Catalytic intramolecular carbonyl-ene reaction with ketones: Evidence for a retro-ene process

Article abstract of DOI:10.1039/c5nj01286d

The ene-process with unsaturated ketones was catalyzed by Lewis acids such as bismuth or indium triflates. Unlike aldehydes, the reverse ene-process occurs with ketones, resulting in incomplete conversions, as shown by control experiments and analysis by ESI-MS.

Full text of DOI:10.1039/c5nj01286d

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Catalytic intramolecular carbonyl–ene reaction
with ketones: evidence for a retro–ene process†
Cite this:DOI: 10.1039/c5nj01286d
P. Tremel, C. Iacobucci, L. Massi, S. Olivero, J.-F. Gal and E. Dunach*
˜
The ene-process with unsaturated ketones was catalyzed by Lewis acids such as bismuth or indium
triflates. Unlike aldehydes, the reverse ene-process occurs with ketones, resulting in incomplete conversions,
as shown by control experiments and analysis by ESI-MS.
Received (in Montpellier, France)
21st May 2015,
Accepted 22nd July 2015
DOI: 10.1039/c5nj01286d
www.rsc.org/njc
amounts of Lewis acids. Non-activated ketones have only been
reported in specific cases with excess AlCl316 or AlMe2Cl.17
Introduction
Since the description by K. Alder of the ‘‘ene’’ reaction in 1943,
We present here our studies on the catalytic ene reaction
this rearrangement has been shown to be a useful methodology with non activated ketones, together with some kinetic experi-
in organic synthesis.1 The carbonyl–ene reaction has been ments and their analysis by mass spectrometry.
widely reported, either under thermal conditions2 or under
Lewis acid catalysis.3 It mainly concerns inter- or intramolecular
reactions of unsaturated aldehydes which afford homoallylic
Results and discussion
Reactivity of model ketone compounds
alcohols (Scheme 1).
Catalysis by a variety of Lewis acids has been reported, for
Interested in the catalytic activity of strong Lewis acids derived
from triflic and triflimidic acids,18 we prepared a series of un-
saturated ketones 1a–1f and aldehyde 1g, via a first diethyl
malonate alkylation with several allylic bromides, followed by a
Michael addition on diversely substituted a,b-enone derivatives
(Scheme 2). The unsaturated ketones were obtained in 53–85%
yields.
example with AlMe2Cl,4 ZnCl2,5 SnCl2 or BF3.OEt2,7 mostly used
6
in stoichiometric amounts. Catalytic and/or asymmetric processes
using chiral ligands have also been reported,8 in particular with
titanium(IV),9 chromium(III)10 or copper(I)11 derivatives and with
ytterbium(III)12 or bismuth(III) triflates.13 Examples concerning the
carbonyl–ene reaction involving ketones are scarce; they generally
need electron-withdrawing groups on the carbonyl moiety to
enhance its electrophilicity, as for reactions involving trifluoro-
methyl ketones14 or a-ketoesters,15 generally using stoichiometric
Scheme 1 Intramolecular carbonyl–ene reaction (LA = Lewis acid).
´
Institut de Chimie de Nice, UMR 7272, Universite Nice Sophia Antipolis, CNRS,
Parc Valrose, 06108 Nice Cedex 2, France. E-mail: dunach@unice.fr
† Electronic supplementary information (ESI) available: 1H and 13C NMR, MS and
ESI-MS data. See DOI: 10.1039/c5nj01286d
Scheme 2 Preparation of unsaturated ketones 1a–1f and unsaturated
aldehyde 1g.
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Scheme 4 Ene reactivity of aldehyde substrate 1g.
selected strong Lewis acids. The formation of the ene-products
(2a + 3a + 4a) occurred in up to 49% yield with Bi(OTf)3 at 0 1C
(entry 6). With In(OTf)3, the ene-products reached 58% yield at
0 1C (entry 7) and 60% with Fe(NTf2)2 (entry 9), though in this
case with formation of the elimination compounds 3a and 4a,
only. Concerning the formation of alcohol 2a, Bi(III) and In(III)
triflates showed the best yields. A diastereoselectivity 2a-cis/
2a-trans of 92 : 8 was reached with In(OTf)3 at 25 1C (entry 2).
In contrast with these results, when comparing with those of
the corresponding ene reaction of the analogous aldehyde 1g,
the reaction catalyzed by Bi(OTf)3 at 25 1C led cleanly to 2g-cis/
2g-trans in 79% yield with a 47/53 isomer ratio (Scheme 4). No
elimination processes were observed in this case.
Scheme 3 Reactivity of substrate 1a in the ene reaction.
Ketone 1a, bearing a trisubstituted double bond, was chosen as
a model compound for examining the catalytic activity of several
metal triflates and triflimides in nitromethane solutions at
different temperatures. Whereas Bi(OTf)3 and In(OTf)3 were
commercially available, Fe(OTf)2, In(NTf2)3 and In(NTf2)3 were
prepared according to electrochemical or sonochemical proce-
dures.19 The expected product from the ene reaction of 1a was
the cyclic alcohol 2a (cis/trans diastereoisomers), as illustrated in
Scheme 3. The reaction led also to the diene 3a, issued from the
Evidence for a retro–ene reaction
alcohol dehydration, together with the non-expected compound The follow-up of the reaction of 1a by GC analysis indicated the
4a. The formation of 4a could be explained by an intramolecular- initial formation of alcohols 2a and their further conversion
type hydroalkoxylation from 2a,20 evolving towards loss of acetone. into 3a and/or 4a. The amount of diene 3a slowly diminished
The loss of acetone in a similar case has already been reported by with time, due to its slow polymerization. The increase of the
the stoichiometric use of BF3ÁEt2O.21 This cyclohexene derivative reaction temperature led generally to higher elimination ratios.
4a was formed in low yields at room temperature and its amount We also observed that at low temperature, the ene reaction
increased with the reaction temperature.
seemed to reach equilibrium. In particular, with 1a and indium
Interestingly, products 2–4 arise all from a first ene-reaction with triflate (10 mol%) in dry nitromethane under nitrogen atmo-
the starting unsaturated ketone. As illustrated in Table 1, at 25 1C, sphere at À5 1C and at 0 1C, the concentration of the different
the best conversions were attained with Bi(OTf)3 and In(OTf)3 compounds remained stable after 2 hours reaction, with 42% of
catalysts (entries 1 and 2); use of In(III) triflate resulted in better 1a, the two isomeric alcohols 2a-cis and 2a-trans in 50% yield
conversion than the corresponding triflimide (entries 2 and 3). The and a 74 : 26 ratio respectively, and only a very small amount of
Fe(II) salts were poorly active (entries 4 and 5). Bi(OTf)3 showed also compounds 3a and 4a (see entry 7 of Table 1).
a good catalytic activity at 0 1C (entry 6), and all the tested catalysts
converted 1a at refluxing nitromethane (101 1C, entries 8–10).
This observation led us to hypothesize a possible reversibility
of the ene reaction for such ketone substrates,22 reversibility that
The results of Table 1 indicate that the ene reaction with may also explain the moderate yields and the incomplete con-
non-activated ketones was possible with catalytic amounts of versions achieved.
Table 1 Catalyst screening for the carbonyl–ene reaction with ketone 1a in nitromethanea
Selectivities
Yield of ene
Entry
Catalyst (Temp., time)
Conv. of 1a (%)
products 2 + 3 + 4
2a (cis : trans)
3a
4a
1
2
3
4
5
6
7
8
9
Bi(OTf)3 (25 1C, 5 h)
In(OTf)3 (25 1C, 5 h)
In(NTf2)3 (25 1C, 5 h)
Fe(NTf2)2 (25 1C, 5 h)
Fe(OTf)2 (25 1C, 5 h)
Bi(OTf)3 (0 1C, 5 h)
In(OTf)3 (0 1C, 4 h)
In(NTf2)3 (101 1C, 14 h)
Fe(NTf2)2 (101 1C, 2 h)
Fe(NTf2)2 (101 1C, 5 h)
85
63
40
18
33
82
58
85
86
100
32
43
31
18
29
49
58
58
60
34
41 (59 : 41)
60 (92 : 8)
65 (80 : 20)
83 (58 : 42)
97 (62 : 38)
60 (69 : 31)
86 (74 : 26)
7 (75 : 25)
Traces
50
33
25
11
3
33
9
62
60
26
9
7
10
6
—
7
5
31
39
74
10
—
a
General conditions: 1a (1 mmol) in distilled nitromethane (5 mL) with the catalyst (0.1 mmol, 10 mol%), stiring at the reported temperature.
Yields are calculated by GC analysis using dodecane as internal standard.
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Thus, after isolation of 2a-cis and 2a-trans, we separately
Paper
tested the reactivity of the two alcohols in order to prove the
occurrence of a retro–ene reaction.
The two isomeric alcohols 2a-cis and 2a-trans were treated
individually with 10% of In(OTf)3 in dry nitromethane, under
nitrogen atmosphere at À5 1C. Their reaction kinetics were
followed by GC/MS using dodecane as internal reference
(Fig. 1). These experiments indicated that both alcohols 2a-cis
and 2a-trans underwent a retro–ene reaction to the starting 1a.
Interestingly, the different kinetic profiles of the two diastereo-
meric alcohols indicated that only the 2a-trans isomer under-
went direct elimination reactions to 3a and 4a. In contrast,
2a-cis led only to isomerization via the retro–ene reaction; after
reformation of 1a, the resulting 2a-trans was responsible for the
appearance of the further elimination products and formation
of 2a-cis.
This evidence is in agreement with the lower yield obtained
for the isomer 2a-trans as compared to that of 2a-cis in the
reaction of 1a and suggests that the diastereoselectivity observed
in the presence of In(OTf)3, derives from stereoselective elimina-
tions reactions rather than from the initial ene reaction.
Looking more precisely at the unexpected loss of acetone,
2a-trans is the only isomer with the hydroxyl group and the
double bond close enough to form a indium five-membered
Scheme 5 Evolution of 2a-trans to dehydration product 3a and/or to
acetone elimination 4a, catalysed by In(OTf)3.
ring intermediate, leading to elimination (Scheme 5). The
ESI-MS follow-up of the reaction mixture (see next section)
shows an indium cationic species at m/z 711, that could
correspond to these transient species.
From the kinetic study, evidence was obtained for the first
time of a retro–ene reaction in the case of an unsaturated
ketone. Moreover, it was shown that both alcohol–ene diastereo-
isomers, 2a-cis and 2a-trans behaved differently in the presence
of the Lewis acid.
ESI-MS investigation
To get some more insight on the ene-reaction with ketone 1a,
we investigated the reaction mechanism by mass spectrometry.
During the last few years, mass spectrometry (MS) has
gained widespread acceptance as a technique for mechanistic
studies of organic reaction and catalysis.23–25 In this context,
electrospray ionization (ESI), owing to its ‘‘soft’’ character,
occupies a prominent position at the interface between the ions
and ionizable species existing in solution and those observed in
the gas phase.
The reaction mixture compositions may be followed over
time by the so-called source capability of ‘‘fishing’’ ionic or
ionizable intermediates from the solution. In favorable cases,
crucial species with short life-times at very low concentrations
can be effectively transferred from the reaction mixture to the
gas phase where they become stable enough to be characterized.
In particular, this would be of interest in characterizing organo-
metallic intermediates with their entire coordination sphere.26
Recently, several MS studies yielded detailed information about
elementary reaction steps of important reactions27 such as the
Heck28,29 or the Stille coupling,30 the Baylis–Hillman,31–34 or the
Biginelli reactions35–37 or some gold-catalyzed reactions.38,39
Fig. 1 Evolution of the retro–ene reactions of 2a-trans and 2a-cis in the
presence of In(OTf)3 (10 mol%) in dry nitromethane, under nitrogen
atmosphere, at À5 1C, as measured by GC analysis using dodecane as
internal standard.
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Electrospray mass spectrometry may be also used to investi- of the ESI-MS reaction monitoring. The first one consisted in
gate the Lewis acid/base interactions involving adducts of metal mixing nitromethane solutions of 1a and In(OTf)3 in a T-shape
triflate (or triflimide) salts with organic functionalities.40
microreactor directly coupled to the ESI source of the mass
An ESI-MS screening of the catalytic systems employed in spectrometer. This configuration reduces the dead time down
Table 1 was realized, in order to optimize electrospray ionization to a few seconds. In the second set-up, the In(OTf)3 solution
process in nitromethane solutions. The use of nitromethane as was injected through the sheath liquid source inlet, while 1a
ESI-solvent has already been reported in the context of charac- was injected using the regular inlet. This setting produced two
terization of metal triflates by ESI-MS.41 This preliminary study coaxial flows that mixed only at the stage of the Taylor cone,
led us to choose In(OTf)3 among the tested Lewis acids, as the less than one second before ionization (see ESI† data). There-
best candidate for the ene-reaction investigation. In fact, nitro- fore, this sheath liquid interface appears to be particularly
methane solutions of indium triflate resulted in excellent quality relevant to the study of reaction mechanisms.
electrospray spectra and this catalyst led to an adapted reaction
rate for detecting possible reaction intermediates.
All these spectra were compared with those recorded from
nitromethane solutions containing only the purified product
We performed off-line ESI-MS screening of the reaction 2a. In all cases, the MS/MS spectra were essentially indistin-
mixture by infusing periodically a nitromethane solution of guishable, suggesting that, even in the gas phase, 2a underwent
1a in the presence of 10% of In(OTf)3. The ESI-MS spectra a fast retro–ene reaction and it further followed the same
collected over time showed the gradual formation of the fragmentation pattern as for 1a.
expected products 2a, 3a and 4a as protonated species, respec-
tively at m/z 299, 281 and 241 and revealed the presence of
adducts containing indium and organic substrates (Fig. 2).
These intercepted organo-indium adducts suggested that the
cycloisomerization proceeds through a metal-based catalysis
Extension to other substrates
The ene-reaction was extended to other unsaturated ketones
under Bi(OTf)3 catalysis. Thus, the phenyl ketone 1b was reacted
according to Scheme 6, to afford compounds 4b and 5b in 74%
involving the activation of the carbonyl moiety.
overall yield. Both products arose from a first ene reaction of 1b.
Since compounds 1a and 2a have the same mass, it should
Compound 4b is formed from the ene-intermediate 2b (not isolated)
be noted that the ion at m/z 299 can be the protonated form of
after acetone elimination. The formation of 5b could be explained
1a or of 2a. Similarly, the ion at m/z 711 could correspond to
by a first dehydration of 2b to 3b, followed by a Friedel–Crafts
both [In(OTf)2(1a)]+ and [In(OTf)2(2a)]+. These two isobaric
cyclization in the presence of the Lewis acid (Scheme 6).42
species are particularly interesting because they could be the
Compound 1c, bearing a methyl ketone group and a tri-
two organometallic intermediates responsible firstly for the
substituted double bond (but on a longer unsaturated side-chain),
ene-reaction and secondly for the elimination reactions. A set
reacted to afford the bicyclic compound 5c in 47% yield with a 73%
of experiments were planned to assign the peaks at m/z 299 and
conversion (Scheme 7). The formation of 5c could be explained
at m/z 711 found in full scan MS spectra. ESI-MS/MS spectra of
through a first ene reaction to afford the seven-membered ring
these ions were collected at several collision energies during
alcohol 2c, followed by acetone elimination to 4c and further
the reaction monitoring experiments.
In addition to MS/MS spectra recorded over time, two other
experiments were carried out in order to shorten the dead time
lactonization. The Lewis acid-catalyzed lactonization of unsaturated
esters has already been reported.43
Fig. 2 Evolution of ESI-MS spectra: ESI-MS over time monitoring of 1a in
the presence of In(OTf)3.
Scheme 6 Ene reaction products obtained from 1b.
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Experimental section
Typical carbonyl–ene reaction procedure
To a nitromethane solution (5 mL, anhydrous and degassed) of
the catalyst (0.05 to 0.1 mmol) was added the substrate 1
(1 mmol) at the desired temperature under a N2 atmosphere.
The consumption of the starting material was monitored by
GC-FID analysis. The reaction mixture was quenched with 5 mL
of water and extracted by 3 Â 5 mL of diethyl ether. After
concentration of organic phases, the residue was purified by
silica gel chromatography to afford the ene compounds.
Conclusions
Scheme 7 Formation of lactone 5c.
In conclusion, the ene-process with unsaturated ketones can be
catalyzed by Lewis acids, in particular by In(OTf)3 and Bi(OTf)3;
nevertheless, it suffers from the low stability of the tertiary
alcohol products formed. Dehydration is one of the main side-
reactions observed. The reverse ene-process can also occur,
resulting in incomplete conversions, as shown by control experi-
ments. The results with ketones bearing terminal dimethyl
substituted double bonds indicate that the ene reaction can be
followed by acetone elimination.
The carbonyl–ene reaction with unsaturated ketones was
examined by following the formation of products and by ESI-MS
analysis of the reacting solutions in the early stage of the
reaction. Some insight on organometallic intermediates and
on reaction mechanism was gained by this approach.
We then turned out our interest to ketones with a 1,2-
disubstituted double bond, such as 1d or 1e (Schemes 8 and 9).
In these cases, the elimination of acetone was not to be expected.
The ene reaction with 1d afforded the water elimination product
3d in 19% yield. The main product was the lactone 5d, issued
from the reaction of one of the ester groups of 1d with the double
bond (Scheme 8).
In the presence of Bi(OTf)3 (10 mol%), ketone 1e led to the
seven-membered ring 3e as the main compound in 44% yield,
with 76% conversion (Scheme 9).
The substituted ketone 1f afforded the expected ene
products 2f and 3f in 87% overall yield, in a 36 : 64 ratio
(Scheme 10).
Acknowledgements
We thank the French ANR project ALEA (2013-009-01) for financial
support. The authors are grateful to Galderma R&D, Sophia-
Antipolis, for the gift of mass spectrometers to our institute.
Notes and references
Scheme 8 Reactivity of 1d with Bi(OTf)3 catalysis.
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