Efficient catalysis of aqueous Morita-Baylis-Hillman reactions of cyclic enones by a bicyclic imidazolyl alcohol

Article abstract of DOI:10.1002/ejoc.201200950

In this paper a new phosphorus-free catalyst for the Morita-Baylis-Hillman reaction is disclosed. A bicyclic imidazolyl alcohol having a Lewis basic center associated with a hydrogen-bond donor group was used as catalyst for the reaction. Aliphatic cycloalkanones such as 2-cyclopentenone and 2-cyclohexanone and aliphatic and aromatic aldehydes were used successfully, and the reaction was found to work nicely using water as solvent in the presence of a phase-transfer additive. Copyright

Full text of DOI:10.1002/ejoc.201200950

Job/Unit: O20950
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FULL PAPER
DOI: 10.1002/ejoc.201200950
Efficient Catalysis of Aqueous Morita–Baylis–Hillman Reactions of Cyclic
Enones by a Bicyclic Imidazolyl Alcohol
Juliana C. Gomes,[a] Manoel T. Rodrigues Jr.,[a] Albert Moyano,[b] and Fernando Coelho*[a]
Keywords: Organocatalysis / Synthetic methods / Heterocycles / Aldehydes / Ketones
In this paper a new phosphorus-free catalyst for the Morita–
Baylis–Hillman reaction is disclosed. A bicyclic imidazolyl
cyclohexanone and aliphatic and aromatic aldehydes were
used successfully, and the reaction was found to work nicely
alcohol having a Lewis basic center associated with a hydro- using water as solvent in the presence of a phase-transfer
gen-bond donor group was used as catalyst for the reaction.
Aliphatic cycloalkanones such as 2-cyclopentenone and 2-
additive.
hydrofuran (THF). Interestingly, when chiral binaphthol
derivatives were employed the resulting adducts could be
obtained in good to moderate enantioselectivities.[14,15] Un-
der these conditions, however, less reactive benzaldehyde or
cinnamaldehyde derivatives gave substantially lower yields
than aliphatic aldehydes.
Introduction
The Morita–Baylis–Hillman (MBH) reaction is an or-
ganocatalyzed carbon–carbon sigma bond-forming trans-
formation that provides rapid and easy access to polyfunc-
tionalized small molecules.[1,2] The products of this reaction
have been and continue to be used as versatile substrates
for the synthesis of natural products,[3] heterocycles,[2e,4] and
drugs.[5] Besides its synthetic versatility, the MBH reaction,
being a catalytic addition process, presents a very high level
of atom-economy. Tertiary amines[6–11] and tertiary phos-
phanes,[12] among other nucleophiles,[2a] are the most widely
used catalysts for this extremely useful reaction.
In 2002, El Gaïed and co-workers[16a] and Cheng and co-
workers[16b] both reported the use of imidazole as a pro-
moter for the MBH reaction of cyclic enones with alde-
hydes. Both research groups found that in 1:1 THF/water
mixtures at room temperature, good yields of the MBH ad-
ducts between 2-cyclopentenone or 2-cyclohexenone and
formaldehyde or aromatic aldehydes could be obtained in
reasonable reaction times, provided that equimolar
amounts of imidazole were used. Subsequently, Cheng and
co-workers[16c] observed a direct dependence between pH
and the rate of the reaction. The reactions run much faster
in 1 m aqueous sodium hydrogen carbonate solution than
in distilled water. A thorough re-examination by Williams
and co-workers[17] of the reaction conditions used by
El Gaïed and co-workers concluded that the use of aqueous
sodium hydrogen carbonate in the absence of an organic
co-solvent is a necessary but not sufficient condition for
imidazole catalysis, and that a surfactant must be added to
the aqueous mixture to achieve useful reaction rates. On the
other hand, Asano and Matsubara found that N-alkylimid-
azoles can efficiently promote the MBH reaction under
aqueous conditions and in “catalytic” (20 mol-%) amounts,
but a more reactive acyclic enone (MVK) must be used as
starting material.[18] Recently, a binary system of guanidine
and azole has been used by Tereda et al. to successfully
catalyze the MBH reaction with cycloakenones.[19]
Cyclopentenones and cyclohexenones are interesting nu-
cleophilic components for the MBH reaction because they
provide adducts that can be readily transformed into poly-
cyclic compounds. However, cyclic enones are relatively
poor Michael acceptors, and they present a low reactivity
in the experimental protocol usually employed for the MBH
process, which requires relatively bulky nucleophiles as cata-
lysts.[2j] To circumvent this drawback, several strategies have
been developed,[13] most of which involve the use of either
strong Lewis acids (TiCl4, Et2Al), strong bases (NaOMe)
as (co)catalysts, or organocatalysts.
On the other hand, Yamada and Ikegami[14] found that
the MBH reaction of cyclic enones can be promoted by
mild cooperative catalysis of trialkylphosphanes with hy-
drogen-bond donors such as phenols in anhydrous tetra-
[a] Laboratory of Synthesis of Natural Products and Drugs,
Institute of Chemistry, University of Campinas,
P. O. Box 1654, 13083-970 Campinas, SP, Brazil
Homepage: http://lspnf.iqm.unicamp.br/
[b] Departament de Química Orgànica, Facultat de Química,
Universidat de Barcelona,
In the light of these results, we hypothesized that 6,7-
dihydro-5H-pyrrolo[1,2-a]imidazole (DPI, 1; Figure 1)
could be a potentially useful catalyst for MBH reactions of
cyclic enones.
C. Martí i Franquès 1–11, 08028 Barcelona, Spain
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200950.
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J. C. Gomes, M. T. Rodrigues Jr., A. Moyano, F. Coelho
FULL PAPER
Results and Discussion
6,7-Dihydro-5H-pyrrolo[1,2-a]imidazole (DPI, 1) was
easily prepared by using the methodology described by
Zhang et al.,[22] which is a modification of that reported
by Weintraub in 1987.[20] Thus, a mixture of imidazole and
acrolein was heated to reflux in dioxane with a catalytic
amount of acetic acid for 24 h to provide, after chromato-
graphic purification, rac-1 in 87% yield (Scheme 1).
Figure 1. 6,7-Dihydro-5H-pyrrolo[1,2-a]imidazole (DPI, 1).
In effect, this readily available bicyclic imidazolyl
alcohol, first described by Weintraub and co-workers a
quarter of a century ago,[20] presents in its structure both
an sp2-nitrogen atom that can act as Lewis base and a hy-
droxyl group that, in turn, can act as a Brønsted acid. The
co-existence of reactive basic and acid centers in the same
molecule would allow the participation of this catalyst both
in the Michael addition step of the MBH reaction mecha-
nism, as well as in the proton-transfer step (RDS of the
MBH reaction).[21] Therefore, the presence of the hydroxyl
group could improve not only the solubility of this com-
Scheme 1. Preparation of rac-1.
With this imidazolic alcohol in hand, we started our
pound, but also increase the rate of the MBH reaction by study. The reaction between an aromatic aldehyde with a
means of cooperative Lewis base/Brønsted acid cataly- cyclic α,β-unsaturated ketone was taken as a model for our
sis.[11b,14,15,21a] Although compound 1 clearly exhibits struc- preliminary evaluation. We decided to test the experimental
tural characteristics that make it an attractive candidate for protocol used by Luo et al.[16c] Thus, an experiment was
the catalysis of the MBH reaction, no report is available carried out in the presence of an aqueous solution of
describing its performance as a catalyst, and, in fact, only NaHCO3 to avoid any changes in pH and, consequently,
recently Zhang et al. have reported the use of enantiopure loss of the imidazole catalytic power; the results are summa-
ethers derived from (R)-1 as catalysts for asymmetric Steg- rized in Table 1. To perform these evaluations, we selected
lich rearrangements[22] and for the kinetic resolution of the reaction between 3-chlorobenzaldehyde and 2-cyclopen-
phosphoramides.[23]
tenone as a model.
In this paper we wish to disclose our results concerning
We started using 0.65 equiv. of 1, and the reactions were
the successful evaluation of 1 as a new catalyst for the aque- carried out in a mixture of solvents in which the amount of
ous MBH reaction between aromatic or aliphatic aldehydes water was gradually changed. Other polar solvents, such as
and α,β-unsaturated cyclic ketones (2-cyclopentenone and MeOH and N,N-dimethylformamide (DMF) were also
2-cyclohexenone).
tested.
Table 1. A bifunctional imidazole catalyzing the MBH reaction.[a]
Entry
Aldehyde
Ketone
MBH adduct
Time [h]
Yield [%][b]
1
2
3
4
5
6
7
3-chlorobenzaldehyde (4)
2-cyclopentenone (2)
2-cyclohexenone (3)
2-cyclopentenone (2)
2-cyclohexenone (3)
2-cyclopentenone (2)
2-cyclohexenone (3)
2-cyclopentenone (2)
8
48
48
24
48
72
72
360
88
63
54
3-chlorobenzaldehyde (4)
9
2-chloropyridinecarbaldehyde (5)
2-chloropyridinecarbaldehyde (5)
2-chloroquinolinecarbaldehyde (6)
2-chloroquinolinecarbaldehyde (6)
3-methoxybenzaldehyde (7)
10
11
12
13
14
73
43[c]
49[c]
42[c]
[a] Reagents and conditions: enone (2 mmol), 1 (0.65 equiv.). [b] Isolated and purified product. [c] Some aldehyde was recovered in these
reactions.
2
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Aqueous Morita-Baylis–Hillman Reactions of Cyclic Enones
It has been known for some time[17] that the inclusion of presence of a mixture THF/H2O, however when less than
surfactants as additives can have beneficial effects for aque- 25% v/v water was present in the mixture the reaction yield
ous MBH reactions. This spurred us on to also evaluate decreased significantly (Table 2, entries 1–3).
the possible effect of using surfactants to speeding up the
Apparently, the same occurs when THF is replaced by
reactions catalyzed by the bicyclic imidazole alcohol 1; the DMF (Table 2, entry 7). Curiously, the reaction did not
results are summarized in Table 2.
work when water or DMF were used as the sole solvents
(Table 2, entries 4 and 6). In the mixture water/ionic liquid
(Table 2, entry 8) the reaction also worked, however, a sig-
nificant increase both in yield as well as in the rate of the
reaction was observed when a mixture of water and sodium
dodecyl sulfate (SDS) was used (Table 2, entry 9).
Table 2. Improving the experimental protocol for catalysis of the
MBH reaction.
This last result is very stimulating because it shows that
it is possible to perform this MBH reaction without
NaHCO3 or any organic cosolvent. Searching to establish
the optimal protocol to carry out this reaction, we also
tested other surfactants; the results are presented in Table 3.
Entry
Experimental conditions
Time [h]
Yield [%][a]
Table 3. Testing surfactants as additives for the MBH reaction cata-
lyzed by 1.
1
2
3
4
5
6
7
8
9
THF/H2O (1:4)
THF/H2O (1:1)
THF/H2O (4:1)
H2O
MeOH
DMF
DMF/H2O (1:4)
H2O/[bmin]PF6
H2O/SDS (10 mol-%)
144
144
144
216
144
144
144
144
72
77
46
21
–
32
–
75
77
83
Entry
Experimental conditions
Time [h] Yield [%][a]
1
2
3
H2O/SDS (10 mol-%)
72
96
96
83
81
52
H2O/CTAB (10 mol-%)[b]
H2O/Triton-X100 (10 mol-%)[c]
[a] Yields refer to isolated and purified product 8. [b] CTAB de-
notes cetyltrimethylammonium bromide. [c] Triton-X100 denotes
polyethylene glycol p-(1,1,3,3-tetramethylbutyl)phenyl ether.
[a] Isolated and purified product.
The mixture of water and SDS still provided the best
Both the yields and the rate of reaction showed a strong medium to perform this MBH reaction, so we decided to
dependence on the solvent. The reaction takes place in the take these conditions as standard for further reactions. The
Table 4. Eco-friendly protocol for a MBH reaction in water in the presence of a new catalyst.[a]
Entry
Aldehyde
Ketone
MBH adducts
Time [h]
Yield [%][b]
1
2
3
4
5
6
7
8
3-chlorobenzaldehyde (4)
2-cyclopentenone (2)
2-cyclohexenone (3)
2-cyclopentenone (2)
2-cyclohexenone (3)
2-cyclopentenone (2)
2-cyclohexenone (3)
2-cyclopentenone (2)
2-cyclohexenone (3)
2-cyclopentenone (2)
2-cyclohexenone (3)
2-cyclopentenone (2)
2-cyclohexenone (3)
2-cyclohexenone (3)
2-cyclohexenone (3)
8
72
21
72
144
21
72
72
21
72
144
21
72
22
72
83
78
96
98
71
85
85
69
91
76
66
58
92
86
3-chlorobenzaldehyde (4)
9
2-chloro-3-pyridinecarbaldehyde (5)
2-chloro-3-pyridinecarbaldehyde (5)
2-chloro-3-quinolinecarbaldehyde (6)
2-chloro-3-quinolinecarbaldehyde (6)
3-metoxybenzaldehyde (7)
3-metoxybenzaldehyde (7)
4-nitrobenzaldehyde (15)
10
11
12
13
14
19
20
21
22
23
24
25
9
10
11
12
13
14
4-nitrobenzaldehyde (15)
propionaldehyde (16)
propionaldehyde (16)
benzaldehyde (17)
4-(methylsulfonyl)benzaldehyde (18)
[a] The reactions were carried out in water in the presence of 1 (0.65 equiv.) and SDS (10 mol-%). [b] Isolated and purified product.
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J. C. Gomes, M. T. Rodrigues Jr., A. Moyano, F. Coelho
FULL PAPER
increase in yield and rate can tentatively be explained as
Finally, it is worth noting that the presence of a stereo-
follows. In the presence of a micellar aqueous solution, the genic center in the structure of 1 could be exploited for
water-insoluble compounds go into the hydrophobic nuclei the development of new chiral catalysts for an asymmetric
of the micelles. In this nonpolar environment, the hydroxyl version of this useful reaction. Efforts toward this goal are
group of the bifunctional catalyst 1 can stabilize the zwitter- ongoing in our laboratories and the results will be disclosed
ionic intermediate generated after the Michael addition of in the due time.
a Lewis base over an activated olefin by means of hydrogen-
bonding interactions (Figure 2).
Experimental Section
General: The progress of the reaction was monitored by thin-layer
chromatography on silica gel (aluminum foil) and spotted under
UV light (254 nm), followed by staining with ethanolic 25% phos-
phomolybdic solution or aqueous KMnO4. Purification by column
chromatography was carried out on silica gel (70–230 or 230–400
Mesh). 1H NMR spectra were recorded at 250 MHz and the 13C
NMR spectra at 62.5 MHz, in CDCl3 at room temperature. Chemi-
cal shifts (δ) are reported in ppm and coupling constants (J) in
Hertz [Hz]. Signal multiplicity was assigned as singlet (s), doublet
(d), double doublet (dd), triplet (t), double triplet (dt), quartet (q),
quintuplet (qt), multiplet (m) and broad (br). The high-resolution
mass spectra were recorded with Q-TOF Micromass equipment
(Waters, UK).
Figure 2. Tentative explanation of the role played by 1 in the
mechanism of the MBH reaction.
The stabilization of the zwitterionic intermediate in the
micellar phase leads to an increase in the rate of both the
aldol addition and the proton transfer steps, consequently
increasing both the overall rate and the yield of the MBH
reaction.[17a,17b]
General Protocol for the MBH Reaction Catalyzed by Bicyclic Imid-
azolic Alcohol 1 in Water and SDS (10 mol-%): A mixture of alde-
hyde (0.1 g, 1 equiv.), cyclic enone (2-cyclopentenone or 2-cyclo-
hexenone; 2 equiv) and catalyst 1 (0.65 equiv.) was reacted in a
solution of SDS/H2O (10 mol-%) for 1–6 d. Upon completion, the
crude material was extracted with ethyl acetate (3ϫ 30 mL) and
the organic phase was separated and dried with Na2SO4. After fil-
tration and solvent removal, the residue was filtered through a pad
of silica gel.
To test the generality of this protocol, we ran several
MBH reactions using aliphatic and activated/deactivated
aromatic aldehydes; the results are summarized in Table 4.
The MBH reactions using this new catalyst worked nicely
to provide the desired adducts in good yields (58–98%) and
reasonable reaction times (21–144 h). It is worth noting that
even deactivated electrophiles such as m-anisaldehyde (7)
and benzaldehyde (17) furnished the adducts in 69 and 92%
yield, respectively (Table 4, entries 8 and 13). Also remark-
able is the case of propanal, which gave reasonable yields
with both cyclic enones (Table 4, entries 11 and 12). This
protocol does not require any pH control, so the use of
NaHCO3 or buffer solutions can be avoided. Furthermore,
this MBH reaction can be performed in an eco-friendly en-
vironment in which no organic cosolvent is necessary.
2-[(3-Chlorophenyl)(hydroxy)methyl]cyclopent-2-en-1-one (8): Col-
orless viscous oil; 83% yield. 1H NMR (250 MHz, CDCl3): δ =
2.37–2.45 (m, 2 H), 2.53–2.62 (m, 2 H), 3.82 (d, J = 4.48 Hz, 1 H),
5.48 (d, J = 4.38 Hz, 1 H), 7.19–7.38 (m, 5 H) ppm. 13C NMR
(62.5 MHz, CDCl3): δ = 26.7, 35.2, 68.9, 124.6, 126.4, 127.9, 129.7,
134.33, 143.5, 147.3, 159.8, 209.4 ppm.
2-[(3-Chlorophenyl)(hydroxy)methyl]cyclohex-2-en-1-one (9): Color-
less viscous oil; 78% yield. 1H NMR (250 MHz, CDCl3): δ = 1.91–
2.05 (m, 2 H), 2.35–2.48 (m, 4 H), 3.54 (d, J = 5.72 Hz, 1 H), 5.49
(d, J = 5.25 Hz, 1 H), 6.76 (t, J = 4.03 Hz, 1 H), 7.18–7.29 (m, 3
H), 7.32–7.37 (m, 1 H) ppm. 13C NMR (62.5 MHz, CDCl3): δ =
22.4, 25.7, 38.5, 71.9, 124.6, 126.5, 127.6, 129.5, 134.2, 140.6, 144.0,
147.7, 200.2 ppm.
Conclusions
We have demonstrated the potential of a bicyclic imid-
azolyl alcohol as a new phosphorus-free catalyst for the
MBH reaction between aromatic and aliphatic aldehydes
and cyclic α,β-unsaturated ketones. The reaction works
nicely to afford the corresponding adducts in good average
yields and reasonable reaction times. The catalyst is easy to
prepare even on a large scale, using inexpensive chemical
reagents (i.e., imidazole and acrolein), and does not require
the use of additional hydrogen-bond donor cocatalysts.
Furthermore, we have demonstrated that this new com-
pound can effectively catalyze the MBH reaction in water
in the presence of a catalytic amount of sodium dodecyl
sulfate. Under the conditions established in this paper, the
organocatalyzed MBH reaction can be performed using an
eco-friendly protocol to provide adducts with great syn-
thetic versatility.
2-[(2-Chloropyridin-3-yl)(hydroxy)methyl]cyclopent-2-en-1-one (10):
A Colorless viscous oil; 96% yield. H NMR (250 MHz, CDCl3):
1
δ = 2.43–2.47 (m, 2 H), 2.57–2.60 (m, 2 H), 4.37 (d, J = 4.77 Hz,
1 H), 5.82 (d, J = 4.25 Hz, 1 H), 7.19–7.20 (m, 1 H), 7.29 (dd, J =
4.75, 7.65 Hz, 1 H), 8.00 (dd, J = 1.82, 7.65 Hz, 1 H), 8.29 (dd, J
= 1.92, 4.72 Hz, 1 H) ppm. 13C NMR (62.5 MHz, CDCl3): δ =
26.7, 35.1, 65.8, 122.9, 135.8, 137.1, 144.7, 148.6, 148.9, 160.7,
209.8 ppm. HRMS (ESI): m/z calcd. for C11H10ClNO2 [M + H]+
137.0966; found 137.0919.
2-[(2-Chloropyridin-3-yl)(hydroxy)methyl]cyclohex-2-en-1-one (11):
Colorless viscous oil; 98% yield. 1H NMR (250 MHz, CDCl3): δ =
1.89–2.00 (m, 2 H), 2.30–2.36 (m, 2 H), 2.40–2.46 (m, 2 H), 4.19
(d, J = 4.97 Hz, 1 H), 5.80 (d, J = 4.56 Hz, 1 H), 6.57 (t, J =
4.34 Hz, 1 H), 7.26 (dd, J = 4.68, 7.61 Hz, 1 H), 7.96 (dd, J = 1.57,
7.78 Hz, 1 H), 8.26 (dd, J = 1.77, 4.71 Hz, 1 H) ppm. 13C NMR
(62.5 MHz, CDCl3): δ = 22.4, 25.8, 38.3, 68.2, 68.2, 122.7, 135.9,
137.4, 138.7, 148.4, 148.5, 149.3, 200.2 ppm.
4
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Aqueous Morita-Baylis–Hillman Reactions of Cyclic Enones
2-[(2-Chloroquinolin-3-yl)(hydroxy)methyl]cyclopent-2-en-1-one 2-[Hydroxy(phenyl)methyl]cyclohex-2-en-1-one (24):[26] Colorless
(12): White solid; 71% yield. 1H NMR (250 MHz, CDCl3): δ =
2.42–2.51 (m, 2 H), 2.51–2.61 (m, 2 H), 4.51 (d, J = 4.75 Hz, 1 H),
5.97 (d, J = 4.48 Hz, 1 H), 7.16–7.23 (m, 1 H), 7.53 (ddd, J = 1.06,
viscous oil; 92% yield. 1H NMR (250 MHz, CDCl3): δ = 1.89–2.03
(m, 2 H), 2.30–2.46 (m, 4 H), 3.61 (d, J = 5.19 Hz, 1 H), 5.54 (d,
J = 4.98 Hz, 1 H), 6.75 (t, J = 4.12 Hz, 1 H), 7.19–7.37 (m, 5
7.97, 7.97 Hz, 1 H), 7.69 (ddd, J = 1.38, 6.98, 6.98 Hz, 1 H), 7.82 H) ppm. 13C NMR (62.5 MHz, CDCl3): δ = 22.4, 25.7, 38.52, 72.2,
(dd, J = 0.78, 8.06 Hz, 1 H), 7.97 (dd, J = 0.81, 8.39 Hz, 1 H), 8.45
(s, 1 H) ppm. 13C NMR (62.5 MHz, CDCl3): δ = 26.8, 35.1, 65.7,
127.2, 127.8, 128.0, 130.5, 133.21, 136.7, 145.3, 147.0, 148.6, 160.9,
209.6 ppm. HRMS (ESI): m/z calcd. for C15H12ClNO2 [M + H]+
276.0610; found 276.0641.
126.4, 127.4, 128.3, 141.1, 141.8, 147.3, 200.3 ppm.
2-[Hydroxy(4-methylsulfonylphenyl)methyl]cyclohex-2-en-1-one
(25): Colorless viscous oil; 86% yield. 1H NMR (250 MHz,
CDCl3): δ = 1.96 (qt, J = 6.18 Hz, 2 H), 2.35–2.45 (m, 4 H), 2.99
(s, 3 H), 3.72 (d, J = 5.77 Hz, 1 H), 5.56 (d, J = 5.66 Hz, 1 H),
6.84 (t, J = 4.04 Hz, 1 H), 7.53 (d, J = 8.13 Hz, 2 H), 7.83 (d, J =
8.40 Hz, 2 H) ppm. 13C NMR (62.5 MHz, CDCl3): δ = 22.4, 25.7,
38.4, 44.4, 71.6, 127.3, 139.3, 140.3, 148.0, 148.58, 199.9 ppm.
HRMS (ESI): m/z calcd. for C14H16O4S [M + H]+ 303.0679; found
303.0667.
2-[(2-Chloroquinolin-3-yl)(hydroxy)methyl]cyclohex-2-en-1-one
1
(13):[8b] White solid; 85% yield. H NMR (250 MHz, CDCl3): δ =
1.90–2.04 (m, 2 H), 2.26–2.38 (m, 2 H), 2.42–2.53 (m, 2 H), 4.16
(d, J = 4.84 Hz, 1 H), 6.01 (d, J = 4.61 Hz, 1 H), 6.56 (t, J =
4.10 Hz, 1 H), 7.52 (ddd, J = 1.00, 8.12, 8.12 Hz, 1 H), 7.69 (ddd,
J = 1.39, 6.97, 6.97 Hz, 1 H), 7.82 (dd, J = 0.81, 8.19 Hz, 1 H),
7.97 (dd, J = 0.82, 8.58 Hz, 1 H), 8.43 (s, 1 H) ppm. 13C NMR
(62.5 MHz, CDCl3): δ = 22.4, 25.8, 38.3, 68.1, 127.2, 127.8, 127.2,
128.0, 130.4, 133.2, 137.1, 139.2, 146.9, 148.6, 149.0, 200.1 ppm.
Supporting Information (see footnote on the first page of this arti-
cle): 1H and 13C NMR spectra for all compounds synthesized in
this work.
2-[Hydroxy(3-methoxyphenyl)methyl]cyclopent-2-en-1-one
(14):
1
Colorless oil; 85% yield. H NMR (250 MHz, CDCl3): δ = 2.39– Acknowledgments
2.46 (m, 2 H), 2.53–2.61 (m, 2 H), 3.62 (d, J = 4.18 Hz, 1 H), 3.79
(s, 3 H), 5.51 (d, J = 2.40 Hz, 1 H), 6.78–6.84 (m, 1 H), 6.90–6.96
(m, 2 H), 7.20–7.30 (m, 2 H) ppm. 13C NMR (62.5 MHz, CDCl3):
δ = 26.6, 35.2, 55.2, 69.6, 111.8, 113.3, 118.6, 129.5, 143.1, 147.6,
159.6, 159.7, 209.6 ppm. HRMS (ESI): m/z calcd. for
C13H14ClNO3 [M + H]+ 200.0837; found 200.0824.
We thank Fundação de Amparo à Pesquisa do Estado de São
Paulo (FAPESP), Conselho Nacional de Desenvolvimento Ci-
entífico e Tecnológico (CNPq) and Ministerio de Ciencia e Innova-
ción (MICINN) (project number AYA2009-13920-C02-02) for fin-
ancial suport. J. C. G. thanks CNPq for
a PhD fellowship.
M. T. R. Jr thanks FAPESP for a post-doc fellowship.
2-[Hydroxy(3-methoxyphenyl)methyl]cyclohex-2-en-1-one (19):[13d]
Colorless oil; 69% yield. H NMR (250 MHz, CDCl3): δ = 1.90–
1
2.04 (m, 2 H), 2.31–2.47 (m, 4 H), 3.58 (d, J = 5.25 Hz, 1 H), 3.78
(s, 3 H), 5.51 (d, J = 5.09 Hz, 1 H), 6.72–6.82 (m, 2 H), 6.86–6.94
(m, 2 H), 7.18–7.27 (m, 1 H) ppm. 13C NMR (62.5 MHz, CDCl3):
δ = 22.5, 25.7, 38.5, 55.2, 72.1, 112.0, 112.9, 118.8, 129.3, 140.9,
143.5, 147.5, 159.6, 200.3 ppm.
[1] a) K. Morita, Z. Suzuki, H. Hirose, Bull. Chem. Soc. Jpn. 1968,
41, 2815–2819; b) A. B. Baylis, M. E. D. Hillman, Ger. Offen.
1972, 2, 155, 113; Chem. Abstr. 1972, 77, 34174q; c) M. E. D.
Hillman, A. B. Baylis, U. S. Patent 1973, 3, 743, 669.
[2] For selected reviews concerning the MBH reaction, see: a) M.
Shi, F.-J. Wang, M.-X. Zhao, Y. Wei, in: The Chemistry of the
Morita–Baylis–Hillman Reaction, RSC Publishing, Cambrigde,
UK, 2011; b) D. Basavaiah, G. Veeraraghavaiah, Chem. Soc.
Rev. 2012, 41, 68–78; c) T.-Y. Lui, M. Xie, Y.-C. Chen, Chem.
Soc. Rev. 2012, 41, 4041–4112; d) D. Basavaiah, S. B. Reddy,
S. S. Badsara, Chem. Rev. 2010, 110, 5447–5674; e) R. O. M. A.
Souza, L. S. M. Miranda, Mini-Rev. Org. Chem. 2010, 7, 212–
220; f) G.-N. Ma, J.-J. Jiang, M. Shi, Y. Wei, Chem. Commun.
2009, 5496–5514; g) V. Singh, S. Batra, Tetrahedron 2008, 64,
4511–4574; h) Y.-L. Shi, M. Shi, Eur. J. Org. Chem. 2007, 2905–
2916; i) D. Basavaiah, K. V. Rao, R. J. Reddy, Chem. Soc. Rev.
2007, 64, 1581–1588; j) D. Basavaiah, A. J. Rao, T. Satyanaray-
ana, Chem. Rev. 2003, 103, 811–891; k) P. Langer, Angew.
Chem. 2000, 112, 3177; Angew. Chem. Int. Ed. 2000, 39, 3049–
3052; l) E. Ciganek, Org. React. 1997, 51, 201–350; m) W. P.
Almeida, F. Coelho, Quim. Nova 2000, 23, 98–101.
[3] a) Y. S. Reddy, P. Kadigachalam, R. K. Basak, A. P. J. Pal,
Y. D. Vankar, Tetrahedron Lett. 2012, 53, 132–136; b) P. H. S.
Paioti, F. Coelho, Tetrahedron Lett. 2011, 52, 6180–6184; c) V.
Kumar, P. Das, P. Ghosal, A. K. Shaw, Tetrahedron 2011, 67,
4539–4546; d) R. L. Reddy, P. Saravanan, E. J. Corey, J. Am.
Chem. Soc. 2004, 126, 6230–6231; e) Y. Iwabuchi, M. Furu-
kawa, T. Esumi, S. Hatakeyama, Chem. Commun. 2001, 2030–
2031; f) A. Masunari, E. Ishida, G. Trazzi, W. P. Almeida, F.
Coelho, Synth. Commun. 2001, 31, 2127–2136; g) J. A. McCau-
ley, K. Nagasawa, P. A. Lander, S. G. Mischke, M. A. Semones,
Y. Kishi, J. Am. Chem. Soc. 1998, 120, 7647–7648.
2-[Hydroxy(4-nitrophenyl)methyl]cyclopent-2-en-1-one
(20):[13d]
White solid; 91% yield. 1H NMR (250 MHz, CDCl3): δ = 2.44–
2.49 (m, 2 H), 2.60–2.64 (m, 2 H), 3.71 (d, J = 4.37 Hz, 1 H), 5.70
(d, J = 2.30 Hz, 1 H), 7.29–7.33 (m, 1 H), 7.60 (d, J = 8.81 Hz, 2
H), 8.2 (d, J = 8.81 Hz, 1 H) ppm. 13C NMR (62.5 MHz, CDCl3):
δ = 26.8, 35.1, 68.9, 123.7, 127.1, 146.7, 147.4, 148.5, 159.9,
209.3 ppm.
2-[Hydroxy(4-nitrophenyl)methyl]cyclohex-2-en-1-one (21):[24] White
1
solid; 76% yield. H NMR (250 MHz, CDCl3): δ = 1.99 (qt, J =
6.09 Hz, 2 H), 2.34–2.49 (m, 4 H), 3.61 (d, J = 5.87 Hz, 1 H), 5.60
(d, J = 5.69 Hz, 1 H), 6.83 (t, J = 4.09 Hz, 1 H), 7.53 (d, J =
8.54 Hz, 2 H), 8.16 (d, J = 8.83 Hz, 2 H) ppm. 13C NMR
(62.5 MHz, CDCl3): δ = 22.4, 25.8, 38.4, 71.9, 123.5, 127.1, 140.2,
147.2, 148.2, 149.4, 200.0 ppm.
2-(1-Hydroxypropyl)cyclopent-2-en-1-one (22):[25] Colorless fluid
oil; 66% yield. 1H NMR (250 MHz, CDCl3): δ = 0.95 (t, J =
7.50 Hz, 3 H), 1.60–1.79 (m, 2 H), 2.41–2.48 (m, 2 H), 2.57–2.66
(m. 2 H), 2.83 (d, J = 5.65 Hz, 1 H), 4.37 (dd, J = 5.65, 11.56 Hz,
1 H), 7.43–7.47 (m, 1 H) ppm. 13C NMR (62.5 MHz, CDCl3): δ =
9.7, 26.6, 28.7, 35.2, 69.1, 147.5, 158.0, 210.1 ppm.
2-(1-Hydroxypropyl)cyclohex-2-en-1-one (23): Colorless fluid oil;
1
58% yield. H NMR (250 MHz, CDCl3): δ = 0.89 (t, J = 7.40 Hz,
3 H), 1.63 (qt, J = 6.89 Hz, 2 H), 1.97 (qt, J = 6.38 Hz, 2 H), 2.34–
2.46 (m. 4 H), 2.94 (d, J = 7.16 Hz, 1 H), 4.20 (q, J = 6.76 Hz, 1
H), 6.86 (d, J = 4.17 Hz, 1 H) ppm. 13C NMR (62.5 MHz, CDCl3):
δ = 0.3, 22.6, 25.6, 29.1, 38.7, 73.0, 140.6, 145.9, 200.6 ppm. HRMS
(ESI): m/z calcd. for C9H14O2 [M + H]+ 137.0966; found 137.0977.
[4] a) K. R. Luna-Freire, C. F. Tormena, F. Coelho, Synlett 2011,
2059–2063; b) A. Albrecht, L. Albrecht, T. Janecki, Eur. J. Org.
Chem. 2011, 2746–2766; c) W. Zhong, Y. Liu, G. Wang, L.
Hong, Y. Chen, X. Chen, Y. Zheng, W. Zhang, W. Ma, Y. Shen,
Y. Yang, Org. Prep. Proced. Int. 2011, 43, 1–66; d) S. Gowrisan-
Eur. J. Org. Chem. 0000, 0–0
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J. C. Gomes, M. T. Rodrigues Jr., A. Moyano, F. Coelho
FULL PAPER
kar, H. S. Lee, S. H. Kim, Y. K. Lee, J. N. Kim, Tetrahedron
2009, 43, 8769–8780.
Synthesis 2005, 3035–3038; e) T. Shibata, K. Soai, Y. Wakat-
suki, Chem. Commun. 1998, 1271–1272; f) S. I. Pereira, J. Ad-
rio, A. M. S. Silva, J. C. Carretero, J. Org. Chem. 2005, 70,
10175–10177.
[5] a) G. W. Amarante, M. Cavallaro, F. Coelho, Tetrahedron Lett.
2010, 51, 2597–2599; b) G. W. Amarante, M. Benassi, R. N.
Pascoal, M. N. Eberlin, F. Coelho, Tetrahedron 2010, 66, 4370–
4376; c) G. W. Amarante, P. Rezende, M. Cavallaro, F. Coelho,
Tetrahedron Lett. 2008, 49, 3744–3748; d) L. K. Kohn, C. H.
Pavam, D. Veronese, F. Coelho, J. E. Carvalho, W. P. Almeida,
Eur. J. Med. Chem. 2006, 41, 738–744; e) G. P. D. Silveira, F.
Coelho, Tetrahedron Lett. 2005, 46, 6477–6481; f) M. A. Fel-
trin, W. P. Almeida, Synth. Commun. 2003, 33, 1141–1146; g)
P. J. Dunn, J. F. Fournier, M. L. Hughes, P. M. Searle, A. S.
Wood, Org. Process Res. Dev. 2003, 7, 244–253; h) R. C. Rossi,
F. Coelho, Tetrahedron Lett. 2002, 42, 2797–2800; i) C. R.
Mateus, F. Coelho, J. Braz. Chem. Soc. 2005, 16, 386–396.
[6] For the first reports on the use of DABCO as catalyst for a
MBH reaction, see: a) S. E. Drewes, N. D. Emslie, J. Chem.
Soc. Perkin Trans. 1 1982, 2079–2083; b) H. M. R. Hoffmann,
J. Rabe, Angew. Chem. 1983, 95, 795; Angew. Chem. Int. Ed.
Engl. 1983, 22, 795–796; c) H. Perlmutter, C. C. Teo, Tetrahe-
dron Lett. 1984, 25, 5951–5952; d) D. Basavaiah, V. V. L.
Gowriswari, Tetrahedron Lett. 1986, 27, 2031–2032; e) H.
Amri, J. Villieras, Tetrahedron Lett. 1986, 27, 4307–4308; f) J. S.
Hill, N. S. Isaacs, Tetrahedron Lett. 1986, 27, 5007–5010; g) P.
Auvray, P. Knochel, J. F. Normant, Tetrahedron Lett. 1986, 27,
5095–5098.
[7] For the use of quinuclidines and derivatives as catalysts for the
MBH reaction, see: a) F. Ameer, S. E. Drewes, S. Freese, P. T.
Kaye, Synth. Commun. 1988, 18, 495–500; b) Y. Hayashi, K.
Okado, I. Ashimine, M. Shoji, Tetrahedron Lett. 2002, 48,
8683–8686; c) V. K. Aggarwal, Y. Emme, S. Y. Fulford, J. Org.
Chem. 2003, 68, 692–700.
[8] For the use of DMAP as catalyst for the MBH reaction, see:
a) F. Rezgui, M. M. El Gaïed, Tetrahedron Lett. 1998, 39,
5965–5966; b) K. Y. Lee, J. H. Gong, J. N. Kim, Bull. Korean
Chem. Soc. 2002, 23, 659–660; c) M. C. Redondo, M. Riba-
gorda, M. C. Carreño, Org. Lett. 2010, 12, 568–571.
[13]
a) M. Shi, X.-G. Lui, Org. Lett. 2008, 10, 1043–1046; b) M. L.
Kantam, L. Chakrapani, B. M. Choudary, Synlett 2008, 1946–
1948; c) S. Luo, X. Mi, H. Xu, P. G. Wang, J. P. Cheng, J. Org.
Chem. 2004, 69, 8413–8422; d) D. Basavaiah, B. Sreenivasulu,
A. J. Rao, J. Org. Chem. 2003, 68, 5983–5991; e) A. Patra, S.
Batra, B. S. Joshi, R. Roy, D. Kundu, A. P. Bhaduri, J. Org.
Chem. 2002, 67, 5783–5788; f) M. Shi, Y. M. Xu, G. L. Zhao,
X. F. Wu, Eur. J. Org. Chem. 2002, 3666–3679; g) M. Shi, Y.-
M. Xu, Eur. J. Org. Chem. 2002, 696–701; h) M. Shi, J.-K.
Jiang, C.-Q. Li, Tetrahedron Lett. 2002, 43, 127–130; i) W. Pei,
H.-X. Wei, G. Li, Chem. Commun. 2002, 2412–2413; j) M. Shi,
Y. M. Xu, Chem. Commun. 2001, 1876–1877; k) G. Li, H.-X.
Wei, J. J. Gao, T. D. Caputo, Tetrahedron Lett. 2000, 41, 1–5.
[14]
[15]
[16]
Y. M. A. Yamada, S. Ikegami, Tetrahedron Lett. 2000, 41,
2165–2169.
N. T. McDougal, S. E. Schaus, J. Am. Chem. Soc. 2003, 125,
12094–12095.
a) R. Gatri, M. M. El Gaïed, Tetrahedron Lett. 2002, 43, 7835–
7836; b) S. Luo, B. Zhang, J. He, A. Janczuk, P. G. Wang, J.-P.
Cheng, Tetrahedron Lett. 2002, 43, 7369–7371; c) S. Luo, P. G.
Wang, J.-P. Cheng, J. Org. Chem. 2004, 69, 555–558.
a) A. Porzelle, C. M. Williams, B. D. Schwartz, I. R. Gentle,
Synlett 2005, 2923–2926; b) B. D. Schwartz, A. Porzelle, K. S.
Jack, J. M. Faber, I. R. Gentle, C. M. Williams, Adv. Synth. Ca-
tal. 2009, 351, 1148–1154; See also: c) B. Pawar, V. Padalkar,
K. Phatanguare, S. Nirmalkar, A. Chaskar, Catal. Sci. Technol.
2011, 1, 1641–1644.
a) K. Asano, S. Matsubara, Synlett 2009, 35–38; b) K. Asano,
S. Matsubara, Synthesis 2009, 3219–3226.
M. Terada, S. Fukuchi, K. Amagi, M. Nakano, H. Ube, Chem-
CatChem 2012, 4, 963–967.
[17]
[18]
[19]
[20] P. M. Wientraub, P. L. Tiernan, J. C. Huffman, J. Heterocycl.
[9] For some examples concerning the use of DBU as catalyst for
MBH reactions, see: a) V. K. Aggarwal, A. Mereu, Chem. Com-
mun. 1999, 2311–2312; b) P. T. Kaye, X. W. Nocanda, Synthesis
2001, 2389–2392; c) N. Azizi, M. R. Saidi, Tetrahedron Lett.
2002, 43, 4305–4308.
[10] For the use of HMT as catalyst for the MBH reaction, see:
R. O. M. A. Souza, B. A. Meireles, C. S. Aguiar, M. L. A. A.
Vasconcellos, Synthesis 2004, 1595–1600.
[11] For examples concerning the use of chiral amines as catalysts
of the MBH reaction, see: a) I. E. Markó, P. R. Giles, N. J.
Hindley, Tetrahedron 1997, 53, 1015–1024; b) Y. Iwabuchi, M.
Nakatani, N. Yokoyama, S. Hatakeyama, J. Am. Chem. Soc.
1999, 121, 10219–10220.
Chem. 1987, 24, 561–563.
[21] a) V. K. Aggarwal, D. K. Dean, A. Mereu, R. Williams, J. Org.
Chem. 2002, 67, 510–514; b) R. O. M. A. Souza, V. L. Pereira,
P. M. Esteves, M. L. A. A. Vasconcellos, Tetrahedron Lett.
2008, 49, 5902–5905; c) H. J. Davies, A. M. Ruda, N. C. O.
Tomkinson, Tetrahedron Lett. 2007, 48, 1461–1464; d) Y. M. A.
Yamada, S. Ikegami, Tetrahedron Lett. 2000, 41, 2165–2169.
[22] Z. F. Zhang, F. Xie, J. Jia, W. B. Zhang, J. Am. Chem. Soc.
2010, 132, 15939–15941.
[23] S. Liu, Z. Zhang, F. Xie, N. A. N. Butt, L. Sun, W. Zhang,
Tetrahedron: Asymmetry 2012, 23, 329–332.
[24] A. Berkessel, K. Roland, J. M. Neudörfl, Org. Lett. 2006, 8,
4195–4198.
[12] For some examples concerning the use of phosphanes as cata-
lyst for MBH reactions, see: a) S. Bertenshaw, M. Kahn, Tetra-
hedron Lett. 1989, 30, 2731–2732; b) T. Imagawa, K. Uemura,
Z. Nagai, M. Kawanisi, Synth. Commun. 1984, 14, 1267–1273;
c) F. Roth, P. Gygax, G. Frater, Tetrahedron Lett. 1992, 33,
1045–1048; d) H. Ito, Y. Takenaka, S. Fukunishi, K. Iguchi,
[25] K. P. Guerra, C. A. M. Afonso, Tetrahedron 2011, 67, 2562–
2569.
[26] T. Kataoka, T. Iwama, S. Tsujiyama, T. Iwamura, S. Watanabe,
Tetrahedron 1998, 54, 11813–11824.
Received: July 17, 2012
Published Online: ᭿
6
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20950
/KAP1
Date: 28-08-12 17:04:46
Pages: 7
Aqueous Morita-Baylis–Hillman Reactions of Cyclic Enones
Morita–Baylis–Hillman Reaction
A bicyclic imidazoyl compound was suc-
cessfully used as a new bifunctional catalyst
for the Morita–Baylis–Hillman reaction.
J. C. Gomes, M. T. Rodrigues Jr.,
A. Moyano, F. Coelho* ..................... 1–7
Efficient Catalysis of Aqueous Morita–
Baylis–Hillman Reactions of Cyclic Enones
by a Bicyclic Imidazolyl Alcohol
Keywords: Organocatalysis
/
Synthetic
methods
Ketones
/
Heterocycles
/
Aldehydes
/
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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