Palladium triggered diene formation from nitro allylic compounds: A versatile entry into naphthalene derivatives

Article abstract of DOI:10.1039/c8cc06536e

Nitro allylic derivatives were converted into dienes through the elimination of the nitro group under basic treatment, in the presence of a palladium catalyst. This reaction probably involves the formation of a palladium π-allyl complex followed by a base-promoted β-hydride elimination. This reaction, combined with the condensation of ketones with nitromethane and the functionalization of the resulting nitrocycloalkenes, constitutes a very powerful synthetic tool for the formation of dienes. Particular attention has been brought to the application of this methodology to the formation of 1-substituted naphthalenes from 1-tetralone.

Full text of DOI:10.1039/c8cc06536e

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Palladium triggered dienes formation from nitro allylic
compounds: a versatile entry into naphthalene derivatives.
Received 00th January 20xx,
Accepted 00th January 20xx
Mansour Dolè Kerim,a Shuanglong Jia,a Chrysoula Theodorakidou,a Sébastien Prévost*a and
Laurent El Kaïm*a
DOI: 10.1039/x0xx00000x
www.rsc.org/
Nitro allylic derivatives were converted into dienes through reactions.9 Since these first works, very few examples of
elimination of the nitro group under basic treatment, in the palladium catalyzed substitution of nitro allylic derivatives
presence of a palladium catalyst. This reaction probably have been reported (Scheme 1.a).10 Albeit an easy access to
involves the formation of a palladium
followed by a base promoted -hydride elimination. This been poorly explored in synthesis. Stimulated by our interest in
reaction, combined with the condensation of ketones with Tsuji-Trost reactions,11 we envisioned that, in the absence of a
nitromethane and the functionalization of the resulting potential nucleophlic group, the -allyl intermediate derived
nitrocycloalkenes, constitutes a very powerful synthetic tool from nitro compounds could afford, under basic conditions, an
for the formation of dienes. A particular attention has been interesting access to dienes or aromatic derivatives after
brought to the application of this methodology to the hydride elimination (Scheme 1.b). Due to the synthetic
π-allyl complex highly functionalized starting materials, these reactions have
β
π
β
-
formation of 1-substituted naphthalenes from 1-tetralone.
importance of 1,3-dienes in organic transformations ([4+2]
cycloadditions, polymerizations or diene functionalizations)12
and their presence in natural products,13 several methods, such
as enyne metathesis, Wittig type reactions or alkynes
isomerisation, have been developed to have access to this
moiety.14 Herein, we report a new synthesis of 1,3-dienes and
aromatic derivatives based on a palladium catalyzed Tsuji-Trost
reaction of nitro allylic derivatives. When coupled with prior
functionalization of nitro compounds, this elimination process
could be the key to valuable synthetic building blocks.
The easy functional modification of the nitro group together
with its strong electron withdrawing properties has turned
aliphatic nitro derivatives into one of the most fascinating
synthetic platform. Indeed, the ability to deprotonate simple
aliphatic nitro derivatives under smooth basic treatment has led
to very efficient carbon-carbon bond formations,1 such as
observed in the Henry reaction,2 the Michael3 or Mannich
additions of nitro derivatives.4 These transformations coupled
with easy reduction to amines, conversion to carbonyl
derivatives (Nef reaction)5 or nitrile oxides (Mukayama
reaction)6 have been at the center of many simple and efficient
syntheses of heterocycles.7 In contrast to these important
progresses made decades ago, transition metal based
transformation of nitro compounds has made little progress
being mainly limited to reductive transformation to amine
derivatives using various hydrogen donors.8 This is particularly
true for palladium catalyzed reactions working on aromatic as
well as aliphatic nitro compounds. However, in the 80’s, the
groups of Hegedus and Tamura reported the properties of nitro
a) Nucleophilic susbition of cyclic nitro allylic derivatives:
O2N
R
R
Nu
Nu = NaCH(CO2Et)2,
NaSO2Ar, MeNO2
PR3, RNH2, "H-"
Nu
Pd(0)
n
n
b) This work, diene and naphtalene syntheses:
O2N
R
R
R
R
O2N
R
R'
R
R'
base
Pd(0)
base
Pd(0)
n
n
Scheme 1 Palladium catalyzed diene synthesis from nitro allylic derivatives
allylic compounds to form
π-allyl complex in presence of a
palladium (0) catalyst in order to realize allylic substitution
Cyclic nitro allylic derivatives are particularly useful synthetic
intermediates. Easily prepared through ethylenediamine
triggered Knoevenagel type reactions between cyclic ketones
and nitroalkanes, the resulting nitrocycloalkenes can be further
functionalized using standard nitro chemistry (Michael, Henry
or Mannich reaction) allowing the formation of highly
a.Laboratoire de Synthèse Organique, CNRS, Ecole Polytechnique, ENSTA ParisTech-
UMR 7652, Université Paris-Saclay, 828 Bd des Maréchaux, 91128 Palaiseau.
France. sebastien.prevost@ensta-paristech.fr; laurent.elkaim@ensta-paristech.fr
Electronic Supplementary Information (ESI) available: details of experimental
procedures, 1H NMR and 13C NMR spectra for all unknown compounds, See
DOI: 10.1039/x0xx00000x
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E
E
E
functionalized nitroderivatives (Scheme 2, see the supporting
information).
O2N
Pd(OAc)2 (10 mol%)
dppe (10 mol%)
O2N
E (3 eq.)
DBU (0.5 eq.)
CH3CN, rt
E
Cs2CO3 (1 eq.)
DMF(0.5 M)
120°C, 30 min
n
n
n
1a
1b
2a
2b
3a
3b
n = 2:
n = 1:
n = 2; E = CN:
n = 2; E = CO2Me:
(89%)
(92%)
n = 2; E = CN:
n = 2; E = CO2Me:
(87%)
(77%)
n = 2; E = SO2Ph : 2c (99%)
n = 2; E = SO2Ph : 3c (78%)
2d
2e
3d
3e
n = 1; E = CO2Me:
n = 1; E = CN:
(68%)
(65%)
n = 1; E = CO2Me:
n = 1; E = CN:
(89%)
(79%)
Scheme 3 Substrate scope of the synthesis of cyclic dienes
Scheme 2 Nitrocycloalkenyl synthetic platform
After having shown the feasibility of this reaction to obtain
cyclic dienes, we were keen to use this strategy for the
synthesis of aromatic derivatives and especially to obtain
naphthalenes and indoles. Indeed, naphthalenes and indoles are
important aromatic skeletons in chemistry,15,16 and the
development of new methods to have access to these scaffolds
is very important. For this purpose, we synthesized several 4-
(nitromethyl)-1,2-dihydronaphthalenes 4a-g in two steps from
1-tetralone and tried our optimized conditions (Scheme 4). We
were planning that, under these conditions, the naphthalene
moiety could be obtained after diene formation and
isomerisation due to the aromatic nature of the final product.
Indeed, seven naphthalenes were synthesized in moderate to
excellent yields. As previously, quaternary nitro derivatives
delivered corresponding naphthalenes 6a-c in very good
isolated yields. In addition, the reaction conditions were
compatible with secondary and tertiary compounds and 1-
methylnaphthalene 6d was obtained in 35% yield whereas
naphthalenes 6e-f were isolated in good yield. Then, we tried
At the outset of these investigations, we focused our attention
on the eliminative Tsuji-Trost reaction of quaternary nitro
derivatives, as potential trapping of
nitronate derivatives may lead to competing homocoupling
reactions. Thus, nitro allylic 2a which can be easily
π-allyl intermediates with
,
synthesized in two steps and very good yields from
cyclohexanone (see the supporting information), was selected
as model substrate to test the reaction (Table 1). Treating 2a
with 5 mol% of palladium diacetate with triphenyphosphine as
ligand and cesium carbonate as base, we were delighted to
obtain expected diene 3a in 62% isolated yield (Table 1, entry
1). Emboldened by this result, different phosphine ligands were
screened and dppe (1,2-bis(diphenylphosphino)ethane) showed
the best yield (82%, Table 1, entry 1-3). After a screening of
the reaction conditions (Table 1, entry 3-7), potassium
carbonate in DMF was selected as the best combination of base
and solvent. Finally, using 10 mol% of palladium diacetate with
10 mol% of dppe afforded the desired diene 3a in 87% isolated
yield (Table 1, entry 8).
our conditions on 4g (R1 =
− −CH2CH2CO2Me)
CH2OAc; R2 =
where the presence of an acetate group could form a second
π
-
allyl complex after the elimination of the nitro group. As
expected, naphthalene 6g bearing an additional double bond
was obtained via double palladium catalyzed elimination.
Finally, very interestingly, this strategy could be applied to the
synthesis of indoles. Substrate 5a reacted smoothly, giving
indole 7a in 67% yield.
Table 1 Optimisation of Tsuji-Trost diene formationa
Entry
Phosphine
PPh3 (15 mol%)
P(o-tol)3 (15 mol%)
dppe (5 mol%)
dppe (5 mol%)
dppe (5 mol%)
dppe (5 mol%)
dppe (5 mol%)
dppe (10 mol%)
Base
Solvent
DMF
T (°C) Yieldb (%)
1
2
3
4
5
6
7
8c
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
120
120
120
120
120
110
80
62
79
83
82
33
57
51
87
DMF
DMF
DMF
DIPEA
Cs2CO3
Cs2CO3
Cs2CO3
DMF
Toluene
CH3CN
DMF
120
a Unless otherwise noted, all reactions were performed on 0.5 mmol scale with 5
mol% of Pd(OAc)2. b Isolated yield. c 10 mol% of Pd(OAc)2 was used.
With these optimized conditions in hand, we investigated the
scope of this transformation regarding the synthesis of cyclic
dienes (Scheme 3). Different nitro allylic derivatives 2a-e were
synthesized in one step and very good yields from 1a-b by just
changing the Michael acceptor and submitted to our eliminative
Tsuji-Trost conditions. Several cyclic dienes bearing different
electron withdrawing groups were obtained in excellent yields.
Scheme 4 Substrate scope of the aromatic compound synthesis
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In order to show the versatility of our system, we applied our
conditions to the synthesis of linear dienes (Scheme 5.a). When
linear nitro allylic substrates 8a-b (E/Z mixture) were treated Conflicts of interest
with 5 mol% of palladium diacetate in presence of cesium
carbonate, dienes 9a-b were isolated in very good yields. The
selective formation of the terminal diene is consistent with an
There are no conflicts to declare.
equilibrium between η3-allyl and
followed by a
σ
-allyl palladium complexes
β
-H elimination from the less hindered -allyl
σ
complex (Scheme 5.b).17. The same mechanistic considerations
may be advanced for the selectivity observed in the conversion
of 2a into 3a. The high functionalization of nitro starting
materials makes our transformation particularly interesting to
synthesize polycyclic compounds in few steps. For instance, by
treating naphthalene 6b with triflic acid, tricyclic tetralone
derivative 10 was obtained in good yield (Scheme 5.c).
Notes and references
1
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Scheme
synthetic transformations
5 Application to linear diene synthesis, proposed mechanism and
To conclude, we have disclosed a new Tsuji-Trost type
elimination of nitro allylic derivatives towards dienes. Whereas
dienes formation in Tsuji-Trost reaction using allylic acetates is
well known,18 it suffers from low synthetic potential compared
to their related substitutions. The situation is quite different for
nitro derivatives. Indeed, the high acidity of nitro alkyl
compounds together with their high yielding additions to
various unsaturated systems make these nitro derivatives a very
powerful synthetic platform. After using these properties to
control C-C bond formations, the ability to eliminate the nitro
group forming dienes offer interesting new strategies in relation
with the important literature on the conversion of 1,3-dienes
into cyclic systems.12
8
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Acknowledgment
11 (a) M. Cordier, A. Dos Santos, L. El Kaïm and N. Narboni,
Chem. Commun., 2015, 51, 1116. (b) H. Elhachemia, M.
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We thank the Islamic Development Bank for a PhD fellowship to M.
D. K. We thank the ENSTA ParisTech for a PhD fellowship to S. J.
We thank LabEx CHARMMMAT for a fellowship to C. T.
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