Iodine-Catalyzed Iso-Nazarov Cyclization of Conjugated Dienals for the Synthesis of 2-Cyclopentenones

Article abstract of DOI:10.1021/acs.orglett.8b03229

Molecular iodine was identified as an efficient catalyst for the cycloisomerization of conjugated dienals to substituted 2-cyclopentenones. DFT calculations suggested an unexpected concerted character for this cyclization.

Full text of DOI:10.1021/acs.orglett.8b03229

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Iodine-Catalyzed Iso-Nazarov Cyclization of Conjugated Dienals for
the Synthesis of 2‑Cyclopentenones
Lucía A. Marsili,† Jorgelina L. Pergomet, Vincent Gandon,*
,¥
†,¥
,‡,§
ticas, Universidad Nacional de Rosario-CONICET,
iaux d’Orsay (ICMMO), CNRS UMR 8182, Univ Paris-Sud, Universite Paris-Saclay,
ulaire (LCM), CNRS UMR 9168, Ecole Polytechnique, Universite Paris-Saclay, route de Saclay,
and Martín J. Riveira*,†
†
Instituto de Química Rosario, Facultad de Ciencias Bioquímicas y Farmaceu
́
Suipacha 531, S2002LRK, Rosario, Argentina
‡
Institut de Chimie Molec
1405 Orsay cedex, France
́
ulaire et des Mater
́
́
9
§
Laboratoire de Chimie Molec
1128 Palaiseau cedex, France
́
́
9
*
S Supporting Information
ABSTRACT: Molecular iodine was identified as an efficient
catalyst for the cycloisomerization of conjugated dienals to
substituted 2-cyclopentenones. DFT calculations suggested an
unexpected concerted character for this cyclization.
yclopentenones are unarguably distinguished chemical
entities. From both marine and terrestrial sources,
Scheme 1. Some Established Methodologies for
Cyclopentenone Construction and the Iso-Nazarov
Cyclization
1
2
C
countless natural products bearing this structural motif have
been isolated and found to possess interesting biological
activities. Notable examples include jasmonoids such as cis-
jasmone 1, a volatile component of the oil of jasmine flowers
3
used in perfumery and as a pesticide; phorbol esters such as
PMA 2 and prostratin, both potential treatments for acute
4
,5
myeloid leukemia and HIV, respectively; and important
biomolecules such as prostaglandins A 3, B , C , and J , which
2
2
2
2
6
present hormone-type activity in animals (Figure 1). In
Notwithstanding the great advances in this field of research, all
these transformations feature at least one of the following
shortcomings. These methodologies involve harsh reaction
conditions, toxic reagents, or the use of substrates which are
difficult to prepare. As a result, an efficient and operationally
simple procedure is lacking, particularly one that employs
readily available materials. In this context, progress on
nontraditional strategies to complement the well-established
ones would be beneficial for synthetic organic chemists.
Particularly in recent decades, the Nazarov reaction has
Figure 1. Distinguished natural 2-cyclopentenones.
particular, research on this last class of cyclopentenones has led
to the discovery of novel potent anticancer drug candidates.
7
From a different chemical viewpoint, the ease with which
selective chemical modifications can be executed at every
corner of these carbocyclic systems makes them versatile
building blocks in organic synthesis which is reflected in the
number of natural products and derivatives synthesized using
13
witnessed considerable evolution. Advancements include,
among several, the extension of the chemistry to the use of
linearly conjugated carbonyl compounds as substrates capable
of affording the key hydroxy-pentadienyl cation intermediates
8
cyclopentenones as key intermediates.
14
en route to cyclopentenones (Scheme 1, eq 2). This
cycloisomerization of dienals, baptized as the iso-Nazarov
Undoubtedly, because of their importance, much attention
has been given to the development of synthetic methodology
15−17
18
9
reaction by Trauner et al.,
has been rarely explored.
for cyclopentenone construction. The synthesis of cyclo-
Examples are limited and have mostly dealt with cis-dienals as
pentenones from acyclic precursors is generally carried out
using standard well-established methods, namely the intra-
10
molecular aldol condensation, the Pauson−Khand reac-
Received: October 10, 2018
1
1
12
tion, and the Nazarov cyclization (Scheme 1, eq 1).
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03229
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Optimization of the Iso-Nazarov Cyclization of Dienal 4a
a
entry
catalyst
solvent
t (° C)
global yield
approximate ratio 5a:5a′
b
1
2
3
4
5
6
7
8
9
−
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
EtOH
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
80 °C
120 °C
120 °C
120 °C
120 °C
120 °C
120 °C
reflux
−
−
−
−
5:1
−
−
−
−
−
−
−
4:1
−
−
5:1
−
c
hv (350 nm)
TFA (5 mol %)
TsOH·H O (5 mol %)
Aib (5 mol %)
−
b
−
d
14%
2
b
−
b
(R)-1,1′-Binaphthyl-2,2′-diyl hydrogen phosphate (5 mol %)
−
b
PhB(OH) (5 mol %)
H PO (5 mol %)
CuCl ·2H O (5 mol %)
AlCl (5 mol %)
FeCl (5 mol %)
FeCl (1 equiv)
InCl (5 mol %)
NIS (5 mol %)
I2 (5 mol %)
I2 (5 mol %)
I2 (5 mol %)
I2 (5 mol %)
I2 (5 mol %)
I2 (5 mol %)
I2 (5 mol %)
I2 (10 mol %)
I2 (5 mol %)
−
2
b
−
−
3
4
b
2
2
b
10
11
12
13
14
15
16
17
18
19
20
21
22
23
−
3
b
−
3
30%
3
b
−
3
b
−
67%
b
−
e
EtOH
26%
5:1
−
−
b
H O
−
2
b
THF
−
b
t-BuOH
EtOAc
EtOAc
EtOAc
−
−
90%
74%
74%
4:1
4:1
5:1
a
b
c
Isolated yields reported. Unless otherwise stated, conversion of 4a was complete. No conversion of 4a. Only isomerization of γ,δ-double bond
d
e
was evidenced. 65% of 4a was recovered. Inseparable from side products. TFA = trifluoroacetic acid, Aib = 2-aminoisobutyric acid, NIS = N-
iodosuccinimide.
substrates which are hard to prepare and are logically more
iron chloride which indeed promoted the reaction when used
stoichiometrically although unsatisfactorily (Table 1, entries 11
and 12). Once iodine was chosen as a suitable catalyst for the
transformation, other solvents, some of them greener than
toluene, were evaluated (Table 1, entries 16−20). No reaction
was observed when water, THF, or t-BuOH were used as
solvents at 120 °C for 2 h. In ethanol, on the other hand,
whereas no reaction occurred at 80 °C, at 120 °C the substrate
did undergo transformation but cyclopentenone products 5a/
a′ were produced accompanied by inseparable side products.
Ethyl acetate proved to be the best substitution for toluene in
the reaction, providing cyclopentenones 5a/a′ in an overall
90% yield (Table 1, entry 21). No further increase in yield was
observed when the amount of catalyst iodine was doubled (10
mol %) (Table 1, entry 22). It should be noted that the
reaction could also be performed under refluxing conditions,
and although conversion was complete in 2 h, slightly lower
yields were then obtained (74% yield) (Table 1, entry 23).
Under these conditions, a gram scale attempt using 1.29 g of
aldehyde 4a was assayed without any deleterious effect on
yields or selectivity (2 h; 72%; ratio 5a/5a′ = 5:1).
15,19
prone to the cyclization.
Very little is known about
substrate compatibility, appropriate catalysts, stereochemical
requirements, and potential applications.
Herein, we report our studies which identified iodine as an
efficient catalyst for this iso-Nazarov reaction of readily
available all-trans dienals.
To initiate our studies, we prepared dienal 4a as a model
substrate via simple aldol condensation between cinnamalde-
20
hyde and propionaldehyde. As shown in Table 1, thermal
treatment did not promote any cycloisomerization of 4a, nor
irradiation with actinic lamps (Table 1, entries 1 and 2).
Twelve readily available acids were then evaluated as potential
catalysts for the desired transformation (Table 1, entries 3−
1
5). These experiments were all performed in toluene at reflux
and with a low amount of the catalyst (5 mol %). To our
surprise, while most of these acids failed to catalyze the
reaction, molecular iodine was found to efficiently promote the
iso-Nazarov cycloisomerization of dienal 4a toward conjugated
2
5
-cyclopentenones 5a and 5a′, both separable and isolated in
6% and 11% yields, respectively, after column chromathog-
raphy purification (Table 1, entry 15).
With these optimized reaction conditions in hand, we then
set out to test the scope of the process. To this aim, several
conjugated dienals 4 were acquired from commercial suppliers
or prepared from simple aldehydes using standard and facile
aldol and vinylogous aldol condensations or Horner−Wads-
worth−Emmons reactions followed by reduction and oxida-
tion. Branched dienals underwent successful cyclizations to the
Of the other promoters assayed, only p-toluenesulfonic acid
caused dienal 4a to cycloisomerize to 5a/a′, albeit in much
lower yield than that attained by iodine (Table 1, entry 4 vs
1
5). Since toluenesulfonic acid is a cheap reagent, increasing
amounts of this catalyst were screened, but without success.
The same tests were performed with environmentally benign
B
DOI: 10.1021/acs.orglett.8b03229
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
2
5
desired 2-cyclopentenones in good yields, regardless of the
position of the substituents (α-, β-, and γ-branching) (Scheme
Pauson−Khand-type reaction. However, in all these cases,
yields were lower than that obtained using this new approach.
Catalysis by iodine, and halogen-bonding catalysis in
2
). Only traces of 2-cyclopentenones were observed in the
26
general, has been receiving considerable interest recently.
Scheme 2. Scope of the Iso-Nazarov Cyclization of Dienals
Remarkably, to the best of our knowledge, the catalysis of
Nazarov-type reactions by environmentally friendly and
inexpensive molecular iodine appears to be largely unknown.
27
To gain insight into the carbonyl mode of activation observed
for dienals 4, DFT computations were performed (see
Supporting Information for full details). Assuming that the
trans,trans-dienals 4 first isomerize into the 2Z-dienals to make
2
8
the cyclization possible, the I -catalyzed cyclization via
2
R
halogen bonding of the model dienal (2Z)-4a (A , R = Me)
was first studied (Scheme 3). We could only identify an
Scheme 3. Calculated Energy Profile (ΔG393, kcal/mol) for
the Iodine-Catalyzed Cycloisomerization of Dienals
reaction crude mixtures when unsubstituted dienals were used
as substrates. Whereas unbranched 5-phenyl-2,4-pentadienal
(4e) was chiefly inert to the reaction conditions (5e, Scheme
2
), commercially available hexa- and decadienal underwent
unexpected concerted process leading directly to the cyclo-
Me
extensive decomposition toward a colored gum (not shown).
This unwanted process could not be overcome by reducing the
amount of catalyst or running the reaction at lower
temperatures. As shown, alkyl and aryl substituents were
compatible with the transformation, decorating the dienal
substrates along the conjugated chain (products 5a−n). In
particular, the end of the polyene chain was compatible with
alkyl groups, heteroaromatics such as furan, and substituted
phenyl groups with both electron-donating and -withdrawing
groups (5i−n). Gratifyingly, natural product dihydrojasmone
pent-3-enone B product. This product is more stable than
Me
A
by 13.7 kcal/mol, but the transition state lies as high as
29.9 kcal/mol on the potential energy surface (PES).
Interestingly, with two iodine molecules instead of one to
Me
activate the carbonyl as in C , this barrier is reduced to 24.1
kcal/mol, which seems accessible at the reaction temperature.
Me
The resulting product D is also obtained in an exergonic
Me
fashion (−15.7 kcal/mol). From D , it is easily conceivable
that the CC bond will spontaneously and rapidly shift to
give a cyclopent-2-enone, with this migration being obviously
more favorable toward the Ph group, as it gives a more
conjugated product (5a vs 5′a) (Table 1 and Scheme 2). As a
comparison, the uncatalyzed reaction was also analyzed (not
shown). It was found to be a concerted process as well, yet the
corresponding transition state lies at 38.1 kcal/mol on the PES
5
l could also be obtained among the cyclopentenone products
in 60% yield. In this manner, a new synthesis of this aromatic
21
compound used in perfumery was achieved. As shown in
Scheme 2, all reactions were highly regioselective, with the
more substituted and conjugated cyclopentenones being
produced either exclusively or predominantly.
Interestingly, apart from 5l, some of the other obtained
cyclopentenones 5 have also been prepared before by other
methodologies. For instance, 2,5-diphenyl-cyclopent-2-enone
(
ΔG −14.1 kcal/mol). Thus, I can be dramatically effective
3
93
2
as a catalyst, and clearly two iodine molecules are better than
one. When R = H (substrate 4e, activated dienal C ), although
H
the use of two iodine molecules significantly lowers the
computed cyclization barrier compared to just one (from 38.3
to 32.6 kcal/mol), it remains too high to be crossed under the
reaction conditions and this is in line with the experimental
findings (Scheme 2, 5e).
The concerted character of this reaction is puzzling.
Standard behavior, within the carbocationic paradigm, would
(5d) was prepared before in low yield by Pauson and Khand
22
using their well-known reaction. 2,3-Diphenyl-cyclopent-2-
enone (5h), obtained in 80% yield, was prepared several times
before via different strategies including the aldol condensa-
2
3
24
tion, a Nazarov-type cyclization, and a Zr-promoted
C
DOI: 10.1021/acs.orglett.8b03229
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
́
comprise a conrotatory 4π-electrocyclization followed by a
Cientifica y Tecnolog
́
ica (ANPCyT, PICT-2014-0408), and
29
suprafacial [1,2]-H shift. The resulting stereochemistry of
this two-step process would have been the same as the one
Agencia Santafesina de Ciencia, Tecnica e Innovacion
́ ́
(ASACTEI) (AC - 2015-00005) for financial support. J.L.P.
thanks CONICET for fellowships. V.G. thanks CNRS, UPS,
Ecole Polytechnique, and IUF for support of this work.
Me
Me
obtained for B or D . The geometries and transition
vectors of the computed transition states actually correspond
to the [1,2]-H shift only. The new C−C bond is virtually fully
formed (1.56−1.58 Å), and the quite large imaginary
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■
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ASSOCIATED CONTENT
Supporting Information
■
*
S
3
The Supporting Information is available free of charge on the
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(PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*
E-mail: riveira@iquir-conicet.gov.ar.
E-mail: vincent.gandon@u-psud.fr.
9
(12)
*
Sesquiterpene Δ
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(
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Vincent Gandon: 0000-0003-1108-9410
Martín J. Riveira: 0000-0002-1682-9855
Author Contributions
2
(
¥
J.L.P. and L.A.M. contributed equally to this work.
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank Universidad Nacional de Rosario (BIO426),
Fundacion
■
́
Josefina Prats, Agencia Nacional de Promocion
́
D
DOI: 10.1021/acs.orglett.8b03229
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
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