Metal-free SN2a′ decarboxylative rearrangement of β-keto esters

Article abstract of DOI:10.1002/ejoc.201100120

Treatment of 2-methoxycarbonyl-(or 3-cyano-)allyl acetoacetates with a tertiary amine or triphenylphosphane afforded α-methylene γ-substituted δ-keto esters (or nitrile) in satisfactory yields. Various bases and nucleophiles were tested to elucidate the m

Full text of DOI:10.1002/ejoc.201100120

FULL PAPER
DOI: 10.1002/ejoc.201100120
Metal-Free SN2Ј Decarboxylative Rearrangement of β-Keto Esters
Vincent Bizet,[a] Valérie Lefebvre,[a] Jérôme Baudoux,*[a] Marie-Claire Lasne,[a]
Agathe Boulangé,[b] Stéphane Leleu,*[b] Xavier Franck,[b] and Jacques Rouden*[a]
Keywords: Nucleophilic substitution / Reaction mechanisms / Organocatalysis / Rearrangement/ Decarboxylation
Treatment of 2-methoxycarbonyl- (or 3-cyano-)allyl aceto-
acetates with a tertiary amine or triphenylphosphane af-
forded α-methylene γ-substituted δ-keto esters (or nitrile) in
satisfactory yields. Various bases and nucleophiles were
tested to elucidate the mechanism. The results of the study
strongly suggest an intermolecular pathway involving a
SN2Ј–decarboxylation–SN2Ј cascade.
through an intramolecular SN2Ј[2,3] reaction of the β-keto
ester enolate with displacement of the acetoacetate group
and further decarboxylation of the latter. It is worth noting
that intramolecular Michael additions of C-nucleophiles
under organocatalytic conditions[4–7] have been relatively
unexplored. “Intramolecular conjugated displacements”
have been successfully applied to the synthesis of carbo-
cycles[8] or nitrogen heterocycles.[9] In these reactions, a
carbanion or an amine generated in situ reacted with an
acrylate with substitution of an acetate (or a carbonate)
group in the allylic position.[10] SN2Ј reactions are also com-
mon reactions for intermolecular functional modifications
of Morita–Baylis–Hillman adducts.[10,11]
Introduction
One of the major challenges in organic chemistry is the
synthesis of highly functionalized molecules in a minimum
of steps with efficient control of the stereochemistry. As a
part of our research on organocatalytic approaches to C–C
or C–H bond formation,[1] we envisaged a metal-free syn-
thesis of δ-keto esters 1 from easily available allylic esters 2
(Scheme 1).
From a slightly different point of view, the transforma-
tion we envisaged could be related to a base-induced Car-
roll reaction, which is a variant of the Claisen rearrange-
ment (Scheme 2).[12] Although described a long time ago,
applications of the Carroll reaction in organic synthesis
have received little attention, probably because of the harsh
thermal conditions required (typically higher than 180 °C)
Scheme 1. Working hypothesis: base-catalyzed rearrangement of
substituted allyl acetoacetates.
We anticipated that, in the presence of a base, an elec-
tron-withdrawing group (EWG = CO2R, CN) on the
double bond of 2 would facilitate the C–C bond formation
[a] Laboratoire de Chimie Moléculaire et Thioorganique, CNRS-
ENSICAEN, Université de Caen, Institut Normand de Chimie
Moléculaire, Médicinale et Macromoléculaire (INC3M), CNRS
6 Boulevard du Maréchal Juin, 14050 Caen, France
Fax: +33-2-31452877
E-mail: jerome.baudoux@ensicaen.fr
jacques.rouden@ensicaen.fr
[b] UMR-CNRS6014 & FR3038 COBRA, Université de Rouen,
INSA de Rouen, Institut Normand de Chimie Moléculaire,
Médicinale et Macromoléculaire (INC3M),
1 rue Tesnière, 76130 Mont Saint Aignan, France
E-mail: stephane.leleu@univ-rouen.fr
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200900xxx.
Scheme 2. Carroll rearrangement catalyzed by a strong base or a
transition metal.
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Metal-Free SN2Ј Decarboxylative Rearrangement of β-Keto Esters
and because of its sensitivity to the structures of the sub- and 8a could be explained by an intermolecular decarboxyl-
strates. Several methods have been designed to circumvent ation–SN2Ј sequence involving two molecules of 2a
these limitations. The reaction can be accelerated by the use (Scheme 4).
of strong bases[13] or a Lewis acid.[14] However, these meth-
ods suffer from the need for two equivalents of base and
requires an additional step to carry out the decarboxyl-
ation. Recently, decarboxylations of allyl β-keto carboxyl-
ates catalyzed by transition metals (Ru,[15] Pd[16]) in the
presence of chiral ligands have been successfully developed.
Adsorption of β-keto esters on neutral alumina has also
been used for the Carroll rearrangement of a precursor of
zincophorin.[17] Under organocatalytic conditions, the treat-
ment of an allylic alcohol with diketene in the presence of
collidine[18] or 4-(dimethylamino)pyridine (DMAP)[19] af-
forded good yields of the rearranged product.
Table 1. Tandem alkylation–decarboxylation of ester 2a.
Entry
Base[a]
Conditions
T [°C] Conv. [%] Ratio [%][b]
1a
7a
8a
1
2
NaH
THF
r.t.
r.t.
100
37
54
13
14
0
29
23
Cs2CO3,
PTC[c]
Et3N[d]
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
CD2Cl2/H2O (1:0.1)
3
CH2Cl2
r.t.
100
100
100
47
60–66
67
40–34
33
33
9
0
4
CH2Cl2 (0.05 or 0.2 m) r.t.
0
5
MeCN
toluene
THF
r.t.
r.t.
r.t.
r.t.
0
67
0
6
23
15
13
19
11
0
7
86
52
21
9
8
MeOH
CH2Cl2
CH2Cl2
THF
80
52
When the R2 group of compound 2 (Scheme 2) was an
electron-withdrawing group, Craig et al.[20] and You et al.[6]
recently observed, under basic conditions, the formation of
γ-lactone derivatives. A Michael addition of the keto enol-
ate to the double bond could account for these observa-
tions. These results prompted us to describe our first results
with model substrates 2 (R = H, Me, allyl, benzyl) and 6
(Scheme 3) and to demonstrate that their reaction in the
presence of a nucleophile catalyst involves an SN2Ј–decar-
boxylation–SN2Ј sequence of the allyl acetoacetate rather
than a base-catalyzed rearrangement.
9
53
20
22
24
23
12
10
11
12
40
65
65
100
100
100
76
77
0
MeOH
88
0
[a] Reagents and conditions: 2a (0.1 m), base (20 mol-%), r.t., 17 h.
[b] Determined from the 1H NMR spectra of the crude product
using 1,4-bis(trichloromethyl)benzene as an internal standard. All
the products were isolated and characterized. [c] Phase-transfer
conditions with NEt3BnBr. [d] Reactions performed with Et3N
loadings of 25, 50, 100, or 150 mol-% gave similar results.
Scheme 3. Synthesis of allyl acetoacetates 2a–d and 6.
Scheme 4. Plausible reaction pathways for the transformation of 2a
under basic conditions.
To optimize the formation of 1a we studied the reaction
parameters in more detail. Phase-transfer catalysis in the
Results and Discussion
Allyl acetocetates 2 were prepared by reaction of the presence of cesium carbonate and triethylbenzyl ammo-
Baylis–Hillman adduct 3[21] with 2,2,6-trimethyl-4H-1,4-di- nium bromide led to a slow reaction in a mixture of CDCl3/
oxin-4-ones 5[22] (Scheme 3). Nitrile 6 was obtained in a H2O (Table 1, entry 2); under these conditions, triester 8a
similar way from nitrile 4[23] and dioxinone 5a. Allyl ester was the major product formed, even after a prolonged reac-
2a could also be prepared in quantitative yield from alcohol tion time. In this context, homogeneous organocatalysis
3 and diketene (1 equiv.) in the presence of DMAP (2 mol- could be a valuable method to synthesize 1a from 2a. The
%) in dichloromethane at room temperature for 24 h.
application of organic bases were therefore tried. Triethyl-
Initial attempts to study the formation of compounds 1 amine was chosen to avoid possible side reactions with the
from allyl esters 2 were performed with 2a and sodium hy- Michael acceptor.[24] Catalytic, stoichiometric, or an excess
dride (1 equiv.) in tetrahydrofuran (THF) at 20 °C for 17 h. amount of Et3N in dichloromethane at room temperature
The expected product 1a, together with diester 7a and tri- for 17 h (Table 1, entry 3) afforded the expected compound
ester 8a, were formed in 54, 14, and 29% molar ratio, 1a and the diester 7a with total conversion of the starting
respectively (Table 1, entry 1). The presence of products 7a material. Regardless of the amount of amine used, the ratio
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1a/7a was in the same range (Table 1, entry 3). Poor conver- be mediated by a nucleophile. Thus, we can assume that
sion (47%) and the formation of a mixture of triester 8a an initial SN2Ј reaction of the nucleophile[29] leads to the
(9%), diester 7a (7%), and target compound 1a (16%) was formation of cation III and acetoacetate anion II
observed with a lower amount of Et3N (5 mol-%, data not (Scheme 5). Rapid decarboxylation of this latter intermedi-
shown). Dilution had no effect on the ratio of 1a/7a, as ate to acetone enolate IV and recombination of IV with III
shown in Table 1, entry 4.
(through a second SN2Ј reaction), would give 1a. Such an
Different solvents were screened at room temperature. SN2Ј–decarboxylation–SN2Ј sequence has been suggested
Acetonitrile (Table 1, entry 5) was as effective as dichloro- when N-p-tolylsulfonyl-substituted carbamates were treated
methane. In toluene (Table 1, entry 6) and in THF (entry with DABCO to afford N-allyl allylamines.[30]
7) the reaction was incomplete. A mixture of products was
also formed when the reaction was performed in methanol
(entry 8), although protic solvents were usually efficient in
Michael addition of β-keto esters enolates.[25]
The influence of temperature was then studied. In dichlo-
romethane at 0 °C (Table 1, entry 9), only half of the start-
ing material reacted, and a mixture of 1a, 7a, and 8a was
formed. At 40 °C (Table 1, entry 10), 1a and 7a were formed
as the sole reaction products with a slightly improved ratio
of 1a/7a (76:24). A similar result was observed in THF at
65 °C (Table 1, entry 11). In methanol at 65 °C (Table 1,
entry 12) the ratio 1a/7a was slightly improved, but other
unidentified side products were also formed.
Scheme 5. Plausible reaction pathways for the transformation of 2a
under nucleophilic conditions.
A deeper analysis of the formation of compounds 1a, 7a,
and 8a was undertaken by considering the ability of non-
nucleophilic bases to catalyze the reaction and by monitor-
Moreover, under the standard conditions, 1H NMR spec-
troscopic monitoring of 2a in the presence of Et3N (Fig-
ure 1) showed that triester 8a (which could not be isolated
in pure form) was rapidly formed in the reaction mixture.
As the reaction proceeded, the amount of 8a decreased as
a function of time, whereas those of compounds 1a and 7a
increased by means of an SN2Ј reaction (Scheme 4).
1
ing the reaction by H NMR and IR spectroscopy. In the
presence of non-nucleophilic bases (Hünig’s base, tri-tert-
butylpyridine, proton sponge, and, to a less extent, tet-
ramethylpiperidine, Table 2, entries 1–4), the conversion
was poor and the triester 8a was the main product formed.
Table 2. Reaction of 2a in the presence of amines or triphenylphos-
phane.
Entry[a]
Catalyst
Time
Conv. [%] Ratio [%][b]
1a
7a
8a
1
2
3
4
5
6
7
8
9
DIPEA
(tBu)3Py[c]
PS[d]
13 d
13 d
17 h
13 d
17 h
17 h
17 h
5 h
35
0
15
94
100
100
100
91
9
0
26
5
0
10
13
0
0
0
19
16
TMP[e]
DABCO
DBU
36
59
67
69
63
67
45
41
33
31
9
DMAP
Ph3P
Ph3P
1
Figure 1. H NMR spectroscopic monitoring the reaction of 2a in
the presence of Et3N (20 mol-%) in CD2Cl2 (at room temperature).
46 h
95
12
[a] Reagents and conditions: catalyst (20 mol-%), solvent (CH2Cl2
or CD2Cl2), r.t. [b] Determined by 1H NMR spectroscopic analysis
of the crude product using 1,4-bis(trichloromethyl)benzene as an
internal standard. [c] 2,4,6-tert-Butylpyridine. [d] Proton sponge or
1,8-diaminonaphthalene. [e] Tetramethylpiperidine.
Under nucleophilic conditions, we suggest an SN2Ј de-
carboxylation cascade reaction takes place, leading to the
formation of 1a and 7a via the intermediates III and IЈ
(Scheme 6).
In the presence of a nucleophilic catalyst (amines such as
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4-diazabicy-
clo[2.2.2]octane (DABCO), or DMAP, Table 2, entries 5–7,
or triphenylphosphane, Table 2, entries 8 and 9), the results
were similar to those obtained with Et3N. The higher nu-
cleophilicity towards C-sp2 centers of DBU,[26] Et3N,[27] and
DABCO[28] compared to that of Ph3P[26] could account for
the total conversion of the starting material observed with
the amines. These results suggest that the transformation of
Scheme 6. Conversion of 8a into 1a and 7a catalyzed by a nucleo-
2a into 1a was not exclusively base-catalyzed but could also phile.
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Metal-Free SN2Ј Decarboxylative Rearrangement of β-Keto Esters
To clarify the overall mechanism, the reaction of 2a in verted into its enolate I, whereas with a nucleophile
the presence of a base (inorganic then organic) were moni- (DABCO), spontaneous appearance of carbon dioxide and
tored by in situ infrared spectroscopy. Spectra were re- acetone enolate IV confirmed the nucleophilic sequence.
corded with a ReactIRTM 4000 instrument fitted with an Whereas the nucleophilic mechanism seems to operate im-
immersible DiComp ATR probe.
mediately, even under catalytic conditions, the stoichiomet-
The in situ IR monitoring of 2a in the presence of NaH ric base-induced reaction takes place with a delayed time.
(1 equiv.) showed a band at 1591 cm–1. This absorption is Therefore, we can speculate that most of the products made
characteristic of the C=C band of an enolate,[31] and sug- in this reaction arose from an initial SN2Ј–decarboxylation
gested that rapid conversion of 2a into enolate I takes place reaction sequence, leading the the formation of acetone
(Figure 2). When the reaction was monitored for longer enolate IV, which is capable of producing 1a (Scheme 5) or
periods of time, this absorption band slowly disappeared undergoing the transformations observed under basic con-
(see the Supporting Information, Figure SI1).
ditions (Scheme 4) through deprotonation of 2a.
Finally, the reaction of methyl ketone methyl ester 2a and
propyl ketone ethyl ester 9 was investigated. Keto ester 9
was first synthesized by using the method previously de-
scribed for keto ester 2a (see the Supporting Information).
Upon treatment with triethylamine (1 equiv.) for 17 h at
room temperature, 9 afforded compounds 10 and 11 (77:23
1
molar ratio determined by H NMR spectroscopic analy-
sis).
A mixture of 2a and 9 was then stirred at room tempera-
ture for 17 h in the presence of triethylamine (1 equiv.).
Analysis of the reaction mixture by GC/MS showed that a
cross-reaction had taken place with the formation of the
four keto esters 1a, 10, 12, and 14 in similar amounts
(Scheme 7), together with the keto diesters 7a, 11, 13, and
15–17. These results strongly support the postulated inter-
molecular SN2Ј reaction of allyl keto esters 2 and 9 in the
presence of a nucleophile.
Figure 2. In situ IR monitoring of 2a in the presence of NaH.
The reaction of 2a in the presence of DABCO (1 equiv.)
was monitored similarly. As soon as 25% of DABCO was
added, an absorption band characteristic of carbon dioxide
appeared at 2340 cm–1 (Figure 3). This band disappeared
with time (CO2 desorption, see the Supporting Information,
Figure SI2). At the same time, a C=C absorption band
clearly appeared at 1632 cm–1. This band was attributed
with confidence to the acetone enolate IV (see the Support-
ing Information, Figure SI3).
Scheme 7. Reaction of 2a and 9 in the presence of Et3N.
The reactivity of esters bearing a methoxycarbonyl (2a),
a nitrile (6), or a hydrogen (20) on the allylic double bond
were then compared (Scheme 8).
Figure 3. In situ IR monitoring of 2a in the presence of DABCO.
These in situ IR monitoring experiments revealed that
As expected, no reaction occurred with substrate 20,
different initial pathways were followed, depending on bearing a monosubstituted allylic double bond, whereas ni-
whether a base or a nucleophile was used as catalyst. With trile 6 afforded the keto nitrile 18 in 78% yield, which was
one equivalent of base (NaH) the substrate was rapidly con- higher than that obtained with ester analogue 2a.
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J. Baudoux, S. Leleu, J. Rouden et al.
FULL PAPER
(or phosphane) catalysis into α-methylene δ-keto esters or
nitrile through a tandem SN2Ј–decarboxylation–SN2Ј se-
quence. By 1H NMR and in situ IR analysis of the reactions
carried out in the presence of various bases or nucleophiles,
it was demonstrated that the use of a non-nucleophilic base
led to low conversion of 1a. With a nucleophilic base, the
transformation of 2a into 1a was followed simultaneously
by a base-catalyzed and a nucleophile-catalyzed pathway. A
cross-experiment demonstrated that an intermolecular
mechanism was operating. Therefore, we can conclude that
the reaction only required a good nucleophile to proceed to
completion. Although it has not been possible to avoid the
formation of diester 7a with the unsubstituted allyl aceto-
acetate 2a, α-substituted β-keto esters afforded products
1b–d, bearing a newly formed stereocenter, nearly exclu-
sively and in good yields. This study, which unveiled the
mechanism and determined the main parameters involved
in the reaction, will enable the scope of the transformation
to be broadened while preventing the formation of side
products. These developments should also allow the stereo-
chemical outcome of the reaction to be controlled. These
aspects are under study in our laboratory.
Scheme 8. Influence of the substituent on the double bond on the
Et3N-catalyzed reaction of allyl acetoacetates.
Moving to the α-methyl acetoacetate 2b (Scheme 9), the
reaction with 20 mol-% Et3N in dichloromethane at room
temperature was tested. The reaction was stopped after 17 h
1
for comparison with the previous experiments. H NMR
analysis of the crude reaction mixture showed that 22% of
the starting material was recovered and that the desired
product 1b was formed in 74% NMR yield, with no diester
7 being observed. However, the reaction product was con-
taminated by triester 8 (molar ratio 1b/8 of 96:4). At –20 °C
(4 d), or at 40 °C (14 h), the amount of 8 formed was higher
(ratio 1b/8, 75:15 and 87:10, respectively, with complete
conversion). Benzyl and allyl acetoacetates 2c and 2d were
less reactive and required longer reaction times (7 and 5 d,
respectively)[32] to afford the expected product 1c or 1d in
59 and 60% NMR yields, or 38 and 60% isolated yields.
We were pleased to observe that the desired products were
formed without any diester 7 or triester 8 being observed
(Scheme 9). The absence of these side compounds is proba-
bly due to the presence of a substituent on the enolate,
which prevents further addition that would lead to the for-
mation of a quaternary carbon atom.
Experimental Section
Typical Procedure for the Synthesis of Allyl Acetoacetates: To a
stirred solution of dioxinone 5 (66.8 mmol, 1.02 equiv.) in xylene
(31 mL) was added the allylic alcohol (65.5 mmol, 1 equiv.). The
mixture was heated at 110 or 140 °C for 10 or 50–80 min, de-
pending on the dioxinone used. After cooling, the mixture was con-
centrated under vacuum and xylene was removed by distillation
(kugelrohr, 60 °C). The residue was purified by flash chromatog-
raphy on silica gel.
Typical Procedure for the Decarboxylative Rearrangement: To a
stirred solution of allyl ester (0.5 mmol, 1 equiv.) in the appropriate
solvent (5 mL), was added the catalyst (0.1 mmol, 0.2 equiv.). The
mixture was stirred at the given temperature for 17 h, then the sol-
vent was evaporated. The residue was diluted in dichloromethane
(5 mL) and saturated NH4Cl (5 mL) was added. The aqueous layer
was extracted with dichloromethane (3ϫ5 mL) and the combined
organic layers were dried with MgSO4, filtered, and concentrated
under reduced pressure.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures and characterization of the products.
Acknowledgments
We gratefully acknowledge the Ministère de l’Enseignement Supéri-
eur et de la Recherche, Agence Nationale de la Recherche (ANR),
“Mesorcat” (Programme Chimie Pour le Développement Durable
CP2D), Centre National de la Recherche Scientifique (CNRS),
Région Basse-Normandie, and the European Union (FEDER
funding) for financial support.
Scheme 9. Et3N-catalyzed reaction of substituted allyl acetoacet-
ates 2b–d.
Conclusions
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Published Online: June 1, 2011
Eur. J. Org. Chem. 2011, 4170–4175
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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