisms proposed by Wang and Koide.
O
O
23
24
O
D
N
Here, a direct application of Koide’s mechanism shows some
limitations in absence of additional amine in our system. In
contrast, Biellman et al. reported that catalytic amounts of
pyridine hydrochloride promoted isomerization of pyridine
alkynol by ring activation at C-2 and C-4.[40-41] Consequently, in
our case, it is reasonable to envision two molecules of
propargylic alcohols bearing a pyridine ring reacting with each
other, one acting as the base to effect the isomerization, making
the process autocatalytic. To identify some of the intermediates
of the reaction pathway, the following reaction was visualized
aiming at trapping the allenolate intermediate (Scheme 2):
pyridine-2-carboxaldehyde was let to react with dimethylzinc and
ethyl propiolate under standard conditions and analytical
samples monitored the progress of the reaction. After complete
reaction of starting materials, a second equivalent of aldehyde
Base H(D)
Base
N
O-
O
OM
O
D
OM
D
OH
N
N
N
N
N
C
3
C2
EtO2C
Not observed
D
D
OEt
OEt
O
O
21-M
21 Instable
O
O
O
OH
O
O
N
N
N
N
N
N
(H)D
(H)D CO2Et
D
CO2Et
Work up
OEt
O
20
Base H(D)
Scheme 3. Proposed mechanism for a two step rearrangement.
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10.1002/ejoc.201701566
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COMMUNICATION
O
O
OH
O
Ehtyl propiolate
n-BuLi
On the basis of the results described in scheme 2, we
postulate a mechanism for the sequential rearrangement from
alkynol to product 20 (Scheme 3). The pyridine within the
product abstracts 4-H from 23 affording cumulene 24, which is
protonated at C2 by reaction with the protonated base to form
allenoate (D)-25. This is supported by the observed deuterium at
this position and the mechanism here is consistent with that
suggested previously by Koide. In the following step, the
formation of aldol compound (D)-21 confirmed reaction of
aldehyde with the intermediate (D)-25 at C3. These results also
rule out any aldol reaction of cumulene 24 at C2 with aldehyde.
The second rearrangement occurs after work up presumably
through the deprotonation of (D)-21 at the picolinic position
facilitated by resonance with the pyridine ring.
H
H
CO2Et
+
+
THF
-78 °C
N
CO2Et
N
26
3
Scheme 4. Cross-over reaction with benzaldehyde.
Conclusions
In summary, we have shown that the alkynylation of azaaryl
aldehydes with ethyl propiolate generated propargylic alcohols
which isomerized spontaneously into corresponding enones. We
have gained significant mechanistic insight based on isotope
labeling and were able to provide evidence for the putative
allenolate intermediate by trapping it in an aldol-type reaction.
The presence of the base within the alkynol product is crucial for
the rearrangement, making the process autocatalytic. The
conceptual novelty of this work could be integrated as a key step
in related synthetic applications.
Abstraction of 4-H may also be effected by Me2Zn or BuLi.
However, this probability is ruled out on the basis of the
observations made in scheme 2 and 3. Such transfer of
deuterium atom from C4 to C2 would not be possible in such an
irreversible process with
a carbon base. To probe the
autocatalytic mechanism a crossover reaction was devised. If
this hypothesis is correct and the pyridine ring within the alkynol
is the base, the isomerization may occur preferentially with
resulting pyridine propargylic alcohol. Thus, an equimolar
mixture of pyridine-4-carboxaldehyde and benzaldehyde was
treated with an excess of nucleophilic ethyl propiolate. In
Experimental Section
See supporting information.
contrast
to
pyridine-2-carboxaldehyde,
pyridine-4-
Acknowledgements
carboxaldehyde has a more exposed N-atom and can act as a
base by itself, but also in the product by preventing an
intramolecular coordination in the metallated alkylol. Surprisingly,
we isolated (E)-enone 3 derived from pyridine-4-carboxaldehyde
along with unmodified alkynol 26 (Scheme 4). This indicates that
the pyridine in neither the aldehyde nor the alkynol/enone is able
to effect the deprotonation of 26. Again, remaining BuLi if any
did not initiate isomerization of 26. Thus, the absence of
This work was supported by the Research Council of Norway
(FRIPRO grant 205271), the University of Oslo, and COST
Action “Emergence and Evolution of Complex Chemical
Systems” (CM 1304).
Keywords: Alkyne addition • Raphael isomerisation • Enone
isomerization with 26 is consistent with
a
self-induced
esters • Rearrangement • Synthetic methods.
isomerization into enone 3 presumably by formation of a homo-
complex of pyridine-alkynols.
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European Journal of Organic Chemistry
COMMUNICATION
Spontaneous Raphael
rearrangement*
Bora Sieng, Matias Funes Maldonado,
Carlo Romagnoli and Mohamed
Amedjkouh *
Page No. – Page No.
O
CO2Et
Self-induced
isomerization
OH
N
CHO
CO2Et
Me2Zn
or
nBuLi
N
N
One-pot Alkynylation of Azaaryl
Aldehydes and Spontaneous Base
free Rearrangement into Enone
Esters: an Autoinductive Mechanism
CO2Et
(No base)
Azaaryls
Z or E
Spontaneous rearrangement of heteroaromatic alkynols into enones involving an
autocatalytic mechanism.
*one or two words that highlight the emphasis of the paper or the field of the study
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