N-heterocyclic carbene-catalyzed michael additions of 1,3-dicarbonyl compounds

Article abstract of DOI:10.1002/chem.201002538

A study of the organocatalytic activity of N-heterocyclic carbenes (NHCs) in the Michael addition of 1,3-dicarbonyl compounds has allowed us to identify 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene (IPr) as an excellent catalyst for this transformatio

Full text of DOI:10.1002/chem.201002538

DOI: 10.1002/chem.201002538
N-Heterocyclic Carbene-Catalyzed Michael Additions of 1,3-Dicarbonyl
Compounds
Thomas Boddaert, Yoann Coquerel,* and Jean Rodriguez*[a]
Abstract: A study of the organocatalyt-
ic activity of N-heterocyclic carbenes
(NHCs) in the Michael addition of 1,3-
dicarbonyl compounds has allowed us
to identify 1,3-bis(2,6-diisopropylphe-
nyl)imidazol-2-ylidene (IPr) as an ex-
cellent catalyst for this transformation
(up to 99% yield with a 2.5 mol% cat-
alyst loading), and the reaction was
found to be of broad scope. Two early
applications of this unprecedented cat-
alytic activity of NHCs are described,
that is, the domino carbocyclization re-
actions of simple cyclic 1,3-dicarbonyl
and malonic acid derivatives, which
allow stereoselective access to bridged
bicyclic compounds, and the stereose-
lective synthesis of cyclohexanols (or
cyclohexene). Early mechanistic inves-
tigations are also reported.
Keywords: carbenes
· dicarbonyl
compounds · domino reactions · Mi-
chael addition · organocatalysis
Introduction
years, the Michael addition has become the cornerstone of
many enantioselective organocatalytic processes.[5]
The Michael addition is one of the most important reactions
for the creation of carbon–carbon bonds.[1] The two essential
features of this reaction are its reliability for the still-chal-
lenging creation of all-carbon chiral quaternary centers, and
its potency in anionic domino reactions[2] for the construc-
tion of several covalent chemical bonds in a single opera-
tion.[3] In the laboratory, these reactions are traditionally
performed by simple treatment of a pronucleophile contain-
ing at least one enolizable or related position with a stoi-
chiometric amount of base in the presence of an a,b-unsatu-
rated carbonyl group or related stabilizing, electron-with-
drawing group. With the advancements in the science of syn-
thesis, several catalytic systems have been made available to
perform efficient Michael addition reactions,[4] and in recent
The discovery of new classes of catalyst for Michael addi-
tion reactions and related domino reactions is of considera-
ble importance. In the past decade, catalysis by N-heterocy-
clic carbenes (NHCs) has received considerable attention,[6]
and we have recently reported the serendipitous discovery
of the excellent organocatalytic activity of N,N-diaryl-1,3-
imidazol(in)-2-ylidenes in intramolecular Michael additions
of 1,3-dicarbonyl compounds, and its application to the ste-
reoselective synthesis of spiro compounds (Scheme 1).[7]
Herein, we report our studies on the scope of the NHC-cat-
alyzed Michael addition[8] of 1,3-dicarbonyl derivatives and
related compounds, some applications to stereoselective or-
ganocatalytic domino carbocyclization reactions, and the re-
sults of early mechanistic investigations.
[a] Dr. T. Boddaert, Dr. Y. Coquerel, Prof. Dr. J. Rodriguez
Institut des Sciences Molꢀculaires de Marseille
iSm2—UMR CNRS 6263, Aix-Marseille Universitꢀ
Centre Saint Jꢀrꢁme, Service 531
13397 Marseille cedex 20 (France)
Fax : (+33)491-289-187
E-mail: yoann.coquerel@univ-cezanne.fr
jean.rodriguez@univ-cezanne.fr
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201002538. It contains the gen-
eral experimental information, full experimental procedures, charac-
terization data of all compounds, and copies of NMR spectra of all
new compounds.
Scheme 1. The NHC-catalyzed Michael-based spirocyclization; HMDS=
1,1,1,3,3,3-hexamethyldisilazane; Mes=mesityl (2,4,6-trimethylphenyl).
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FULL PAPER
Table 2. Scope of the NHC-catalyzed Michael addition reaction.
Results and Discussion
The work started with a brief optimization study of the ar-
chetypal intermolecular NHC-catalyzed Michael addition of
methyl 2-oxocyclopentanecarboxylate (5a) to methyl acry-
late (Table 1), which indicated that IPr (3, 2.5 mol%) in di-
Table 1. Optimization study of the NHC-catalyzed Michael addition re-
action.
Substrate R1
EWG
OMe CO2Me
OMe CONH2 15
IPr (3) [mol%] Product Yield [%][a]
1
2
3
4
5
6
7
8
5a
5a
5a
5b
5c
5d
7a
7a
2.5
6a
6b
6c
6d
6e
6 f
8a
8b
8c
96
82
97
74
94
99
99
95
78
OMe SO2Ph
OtBu CN
Me
NHPh CN
Me
Me
H
5
10
5
Solvent
NHC[a]
Yield [%][b]
CO2Me
1
2
3
4
5
6
7
8
9
CH2Cl2
toluene
THF
Et2O
DMF
CH3CN
CHCl3
MeOH
pentane
CH2Cl2
CH2Cl2
IPr (3)
IPr (3)
IPr (3)
IPr (3)
IPr (3)
IPr (3)
IPr (3)
IPr (3)
IPr (3)
IMes
98
42
68
34
96
71
47
6
5
CHO
2.5
COMe
COMe
2.5
2.5
9[b] 7b
[a] Yields for isolated products obtained after silica gel flash column
chromatography. [b] Reaction performed with 1.0 equivalent of the acryl-
ic derivative.
<5
95
75
10
11
Table 3. The NHC-catalyzed domino Michael–aldol reaction.
SIMes
Substrate
Conditions[a]
Product
(Yield, d.r. OHax/OHeq
[a] IPr=1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene;
bis(2,4,6-trimethylphenyl)imidazol-2-ylidene;
methylphenyl)imidazolin-2-ylidene. [b] Yields were determined by GC
using naphthalene as the internal standard.
IMes=1,3-
SIMes=1,3-bis(2,4,6-tri-
[b]
)
ACHTUNGTRENNUNG
3 (20 mol%)
1
2
3
5a
5c
5d
CH2Cl2, 4 h
chloromethane or DMF gave the best results (Table 1, en-
tries 1 and 5, respectively). Alternatively, IMes and SIMes
(generated in situ by treatment of their respective chlorohy-
drates with KHMDS) were also efficient catalysts, leading
to Michael adduct 6a in 95 and 75% yield, respectively
(Table 1, entries 10 and 11).[9] The scope of the reaction with
various 1,3-dicarbonyl compounds and representative acrylic
derivatives was examined next (Table 2). The reaction
proved to be very general and proceeded in good to excel-
lent yields, with either cyclic or acyclic pronucleophiles (5
and 7, respectively), such as 1,3-ketoesters, 1,3-diketones,
1,3-ketoamides, and 1,3-diesters (Table 2, entries 1–4, 5, 6,
and 7–9, respectively) in combination with methyl acrylate,
acrylamide, phenyl vinyl sulfone, acrylonitrile, methyl vinyl
ketone, or acrolein (Table 2, entries 1 and 5, 2, 3, 4 and 6, 8
and 9, and 7, respectively).
3 (10 mol%)
CH2Cl2, 20 h
3 (5 mol%)
CH2Cl2, 20 h
3 (10 mol%)
CH2Cl2, 20 h
4
5
10
3 (10 mol%)
MeOH, 20 h
11 (90%, d.r.=1:1)
[a] All reactions performed with acrolein (1.2 equiv) at room tempera-
ture; reaction times and catalyst loading were not optimized. [b] Yields
for isolated products obtained after silica gel flash column chromatogra-
phy; the diastereomeric ratios were determined from 1H and 13C NMR
data of the crude material.
Interestingly, for the reaction of cyclic 1,3-ketoester 5a
(as the pronucleophile) with acrolein, the reaction evolved
through the known domino Michael–aldol sequence,[10] lead-
AHCTUNGTRENNUNG
ing to bicycloACHTUNGTRENNUNG
[3.2.1]octanol[11] 9a as a 4:1 mixture of two dia-
stereomers (Table 3, entry 1). This transformation proved
equally efficient with 1,3-diketone 5c and ketoamide 5d
(Table 3, entries 2 and 3, respectively), and was successfully
extrapolated to the formation of the corresponding bicyclo-
(MARDi cascade) previously developed in our laboratory
(Scheme 2).[13] Thus, 5a was allowed to react with crotonal-
dehyde in methanol in the presence of IPr (3; 20 mol%),
which provided bicycloACHTNUTRGNE[UGN 3.2.1]octanols 12 (41%, d.r. OHax/
OHeq =2.9:1) and the expected cycloheptanol 13 (39%, only
A
10 (Table 3, entries 4 and 5).
a single diastereomer was detected). In a separate experi-
Encouraged by these results, we examined the possibility
of preparing cycloheptanol 13 from b-keto ester 5a, croton-
ment, the diastereomeric mixture of bicyclo
12 (d.r.=2.9:1) was placed back under the reaction condi-
ACHTUNGTREN[NGNU 3.2.1]octanols
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2267

Y. Coquerel, J. Rodriguez, and T. Boddaert
(Scheme 3). It is worth noting
that
comparable
domino
double-Michael–aldolization se-
quences have only been report-
ed to proceed efficiently with
organometallic catalysts for 1,3-
dicarbonyl derivatives[14] or
with a stoichiometric amount of
base for nitroalkanes.[15] The
Scheme 2. The NHC-catalyzed three-component domino Michael–aldol–retro-Dieckmann reaction.
tions (MeOH, 3 (20 mol%)) without any detectable change
in the diastereomeric ratio. These two experiments indicate,
by comparison with the mechanism of the base-promoted
MARDi cascade reaction,[13c] which involves a fully reversi-
ble Michael–aldol sequence and the selective retro-Dieck-
domino reaction proceeded well with a variety of pseudoa-
cids, yielding minor amounts of double Michael adducts 14
and the expected cyclohexanols 15 with generally good to
excellent diastereoselectivities (Scheme 3). If acrolein is
used as the Michael acceptor, the domino Michael–Mi-
chael–aldol sequence is extended by a dehydration step to
give a,b-unsaturated aldehyde 16. Importantly, in a separate
experiment, the reaction of double Michael adduct 14e with
IPr (3, 10 mol%) at room temperature for 48 h yielded aldo-
lization product 15e (93%, d.r.=3:1:1:e). This experiment
demonstrates that IPr (3) is not only an excellent catalyst
for the Michael addition, but also for the intramolecular
aldol reaction, although at a slower rate due to a higher pKa
value of the pronucleophile.
ACHTUNGTRENNUNGmann fragmentation of only the bicycloHCATUNGTRENN[UGN 3.2.1]octanol that
has both methyl and hydroxyl substituents in equatorial po-
sitions, that the NHC-catalyzed domino Michael–aldol reac-
tion is not reversible (or is reversible at a very slow rate),
under the conditions studied.
During our studies on NHC-catalyzed Michael addition
reactions with 1,3-dicarbonyl pronucleophiles containing an
activated methylene reaction site (e.g., 7b in Table 2), we
observed minor amounts of double Michael-addition prod-
ucts 14 (Scheme 3). In light of this precedent, we surmized
that this reactivity could be exploited for the preparation of
cyclohexanols by following an organocatalytic, domino Mi-
chael–Michael–aldol reaction if the reaction is performed in
the presence of an excess of methyl vinyl ketone
With few exceptions, the NHC-catalyzed Michael addition
reactions described herein have allowed the formation of
chiral, all-carbon quaternary centers. Logically, we have ex-
amined the possibility of an asymmetric version of these re-
actions by using some known chiral NHCs (Scheme 4). The
triazolylidene NHC derived
from 17a[16] did not promote a
Michael addition in the model
reaction between benzyl 2-oxo-
cyclopentane carboxylate (5e)
and acrylonitrile, and no enan-
tioselectivity was observed on
using the C2-symmetric chiral
imidazolin-2-ylidene NHC de-
rived from 17b[17] or the imida-
zol-2-ylidene NHC derived
from 17c[18] in the reaction be-
tween 5e and methyl vinyl
ketone to give adduct 6h
(Scheme 4).
These results raise questions
about the origin of the excellent
catalytic activity of the NHCs
in Michael addition reactions.
A deuterium labeling experi-
ment confirmed that, in the cat-
alytic cycle, the acidic deuteri-
um atom in d1-5a is quantita-
tively transferred to the a posi-
tion of the Michael acceptor in
the adduct d1-6a (Scheme 5).
To better understand the role
of the NHC catalyst in these
Michael additions, a series of
Scheme 3. The NHC-catalyzed domino Michael–Michael–aldol reaction. Only the major diastereomer is de-
picted. [a] The crude mixture contained 16 (ꢀ90% yield) but the product, not surprisingly, partially decom-
posed upon silica gel purification.
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Chem. Eur. J. 2011, 17, 2266 – 2271

Micheal Addition Reactions
FULL PAPER
Table 4. Control experiments.[a]
Substrate Conditions
Yield [%][b]
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1a
1a
1a
1b
1a
basic Al2O3 (excess), MeOH, 508C, 24 h
<5
<5
<5
<5
KHMDS (1 equiv), THF, RT, 6 h
tBuOK (1 equiv), THF, RT, 6 h
iPrNEt2 (1 equiv), CH3CN, RT, 6 h
K2CO3 (1 equiv), acetone, RT, 6 h
DBU (1 equiv), CH2Cl2, RT, 6 h
DBU (20 mol%), CH2Cl2, RT, 6 h
basic Al2O3 (excess), MeOH, 508C, 24 h
nBu3P (20 mol%), CH2Cl2, RT, 6 h
<5
Scheme 4. NHC-catalyzed Michael addition reactions with chiral NHCs.
degradation
degradation
<5
<5
10 1a
11 1a
12 1a
13 1b
14 1b
15 1b
16 1a
17 1b
nBu3P (1 equiv), CH2Cl2, 1008C, 20 min[c] <5
Cy3P (1 equiv), CH2Cl2, 1008C, 20 min[c]
<5
<5
DABCO (20 mol%), CH2Cl2, RT, 6 h
nBu3P (1 equiv), CH2Cl2, 1008C, 20 min[c] <5
DMAP (20 mol%), CH2Cl2, RT, 48 h
PhNC (20 mol%), CH2Cl2, RT, 48 h
3 (20 mol%), CH2Cl2, RT, 20 h
3 (20 mol%), CH2Cl2, RT, 3 h
<5
<5
97
Scheme 5. A deuterium labeling experiment (ca. 80% deuterium incor-
poration in both d1-5a and d1-6a).
93
[a] DBU=1,8-diazabicycloundec-7ene;
DABCO=1,4-diazabicyclo-
AHCTUNGERTG[NNUN 2.2.2]octane; DMAP=4-dimethylaminopyridine. [b] Yields determined
by 1H NMR spectroscopy of the crude reaction mixture for entries 1–15,
and for isolated products obtained after silica gel flash column chroma-
tography for entries 16 and 17. [c] Reaction performed in a sealed vessel
under microwave irradiation.
control experiments was performed. We have examined the
intramolecular Michael addition of substrates 1a and b[19] to
give spiro products 4a and b, first with a representative set
of bases (Table 4, entries 1–8), and then with a set of nucleo-
philic additives known to catalyze Michael addition reac-
tions (Table 4, entries 9–15). Surprisingly, under none of
these conditions could the desired spiro products 4 be ob-
tained efficiently (very minor amounts of 4 were detected in
some cases), whereas NHC 3 afforded both spiro products
4a and b in high yields and diastereoselectivities (Table 4,
entries 16 and 17, respectively). Although N,N-dialkylimida-
zol(in)-2-ylidene NHCs have been described as strong
Brønsted bases (ca. pKa,DMSO =21–24),[20] the N,N-diaryl ana-
logues are somewhat less basic (ca. pKa,DMSO =16–17).[21]
From the results in Table 4, entries 1–8, it seems that, in
these reactions, NHC catalyst 3 is not acting as a “classic”
Brønsted base. From the results of Table 4, entries 9–15, a
mechanism initiated by conjugate nucleophilic addition of
NHC 3 to the activated olefin to generate a basic imidazoli-
um enolate appears unlikely.[22] Plausible alternative mecha-
nisms have been considered. Among these, a mechanism in-
volving NHC 3 as a simple Brønsted base initiator of the re-
action could not be totally ruled out, although it is unlikely
considering its potency in the catalyzation of aldol reactions
(e.g., 14e!15e). A non-coordinating counterion effect of
the protonated NHC may also be envisioned by analogy to
the chemistry of quaternary ammonium ions.[23] The purely
carbenic properties of the NHC could also be involved, with
a catalytic cycle initiated by an insertion reaction of the car-
Based on the above set of data, we propose that in these
Michael additions the NHC is acting as a unique and opti-
mal combination of a catalytic Brønsted base and Lewis
acid on the same carbon atom, as illustrated in Scheme 6.[25]
The catalytic cycle would be initiated by the formation of
enolate–imidazolium complex I in which the carbene plays
ꢁ
bene into the activated C H bond of the pseudoacid, as de-
scribed by Arduengo,[24] but in this case, some enantioselec-
tivity would be expected with optically active chiral NHCs.
Scheme 6. The proposed catalytic cycle.
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2269

Y. Coquerel, J. Rodriguez, and T. Boddaert
[2] Monograph: a) L. F. Tietze, G. Brasche, K. M. Gericke, Domino Re-
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1085–1109.
[3] For discussions on the terminology of multiple-bond-forming reac-
tions, see: a) L. F. Tietze, U. Beifuss, Angew. Chem. 1993, 105, 137–
170; Angew. Chem. Int. Ed. Engl. 1993, 32, 131–163; b) Y. Coquerel,
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the role of a Brønsted base in a similar manner to the
methyl acetoacetate–IAd (IAd=1,3-bis(1-adamantyl)imida-
zol-2-ylidene) complex reported by Nolan.[26] Complex I
would then behave as a Lewis acid and activate the electro-
phile, as depicted in complex II, which would evolve to
afford the Michael adduct and regenerate the NHC.
Conclusion
In summary, the unprecedented organocatalytic activity of
N,N-diaryl-1,3-imidazol(in)-2-ylidene NHCs in the Michael
addition of 1,3-dicarbonyl compounds and their analogues
has been studied. IPr (3) was identified as the most potent
catalyst for this transformation (up to 99% yield with a
2.5 mol% catalyst loading), and the reaction was found to
be broad in scope. Some applications of this catalytic reac-
tion are described, that is, the domino carbocyclization reac-
tions of simple cyclic 1,3-dicarbonyl compounds and malonic
acid derivatives, which allow, respectively, a stereoselective
route to bridged bicyclic compounds or cycloheptanols, and
the stereoselective synthesis of cyclohexanols (or cyclohex-
ene). The excellent catalytic activity of NHCs in these Mi-
chael addition reactions appears to entail a dual activation
mode, in which both the s-donor and p-acceptor properties
of the NHC are involved. We surmise that other applica-
tions of the unique reactivity of NHCs with pseudoacids de-
scribed herein will soon be discovered.
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Representative procedure: the synthesis of 6c (Table 2, entry 3): Phenyl
vinyl sulfone (50 mg, 0.30 mmol) and IPr (3, 5 mg, 0.013 mmol) were suc-
cessively added to a solution of 5a (31 mL, 0.25 mmol) in dichlorome-
thane (2.5 mL), and the resulting mixture was stirred for 3 h at room
temperature, whereupon the reaction mixture was concentrated under
vacuum. The resulting crude product was directly purified by silica gel
flash column chromatography eluted with EtOAc/petroleum ether (3:2)
to afford pure 6c (75 mg, 97%) as a colorless oil. Rf =0.14 (EtOAc/petro-
leum ether, 3:7); 1H NMR (300 MHz, CDCl3): d=7.83 (d, J=7.6 Hz,
2H), 7.60 (d, J=8.1 Hz, 1H), 7.52 (dd, J=7.6, 8.1 Hz, 2H), 3.58 (s, 3H),
3.26–3.41 (m, 1H), 3.02–3.16 (m, 1H), 2.45–1.74 ppm (m, 8H); 13C NMR
(75 MHz, CDCl3): d=213.5 (C), 170.8 (C), 138.5 (C), 133.6 (CH), 129.1
(2CH), 127.7 (2CH), 57.8 (C), 52.5 (CH3), 51.7 (CH2), 37.6 (CH2), 33.9
(CH2), 26.1 (CH2), 19.3 ppm (CH2); HRMS (ESI+): m/z calcd for
C15H19O5S+: 311.0948; found: 311.0953 [M+H]+; m/z calcd for
C15H22NO5S+: 328.1213; found: 328.1214 [M+NH4]+.
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Received: September 2, 2010
Published online: January 5, 2011
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