Efficient tandem Morita-Baylis-Hillman/double cross-aldol reaction between cyclic enones and formaldehyde promoted by N-methylpyrrolidine

Article abstract of DOI:10.1002/ejoc.201001612

The Lewis base N-methylpyrrolidine acts in water as an efficient promoter of tandem reactions between 2 cyclopenten-1-one and aqueous formaldehyde. The reaction pathway includes, as consecutive independent steps, a MBH reaction and a double cross-aldol re

Full text of DOI:10.1002/ejoc.201001612

FULL PAPER
DOI: 10.1002/ejoc.201001612
Efficient Tandem Morita–Baylis–Hillman/Double Cross-Aldol Reaction
between Cyclic Enones and Formaldehyde Promoted by N-Methylpyrrolidine
Krassimira P. Guerra[a,b] and Carlos A. M. Afonso*[a,b]
Keywords: Enones / Aldehydes / Aldol reactions / Domino reactions / Allylic compounds
The Lewis base N-methylpyrrolidine acts in water as an ef-
ficient promoter of tandem reactions between 2 cyclopenten-
1-one and aqueous formaldehyde. The reaction pathway in-
cludes, as consecutive independent steps, a MBH reaction
and a double cross-aldol reaction to furnish the new 2,5,5-
tris(hydroxymethyl)-2-cyclopenten-1-one in excellent yield.
A range of cyclic enones and 4-nitrobenzaldehyde undergo
the tandem reaction similarly. The reaction mechanism was
also investigated.
(OH)2 keeping in mind the prospect of further synthetic
application of MBH derivative 2.[7] We observed the emer-
gence of new products 3 and 4 from the reaction mixture
along with previously reported 2 (Scheme 1). The pro-
duction of abnormal products using MBH conditions with
different types of alkenes, electrophiles, catalysts, and sol-
vents has been observed by several groups.[8]
Introduction
The Morita–Baylis–Hillman (MBH) and aldol addition
reactions furnish important molecules with aldol and/or all-
ylic alcohol motifs.[1,2] The development of asymmetric
methodologies from classical variants using small-molecule
organocatalysts, which display several advantages over
metal catalysts including a lower toxicity, tolerance to water
and air, low cost and accessibility, and operational sim-
plicity, are of interest to the pharmaceutical industry.[3] The
concept of the organocatalytic domino reaction consists of
a transformation in which conversion of the starting materi-
als triggers production of a transiently formed product that
is used as a substrate for the next reaction, which, upon
completion, affords stable final products. The tandem reac-
tion notion becomes more appealing because it offers the
possibility of enlarging molecular complexity with economy
of reagent consumption and purification.[4] Thus far, a
number of two-step domino reactions have been reported.[5]
Sequences that include the MBH reaction as an indepen-
dent cycle have been explored,[6] and important natural
products such as chromenes, coumarins,[6a,6f] and tetra-
hydroxanthones[6b] have been obtained in good yields using
such approaches.
Scheme 1. Tandem MBH–cross-aldol reaction.
The formation of aldol-type derivatives of cyclic enones
has been reported. These types of products have been char-
acterized and their formation found often to be indepen-
dent of the MBH pathways activated by specific reaction
conditions.[9] Notably, the polyol cyclopentenone structural
motif is frequently found in biologically active substances
such as antibiotics and antitumor agents and represents an
excellent target opportunity to develop a new diastereo-
and enantioselective route to this important class of com-
pounds.[7] We envisioned an efficient, cheap, and environ-
mentally safe reaction based on a domino MBH–cross-
aldol pathway to prepare compound 3. We report here ini-
tial studies into the application of this domino reaction as
a means to produce 3 in optimized yields; details disclosed
also provide insight into the reaction mechanism.
In a prior stage of our work we investigated the direct
hydroxymethylation of cyclopentenone with 36% HCHO in
water promoted efficiently by N-methylpyrrolidine/Ba-
[a] iMed.UL, Faculdade de Farmácia da Universidade de Lisboa,
Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal
Fax: +351-21-7946470
E-mail: carlosafonso@ff.ul.pt
Results and Discussion
[b] CQFM, Centro de Química-Física Molecular and IN –
Institute of Nanosciences and Nanotechnology, Instituto
Superior Técnico
HPLC Optimization Studies
1049-001 Lisboa, Portugal
Fax: +351-21-8464455/7
Reaction catalyst, starting solvent, and the amount of
36% HCHO were evaluated on the basis of product forma-
tion as realized by HPLC, and the results are outlined in
E-mail: carlosafonso@ist.utl.pt
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201001612.
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 2372–2379

Efficient Tandem Morita–Baylis–Hillman-Double Cross-Aldol Reactions
Table 1. Based on recent reports of the MBH reaction vealed the optimal conditions for reaction of 1 and 36%
mechanism, we employed DMSO as a polar aprotic solvent HCHO to be: NMP (30 mol-%), HCHO (5 equiv.), and
and CH3OH and H2O as protic media; the expectation was H2O as the solvent.
that an acceleration of the reaction would result due to sta-
bilization of the ionic transition states or promotion of a
proton-transfer step.[10] Barbas and co-workers as well as
Janda and co-workers and various other authors have de-
Preparative Synthetic Experiments
scribed H2O as an efficient medium for direct aldol reac-
We next performed several preparative synthetic experi-
tions.[11] DMSO has been reported to favor cross-aldol ments to verify the optimized reaction conditions identified
asymmetric hydroxymethylation.[11d] Low-costing commer- by using HPLC to generate 3 (Table 1, Entries 11 and 14);
cially available compounds such as the Lewis base N- the resulting data is depicted in Table 2. The best isolated
methylpyrrolidine (NMP)[12a] and the inorganic base yields of 3 were attained by using NMP as a reaction pro-
[12b]
Ba(OH)2
at 30 mol-% were selected among others to moter (Table 2, Entries 6 and 7). Efforts to optimize the re-
promote the reaction. Both additives promote the reaction action conditions with Ba(OH)2 as the catalyst were unsuc-
depicted in Table 1 and promote the formation of com- cessful, possibly due to the formation of a precipitate
pounds 2 and 3; addition of NMP allows formation of 4. (Table 2, Entries 1–5). Interestingly, after 15 min, TLC
The use of 5 equiv. of 36% HCHO increases the yield of analysis of the reaction showed the presence of 2 together
3, whereas 2 (MBH derivative) is the major product when with unconsumed 1 and a light spot of a more-polar prod-
1.2 equiv. of aldehyde is used. Superior yields of 3 were uct with an Rf value characteristic of 3. The spot represent-
achieved in H2O, and NMP showed better reaction-pro- ing compound 2 was imperceptible, whereas the spot repre-
moting activity than Ba(OH)2 (Table 1, Entry 14 vs. 11). In sentative of 3 became stronger after a reaction time of 1 h.
the case of Ba(OH)2, precipitate formation was observed, When the reaction was complete, the spot for 3 appeared
which might be due to the insolubility of its microcrystal- to be unique. Apparently, the reaction leading to 3 was car-
line structure.[12b] The low yields of compound 3 observed ried out under the catalytic action of NMP (30 mol-%) in
in DMSO and CH3OH reflect the potential resistance to water and was a consequence of the formation of 2.
product formation in these solvents. HPLC analyses re-
Table 2. Examples of preparative syntheses of 3 and 4 based on
HPLC optimized conditions.[a]
Table 1. HPLC screening results.
Entry
Additive
HCHO
1
t
Yield [%][b]
[equiv.] [mg]
[min]
2
3
4
Entry[a] Additive HCHO
[equiv.] [min]
t
Yield [%][b]
[c]
2
3
4
1
1
2
3
4
5
6
7
8
9
Ba(OH)2
Ba(OH)2
Ba(OH)2
Ba(OH)2
Ba(OH)2
NMP
5
5
5
100
200
100
80
40
80
35
240
110
150
110
90[e]
230[e]
–
–
–
–
–
–
–
30
42
66
63
64
58
52
91
89
46
6
–
–
–
–
–
2
6
3
7
[c]
[c]
[c]
CH3OH
20
[c]
[c]
[c]
1
2
3
4
5
Ba(OH)2
Ba(OH)2
Ba(OH)2
NMP
10
5
1.2
5
1
n.d.
23
31.4
41
58.7
27.8
6.4
50
–
–
–
5
5
0.6
n.d.
3.5
11.5
38
5
[c,d]
40
40
10
5
5
5
1.2
100
300
100
400
200
4.5[d]
15[d]
NMP
NMP
NMP
NMP
1.2
2
DMSO
[a] Reaction conditions: 36% HCHO (5 equiv.) and additive
(30 mol-%) in H2O at r.t. [b] Isolated yield. [c] Precipitate formation
increased with time. [d] CH3OH was used as solvent. [e] Hours.
[c]
[c]
6
7
8
9
Ba(OH)2
Ba(OH)2
NMP
NMP
NMP
5
1.2
5
5
1.2
55
20
0.63
2.3
12.3
8
44.2
1.8
6.4
40.7
9.3
1.4
12.8
27.3
33.3
1.8
1.2
19
43.4
5.2
38
24[d]
20[e]
4[d]
10
2.8
H2O
[c]
[c]
Scope of MBH and Tandem MBH–Aldol Reactions to
Other Cyclic Enones
11
12
13
14
15
16
Ba(OH)2
Ba(OH)2
NMP
NMP
NMP
5
1.2
5
5
1.2
1.2
40
40
15
0.7
n.d.
27
2
23.4
25
71.4
29
56
85
22.5
29
–
–
11
10
26.6
31.6
1.7
n.d.
4
1
14.6
14
45
The next step was to explore the reaction scope with
other cyclic enones (Table 3). Enones 5, 7, and 11[9e] were
found to participate in the reaction in H2O or H2O/CH3OH
(5:1) in a manner identical to that for the reaction of 1.
Bisaldol derivative 6 (Table 3, Entry 1) and MBH–aldol de-
rivatives 9 and 13 (Table 3, Entries 4, 5, and 7) were ob-
tained in good yields. A better yield of 9 was obtained by
45
NMP
2.5[d]
[a] Reaction conditions: 1 (10.5 μL, 0.12 mmol), 36% HCHO (1.2
or 5 equiv.; 11 μL, 0.144 mmol or 46 μL, 0.580 mmol) and NMP
(3.87 μL, 0.036 mmol, 30 mol-%) in different solvents (0.250 mL) at
r.t. [b] Determined by HPLC; n.d. = not determined. [c] Precipitate
formation. [d] Hours. [e] Days.
Eur. J. Org. Chem. 2011, 2372–2379
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K. P. Guerra, C. A. M. Afonso
FULL PAPER
Table 3. MBH and MBH–aldol reactions with formaldehyde and using H2O/CH3OH (5:1) as the solvent (Table 3, Entry 4 vs.
other cyclic enones.
5). Respective MBH derivatives 8 and 12 were isolated in
very low yield (Table 3, Entries 4, 5, and 7) when an excess
amount of formaldehyde was used. When 1.2 equiv. of 36%
HCHO was employed, products 8 and 12 (Table 3, Entries 3
and 6) were obtained in high (89%) and moderate (42%)
yield, respectively. The bisaldol hydroxymethyl derivative of
7 (i.e., 10) was isolated in fairly good yield (21–30%;
Table 3, Entries 4 and 5). The MBH reaction and the tan-
dem MBH–double aldol reaction with disubstituted enone
11 were sluggish most likely due to steric factors.[9d] The
bisaldol analogue of 11 was not isolated, whereas the corre-
sponding analog of 5 (i.e., 6; Table 3, Entry 1) was attained
in good yield (58%). Substrate 5 cannot undergo the 1,4-
addition step of the MBH pathway owing to steric hin-
drance at the β-position of the α,β-unsaturated 3-methyl-2-
cyclopentenone ring. Accordingly, substrate 5 participates
only in the aldol reaction route.[9c–9e]
Tandem MBH–Aldol Reaction with 1 and Representative
Aryl Aldehydes
The scope of the reaction was also investigated with aryl
aldehydes. Complex reaction mixtures were observed and
only half of the initial amount of aldehyde was recovered
when benzaldehyde (5 equiv.) and 2-furaldehyde (5 equiv.)
were used (Table 4, Entries 2 and 8). The reactions for
which an excess amount of 4-methoxybenzaldehyde and 2-
naphthaldehyde was employed were sluggish, although
MBH derivatives 16-iv and 16-ix were isolated in good yield
(Table 4, Entries 4 and 9). When 1.2 equiv. of aldehyde was
used, MBH products 16-i, 16-iii, 16-v, and 16-vii were
[a] Substrate (200 mg), 36% HCHO (5 equiv.), NMP (30 mol-%),
and H2O/CH3OH (5:1) at r.t. [b] Substrate (100 mg), 36% HCHO
formed in very good yields (Table 4, Entries 1, 3, 5, and 7).
When the active electrophile 4-nitrobenzaldehyde was used
(1.2 equiv.), NMP (5 mol-%)/Ba(OH)2 (1.5 mol-%) as catalytic sys-
in excess amount, MBH–aldol product 17-vi was isolated
in 20% yield and the MBH derivative 16-vi was formed in
31% yield after a 5-h reaction time (Table 4, Entry 6).[9b]
tem at 0 °C. [c] Substrate (100 mg), 36% HCHO (5 equiv.), NMP
(30 mol-%) in H2O at r.t. [d] 36% HCHO (1.2 equiv.) and NMP
(15 mol-%)/Ba(OH)2 (7.5 mol-%).
Table 4. Scope of MBH and tandem MBH–aldol reactions between 1 and representative aldehydes.[a]
Entry
Aldehyde
ArCHO
[equiv.]
t
Yield [%][b]
[h]
16
17
1
1
2
3
4
5
6
7
8
9
benzaldehyde
benzaldehyde
4-methoxybenzaldehyde
4-methoxybenzaldehyde
4-nitrobenzaldehyde
4-nitrobenzaldehyde
2-furaldehyde
1.2[c,d]
5
47
91
50
133
4
16-i, 73
–
–
–
–
–
42
–
20
–
22
–
58
15
10
[e]
[e]
–
1.2[c,d]
5
16-iii, 83
16-iv, 73
16-v, 65
1.2[c]
3
1.2
5
–
17-vi, 20
–
5
16-vi, 31
16-vii, 77
10
91
14
20
[e]
[e]
2-furaldehyde
2-naphthaldehyde
2-naphthaldehyde
–
–
2.5
16-ix, 67
16-x, 45
–
10
1.2[c]
[a] Reaction conditions: 1 (100 mg, 1.22 mmol) and NMP (30 mol-%) at r.t. [b] Isolated yield. [c] CH3OH/CH2Cl2 (3:1) was employed.
[d] Reaction was performed at 0 °C. [e] Unidentified mixture was observed.
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Eur. J. Org. Chem. 2011, 2372–2379

Efficient Tandem Morita–Baylis–Hillman-Double Cross-Aldol Reactions
HPLC and NMR Studies of Tandem MBH–Aldol Reaction
Mechanism
The combined information allows us to propose a plaus-
ible mechanism for the reaction between HCHO and 1
(Scheme 2). The MBH pathway[10] is catalyzed by the nucleo-
philic base NMP, which undergoes initial 1,4-addition to
the enone, thereby producing intermediate A, the enolate of
which reacts with HCHO to afford MBH product 2. Inter-
mediate dienolate B[9d,9e] forms under moderately basic
conditions (NMP pK = 10.18)[13a] and is stabilized intramo-
lecularly by the adjacent hydroxy group.[13b] From dienolate
B final product 3 is then formed following double aldol re-
action with HCHO. Notably, the MBH monoaldol product
has never been isolated under our experimental conditions.
The catalyst may therefore play a dual role; NMP activates
the first cycle of formation for the MBH adduct, which
serves as the substrate for a second one in moderately basic
aqueous solution. 4-Nitrobezaldehyde is a good electrophile
and might enter into an aldol condensation process too.
The reaction depicted in Table 1 was monitored with
HPLC to understand better the phenomenon we had in our
hands. The chromatograms of the reaction mixtures taken
at reaction times of 15 and 45 min are shown in Figure 1.
After a reaction time of 15 min (Figure 1, top) the existence
of a mixture of species 2 (MBH derivative), 3 (MBH–aldol
product), and a small amount of 4 (aldol derivative) is ap-
parent. Compound 4 is formed readily from the starting
products together with considerable fractions of 2 and 3.
The amount of 4 was found not to vary during the course
of the reaction (see the area numbers). After a reaction time
of 45 min (Figure 1, bottom) the peak representative of 2
was found to almost disappear although the peak represen-
tative of 3 was found to increase. Thus, the reaction might
progress with 2 as the principal precursor to 3. The quanti-
tative data is listed in Table 1, Entries 13 and 14. An iden-
tical pattern of behavior was observed by following the re-
1
action with H NMR spectroscopy (Figure S8, Supporting
Information).
Scheme 2. Plausible mechanism of domino MBH/double cross-
aldol reaction.
Conclusions
In conclusion, a unique reaction between 2-cyclopenten-
1-one (1) and formaldehyde, promoted by the simple cata-
lyst NMP in water as a medium, was accomplished, and 3,
a new polyhydroxymethyl derivative of cyclopentenone 1,
was isolated in 91% yield. Other cyclic enones were found
to behave similarly. The reaction tentatively described as a
MBH–cross-aldol tandem reaction creates three new C–C
bonds in the polyhydroxymethyl derivative, one of which is
a quaternary C center. The reaction scope with 1 was ex-
tended to include aryl aldehydes. However, of the aryl alde-
hydes investigated, only 4-nitrobenzaldehyde was found to
react with 1 in the desired fashion. Further applications of
the methodology, including an asymmetric version, are cur-
rently under study.
Experimental Section
General Remarks: Dichloromethane (CH2Cl2), ethyl ether (Et2O),
and methanol (CH3OH) were freshly distilled prior to use. Ethyl
acetate (EtOAc) was distilled from potassium carbonate. The water
used for HPLC studies was Milli-Q grade and the acetonitrile was
HPLC grade. Preparative thin-layer chromatography plates were
prepared with silica gel 60 GF254 Merck (Ref. 1.07730.1000),
whereas flash chromatography was carried out on silica gel 60M
Figure 1. HPLC analyses of the reaction between 1 and formalde-
hyde (5 equiv.) in H2O at r.t. catalyzed by NMP (30-mol-%) after
a reaction time of 15 (top) and 45 min (bottom).
Eur. J. Org. Chem. 2011, 2372–2379
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2375

K. P. Guerra, C. A. M. Afonso
FULL PAPER
purchased from MN (Ref. 815381). Reaction mixtures were ana-
lyzed by TLC using ALUGRAM SIL G/UV254 from MN (Ref.
818133, silica gel 60), and visualization of TLC spots was effected
by using UV and ninhydrin (2,2-dihydroxyindane-1,3-dione) or
phosphomolybdic acid (PMA) staining. The additives used on TLC
and HPLC screening studies were purchased from Aldrich, Merck,
and Fluka and used without further purification. 36% HCHO with
methanol as a stabilizer was purchased from Fluka, and the 2-
cyclopenten-1-one, (1) 2-cyclohexen-1-one (7), 3-methyl-2-cy-
clopenten-1-one (5), and 4,4 dimethyl-2-cyclohexen-1-one (11) were
purchased from Aldrich. N-Methylpyrrolidine, 4-nitrobenzalde-
hyde, and 2-naphthaldehyde were obtained from Aldrich and used
as received. Benzaldehyde, 4-methoxybenzaldehyde, and furan-2-
carbaldehyde were used after purification by distillation under vac-
uum. NMR spectra were recorded with a Bruker AMX 400 using
CDCl3 and D2O as solvents. HPLC studies were done with a Shim-
adzu Prominence system apparatus using a C18 Kromasil 100 5 μm
column, 250ϫ 4.6 mm and 5% CH3CN in Milli-Q water as the
mobile phase. A SPD-20A UV/Vis detector was used with sensitiv-
ity to the limit [Noise level 0.5ϫ10(–5) AU], wide linearity
(2.5 AU) and wavelength range from 190 to 700 nm. IR spectra
were obtained with a Shimadzu FTIR-8400S spectrometer and
GC–MS spectra with a Shimadzu GC 2010 gas chromatograph
combined with GC–MS-QP 201008 mass spectrometer. GC pro-
gram: column oven temperature: 50.0 °C; injection temperature:
250.00 °C; pressure: 77.9 kPa, total flow: 17.7 mL/min; column
flow: 1.34 mL/min; linear velocity: 42.0 cm/sec; purge flow: 3.0 mL/
min split ratio: 10.0, high press. inj. pressure: 100.0 kPa, high press.
inj. time: 1.00 min. GC–MS program: start time: 3.00 min; end
time: 50.00 min; event time: 0.50 s; scan speed: 666; start: m/z =
40.00; end: m/z = 350.00.
reaction analyses. The time between each injection was 10 to
15 min. The routine sample calculations were based on the com-
parison of peak areas of BH product 2 and 1, with external stan-
dard peak area from previously obtained calibration curves at
equal working conditions. Six samples with concentrations ranging
from 0.0036 to 0.0001 mg for 1 were used, whereas the seven sam-
ples for the BH product ranged in concentration between 0.005 and
0.0003 mg. Also, six samples of compound 3 and seven of com-
pound 4 were employed with concentrations from 0.00098 to
0.0071 mg and from 0.00002 to 0.0051 mg, respectively. Each cali-
bration curve was obtained based of the ratio area of respective
peak and concentration on the sample.
General Procedure for the MBH–Cross-Aldol Reaction between 2-
Cyclopenten-1-one and 36% HCHO for the Preparation of Com-
pounds 3 and 4: To a stirred mixture of N-methylpyrrolidine
(38.7 μL, 30 mol-%, 0.363 mmol) in H2O (2.5 mL) was added se-
quentially 36% HCHO (0.5 mL, 6.1 mmol) and 2-cyclopenten-1-
one (100 mg, 104.2 μL, 1.21 mmol). The resulting mixture was
stirred at room temperature. Upon completion or after the time
indicated in Table 2 (Entry 6), the reaction was quenched with 1 n
HCl until pH 3. To the mixture was added NaHCO3 to achieve a
pH of about 7, and samples were then concentrated under reduced
pressure. The resulting residue was taken up in CH3OH (1 mL) and
purified by preparative silica gel TLC eluted with EtOAc/hexane/
CH3OH (9.0:0.75:0.25). 2,5,5-Tris(hydroxymethyl)-2-cyclopenten-
1-one (3; 190 mg, 91% yield) and 5,5-bis(hydroxymethyl)-2-cy-
clopenten-1-one (4; 3.5 mg, 2% yield) were obtained as colorless
oils. The spectral characteristics of known compound 2 (Table 2,
Entry 8) were found to be in agreement with previously reported
data.
2-(Hydroxymethyl)-2-cyclopenten-1-one (2):[14] Translucent crystals,
Rf = 0.36 (silica; EtOAc/hexane, 9:1). 1H NMR (400 MHz, CDCl3):
δ = 2.259–2.298 (t, J = 8 Hz, 1 H), 2.458–2.466 (m, 2 H), 2.482–
2.651, (m, 2 H), 4.383–4.403 (d, J = 8 Hz, 2 H), 7.535, (m, 1
H) ppm. 13C NMR (400 MHz, CDCl3): δ = 26.86, 35.01, 57.57,
144.91, 159.05, 209.98 ppm.
General Procedure for the MBH–Cross-Aldol Reaction with Dif-
ferent Additives: Reactions were performed with a homemade
carousel reaction station apparatus in appropriately sized reaction
flasks by using 2-cyclopenten-1-one (1; 10 mg, 10.5 μL, 0.12 mmol)
and aqueous formaldehyde (11 μL, 0.144 mmol OR 46 μL,
0.58 mmol) in the solvent (0.250 mL). For every reaction, catalytic
amount (30 mol-%) of each respective additive was employed. The
reactions were allowed to proceed at room temperature and reac-
tion times normally varied from minutes to 2–3 h; some reactions
were carried out for 11–48 h, as the major amount of substrate was
found to disappear as revealed by TLC (EtOAc/hexane, 9:1).
2,5,5-Tris(hydroxymethyl)-2-cyclopenten-1-one (3): Colorless oil, Rf
= 0.04 (silica; EtOAc/hexane, 9:1). IR (film, KBr/CH OH): ν =
˜
3
3373, 2943, 2518, 1693, 1636, 1448, 1423, 1113, 1030, 663 cm–1. 1H
NMR (400 MHz, D2O, 25 °C):
δ = 2.733–2.749 (m, 2 H,
C3HC4H2C5), 3.578–3.606 (d, J = 11.2 Hz, 2 H, C5CH2OH), 3.695–
3.723, (d, J = 11.2 Hz, 2 H, C5CH2OH), 4.252–4.264 (m, 2 H,
C2CH2OH), 7.866–7.873, (m, 1 H, C2C3HC4H2) ppm. 13C NMR
(400 MHz, D2O): δ = 34.522 (C3HC4H2C5), 55.305 (C2CH2OH),
56.253 [C=OC5(CH2)2], 62.997 [C5(CH2)2(OH)2], 144.036
(C=OC2CH2), 163.855 (C2C3HC4H2), 213.340 (C=O) ppm. The
spectroscopic data were assigned on the basis of 2D HMQC and
2D COSY NMR spectroscopy. GC–MS: m/z = 172 [M].
General Procedures for HPLC Screening of the MBH–Cross-Aldol
Reaction between 2-Cyclopenten-1-one and 36% HCHO with Dif-
ferent Additives: These experiments were performed on the basis of
prior TLC results obtained for each reaction. From each reaction
was taken 10 μL of the reaction solution, and each aliquot was
diluted in 1 mL H2O (Milli-Q)/acetonitrile (95:5). From these solu-
tions, 20 μL was injected on the Shimadzu Prominence system ap-
paratus with the C18 Kromasil 100 5 μm column, 250ϫ4.6 mm and
5% of CH3CN in water as a mobile phase was used. The detection
of the analyzed samples took place at 206 nm. The flow rate em-
ployed was 0.7 mL/min. Under these experimental conditions, the
retention time (tR) observed for BH product 2 was between 17 and
18.5 min. HPLC retention times for reactions using 2-cyclopenten-
1-one (1) were between 23 and 24.5 min depending of the column
equilibrium and temperature. The retention times (tR) for com-
pounds 3 and 4 were between 7.3 and 8.0 min and between 8.50
and 9.40 min, respectively. The column temperature was approxi-
mately 25 °C. To obtain reproducible results with HPLC, daily
“back flushes” were performed. The daily work proceeded for
slightly longer than 10 h and at the finish of each work day the
column was cleaned with the same solvent gradient used to do
5,5-Bis(hydroxymethyl)-2-cyclopenten-1-one (4): Colorless oil, Rf =
0.08 (silica; EtOAc/hexane, 9:1). IR (film, KBr/CH Cl ): ν = 3356,
˜
2
2
2944, 2518, 1693, 1636, 1448, 1419, 1115, 1028, 659 cm–1. 1H NMR
(400 MHz, D2O, 25 °C): δ = 2.802–2.814 (t, 2 H, C3HC4H2C5),
3.574–3.602 (d, J = 11.2 Hz, 2 H, C5CH2OH), 3.686–3.714 (d, J =
11.2 Hz, 2 H, C5CH2OH), 6.238–6.263 [m, 1 H, (C=OC2HC3H)],
8.064–8.092 (m, 1 H, C2HC3HC4H2) ppm. 13C NMR (400 MHz,
D2O): δ = 37.253 (C3HC4H2C5), 56.071 [C=OC5(CH2)2], 63.718
[C5(CH2)2(OH)2], 133.904 (C=OC2CH2), 170.764 (C2C3HC4H2),
216.815 (C=O) ppm. The spectroscopic data were assigned on the
basis of 2D HMQC and 2D COSY NMR spectroscopy. GC–MS:
m/z = 142 [M].
General Procedure for the MBH–Cross-Aldol Reaction between 3-
Methyl-2-cyclopenten-1-one (5), 2-Cyclohexen-1-one (7), or 4,4-Di-
2376
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 2372–2379

Efficient Tandem Morita–Baylis–Hillman-Double Cross-Aldol Reactions
methyl-2-cyclohexen-1-one (11) and 36% HCHO for the Preparation
of Compound 6, 9, 10, and 13: To a stirred mixture of N-methylpyr-
rolidine (30 mol-%; 64.86 μL, 0.624 mmol for 5 and 7; 49.8 μL,
CDCl3, TMS, 25 °C): δ = 1.818–1.849 (t, 2 H, C4HC5H2C6), 2.440–
2.486 (m, 2 H, C3C4H2C5H2), 2.926–2.958 {q, 2 H, [C6(CH2OH)
2]}, 3.642–3.690 (m, 2 H, C6CH2OH), 3.876–3.915 (m, 2 H,
0.480 mmol for 11) in H2O (5.0 mL for 5 and 7) or H2O/CH3OH C6CH2OH), 5.979–6.014 (tt, J = 2 Hz, 1 H, C=OC2HC3H), 6.979–
(5:1 for 11) was added sequentially 36% HCHO (0.8 mL,
7.024 [m, 1 H, (C2HC3HC4H2)] ppm. 13C NMR (400 MHz, CDCl3,
10.4 mmol for 5 and 7; 0.62 mL, 8 mmol for 11) and 0.205 mL TMS, 25 °C): δ = 22.790 (C3HC4H2C5), 25.730 (C4H2C5H2C6),
(2.1 mmol) of 3-methyl-2-cyclopenten-1-one (5) or 2-cyclohexen-1-
one (7) or 4,4-dimethyl-2-cyclohexen-1-one (11, 0.22 mL,
50.410 [C=OC6(CH2)2], 65.386 [C6(CH2)2(OH)2], 128.883
(C=OC2HCH2OH), 150.786 (C2C3HC4H2), 204.479 (C=O) ppm.
1.61 mmol). The resulting mixture was stirred at room temperature. The spectroscopic data were assigned on the basis of 2D HMQC
Upon completion or after the time indicated in Table 3, the reac-
tions were quenched with brine (100 mL) and then extracted 4ϫ
with EtOAc/hexane (9:1). The organic layers were dried with anhy-
drous MgSO4 and concentrated under reduced pressure. The reac-
tion mixture of compound 5 was quenched with 1 n HCl until
pH 3. To the mixture was added NaHCO3 to a pH of about 7, and
the mixture was concentrated under reduced pressure. The resulting
residue was taken up in CH3OH (1 mL) and purified by preparative
silica gel TLC (EtOAc/hexane, 9:1). The concentrated residues of
the reaction mixtures of 7 and 11 also were purified by silica gel
TLC (EtOAc/hexane, 4:1). Compounds 6, 9, 10, and 13 were ob-
tained as oils in the following yields: 6, 58% (190 mg); 9, 65%
(260 mg); 10, 21% (70 mg); and 13, 50% (180 mg). The correspond-
ing known BH products of 7 and 11, compounds 8 and 12, were
obtained in the following yields: 8, 7% (20 mg) and 12, 9% (22 mg).
The spectral characteristics of known compounds 8 and 12 were
found to be in agreement with previously reported data.
and 2D COSY NMR spectroscopy. GC–MS: m/z = 156 [M].
2-(Hydroxymethyl)-4,4-dimethyl-2-cyclohexen-1-one (12):[16] Color-
less oil, Rf = 0.72 (EtOAc/hexane, 1:2). 1H NMR (400 MHz,
CDCl3): δ = 1.173 (s, 6 H), 1.878–1.844 (t, J = 6.8 Hz, 2 H), 2.501–
2.467 (t, J = 8 Hz, 2 H), 4.216–4.202 (d, J = 5.6 Hz, 2 H), 6.587
(s, 1 H) ppm. 13C NMR (400 MHz, CDCl3): δ = 27.89, 33.02,
34.75, 36.06, 62.48, 135.43, 156.35, 201.03 ppm.
2,6,6-Tris[hydroxy(4,4-dimethyl)methyl]-2-cyclohexen-1-one
Colorless crystalline oil, Rf = 0.18 (silica; EtOAc/hexane, 2:1). IR
(film, KBr/CH Cl ): ν = 3053, 2988, 2365, 1419, 1265, 895, 740,
(13):
˜
2
2
705, 671 cm–1. 1H NMR (400 MHz, CDCl3, TMS, 25 °C): δ =
1.219–1.224 {ss, 6 H, [C4(CH3)2]}, 1.734 (s, 2 H, C4C5H2C6), 3.085
{br., 2 H, [C6(CH2OH)2]}, 3.636–3.664 [d, J = 11.2 Hz, 2 H,
(C6CH2OH)], 3.857–3.885 [d, J = 11.2 Hz, 2 H, (C6CH2OH)],
4.030–4.033 (d, J = 1.2 Hz, 2 H, C2CH2OH), 6.677 (s, 1 H,
C2C3HC4) ppm. 13C NMR (400 MHz, CDCl3, TMS, 25 °C): δ =
31.049 [C4(CH3)2], 32.425 (C3HC4C5H2), 38.181 (C4C5H2C6),
50.884 [C=OC6(CH2OH)2], 61.620 (C2CH2OH), 65.826 [C6(CH2)
2(OH)2], 134.117 (C=OC2CH2OH), 155.960 (C2C3HC4H2), 205.043
(C=O) ppm. The spectroscopic data were assigned on the basis of
2D HMQC and 2D COSY NMR spectroscopy. GC–MS: m/z =
213 [M – 1].
5,5-Bis[(hydroxy(3-methyl)methyl)]-2-cyclopenten-1-one (6): Color-
less oil, Rf = 0.13 (silica; EtOAc/hexane, 2:1). IR (film, KBr/
CH Cl ): ν = 3455, 3053, 2986, 2373, 2308, 1684, 1616, 1421, 1265,
˜
2
2
1026, 895, 744, 704 cm–1. 1H NMR (400 MHz, CDCl3, TMS,
25 °C): δ = 2.18 (s, 3 H, C3CH3), 2.310–2.339 {t, J = 5.6 Hz, 2 H,
[C5(CH2)2(OH)2]}, 2.542 (s, 2 H, C3HC4H2C5), 3.766–3.780 {d, J
= 5.6 Hz, 4 H, [C5(CH2OH)2]}, 5.906 (s, J = 1.6 Hz, 1 H,
C=OC2HC3) ppm. 13C NMR (400 MHz, CDCl3, TMS, 25 °C): δ
= 19.825 (C3CH3), 40.860 (C3HC4H2C5), 55.699 [C=OC5(CH2)2],
64.679 [C5(CH2)2(OH)2], 129.354 (C=OC2HC3), 180.521
(C2HC3CH3), 213.050 (C=O) ppm. The spectroscopic data were as-
signed on the basis of 2D HMQC and 2D COSY NMR spec-
troscopy. GC–MS: m/z = 156 [M].
General Procedure for MBH–Cross-Aldol Reaction between 2-Cy-
clopenten-1-one and Aryl Aldehydes: To stirred separate mixtures
of N-methylpyrrolidine (38.7 μL, 30 mol-%) in H2O/CH3OH (5:1,
2.5 mL) was added benzaldehyde (610 μL, 6.05 mmol or 150 μL,
1.46 mmol), 4-methoxyphenylaldehyde (750 μL, 6.05 mmol or
158 μL, 1.46 mmol), 4-nitrophenylaldehyde (546 mg 3.6 mmol or
220 mg, 1.46 mmol); furan-2-carbaldehyde (0.5 mL, 6.05 mmol or
0.12 mL, 1.46 mmol), and 2-naphthaldehyde (470 mg, 3.1 mmol or
220 mg, 1.46 mmol) previously dissolved in a small amount
CH3OH. Afterwards, 1 (0.105 mL, 1.2 mmol) was added to each
solution. The resulting mixtures were stirred at room temperature.
Upon completion or after the time indicated in Table 4 saturated
NaCl was added (100 mL), and the reaction mixtures were ex-
tracted with CH2Cl2 (4ϫ). The organic fractions were dried with
anhydrous MgSO4, filtered, and concentrated under reduced pres-
sure to afford slurry residues. The residues were purified by silica
gel flash column chromatography (EtOAc/hexane, 1:4 to 1:2). The
combined organic layers were concentrated under reduced pressure
2-(Hydroxymethyl)-2-cyclohexen-1-one (8):[14b,14c,15] White powder,
1
Rf = 0.28 (EtOAc/hexane, 1:1). H NMR (400 MHz, CDCl3): δ =
1.970–2.034 (m, J = 6.0 Hz, 2 H), 2.370–2.411 (m, 4 H), 2.424 (t,
1 H), 4.222–4.241 (d, J = 5.2 Hz, 2 H), 6.920–6.940 (t, J = 6.0 Hz,
1 H) ppm. 13C NMR (400 MHz, CDCl3): δ = 22.81, 25.72, 38.31,
62.17, 138.35, 147.10, 200.78 ppm.
2,6,6-Tris(hydroxymethyl)-2-cyclohexen-1-one (9): Colorless oil, Rf
= 0.055 (silica; EtOAc/hexane, 2:1). IR (film, KBr/CH Cl ): ν =
˜
2
2
3344, 2944, 2831, 2521, 2364, 2044, 1664, 1453, 1415, 1113, 1032,
659 cm–1. 1H NMR (400 MHz, CDCl3, TMS, 25 °C): δ = 2.043–
2.074 (t, 2 H, C4HC5H2C6), 2.527–2.568 (m, 2 H, C3C4H2C5H2), and dried under vacuum. The isolated compounds were obtained
3.613–3.642 (d, J = 11.6 Hz, 2 H, C6CH2OH), 3.834–3.863 (d, J =
as follows: 16-i in 73% yield (165 mg, pale yellow solid), 16-iii in
11.6 Hz, 2 H, C6CH2OH), 4.200, (s, 2 H, C2CH2OH), 7.144–7.164 83% (220 mg), and 16-iv in 73% (194 mg) as light yellow solids;
(t, J = 4 Hz 1 H, C2C3HC4H2) ppm. 13C NMR (400 MHz, TMS, 16-v in 65% (187 mg) and 16-vi in 31%, (84 mg) as yellow solids;
CDCl3, 25 °C): δ = 22.246 (C3HC4H2C5), 25.566 (C4H2C5H2C6),
52.159 [C=OC6(CH2)2], 59.492 (C2CH2OH)2, 62.795 [C6(CH2)2-
(OH)2], 136.660 (C=OC2CH2OH), 150.569 (C2C3HC4H2), 203.420
(C=O) ppm. Spectral data were assigned on the basis of 2D
HMQC and 2D COSY NMR spectroscopy. GC–MS: m/z = 185
[M – 1].
16-vii in 77% (167 mg), 16-ix in 67% (190 mg), and 16-x in 45%
(127 mg) as light yellow crystalline solids; and compound 17-vi in
20% (95 mg) as an oil. The spectral characteristics of the prepared
known compounds were found to be in agreement with previously
reported data.
2-(Hydroxyphenylmethyl)-2-cyclopenten-1-one (16-i):[9b,9e,14c,15,17]
1
6,6-Bis(hydroxymethyl)-2-cyclohexen-1-one (10): Colorless oil, Rf =
Pale yellow solid, Rf = 0.31 (silica; EtOAc/hexane, 1:1). H NMR
0.14 (silica; EtOAc/hexane, 2:1). IR (film, KBr/CH Cl ): ν = 3053,
(400 MHz, CDCl3): δ = 2.43–2.459 (m, 2 H), 2.575 (m, 2 H), 3.56–
3.57 (d, J = 4.4 Hz, 1 H), 5.546 (s, 1 H), 7.26–7.38 (m, 6 H) ppm.
˜
2
2
2365, 1419, 1265, 895, 740, 705, 671 cm–1. 1H NMR (400 MHz,
Eur. J. Org. Chem. 2011, 2372–2379
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2377

K. P. Guerra, C. A. M. Afonso
FULL PAPER
13C NMR (400 MHz, CDCl3): δ = 26.73, 35.32, 69.86, 126.42,
127.93, 128.57, 141.41, 147.80, 159.59, 209.77 ppm.
Fundo Europeu de Desenvolvimento Regional (FEDER) for finan-
cial support (SFRH/BPD/28038/2006 and PTDC/QUI-QUI/
099389/2008) and the Portuguese Nuclear Magnetic Resonance
Network (Instituto Superior Técnico) for NMR spectroscopy.
2-[Hydroxy(4-methoxyphenyl)methyl]-2-cyclopenten-1-one
(16-
iv):[9b,9e,15,17] Yellow solid, Rf = 0.25 (silica; EtOAc/hexane, 1:1). 1H
NMR (400 MHz, CDCl3): δ = 2.441–2.463 (m, 2 H), 2.508–2.590
(m, 2 H), 3.36–3.37 (d, J = 4 Hz, OH), 5.506 (s, 1 H), 6.869–6.898
(m, 2 H), 7.268–7.2309 (m, 3 H) ppm. 13C NMR (400 MHz,
CDCl3): δ = 26.727, 35.417, 55.409, 69.740, 114.010, 127.804,
133.647, 148.052, 159.228, 209.783 ppm.
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2-[Hydroxy(4-nitrophenyl)methyl]-2-cyclopenten-1-one
(16-
vi):[9b,9e,15,18] Slightly yellow crystalline solid, Rf = 0.44 (silica;
EtOAc/hexane, 1:1), 1H NMR (400 MHz, CDCl3): δ = 2.46–2.48
(m, 2 H), 2.61–2.63 (m, 2 H), 3.76 (s, 1 H), 5.66 (s, 1 H), 7.302–
7.309 (m, 1 H), 7.564–7.586 (d, J = 8.8 Hz, 2 H), 8.186–8.208 (d,
J = 8.8 Hz, 2 H) ppm. 13C NMR (400 MHz, CDCl3): δ = 26.96,
35.26, 69.06, 123.84, 127.21, 146.81, 147.57, 148.65, 160.06,
209.47 ppm.
2-[1-Hydroxy(2-furyl)methyl]-2-cyclopenten-1-one (16-vii):[14c] Yel-
low solid, Rf = 0.28 (silica; EtOAc/hexane, 1:1). 1H NMR
(400 MHz, CDCl3): δ = 2.47–2.50 (m, 2 H), 2.65 (m, 2 H), 3.450–
3.468 (d, J = 7.2 Hz, 1 H), 5.58 (s, 1 H), 6.28–6.29 (d, J = 4.4 Hz,
1 H), 6.33–6.34 (m, 1 H), 7.38 (m, 1 H), 7.52 (m, 1 H) ppm. 13C
NMR (400 MHz, CDCl3): δ = 26.92, 35.21, 64.01, 107.48, 110.52,
142.63, 144.84, 153.82, 160.27, 209.38 ppm.
2-[(Hydroxy(naphthalene-1-yl)methyl)]-2-cyclopenten-1-one
(16-
ix):[19] Colorless oil, Rf = 0.725 (silica, Et2O/CH2Cl2, 1:1). 1H
NMR (400 MHz, CDCl3, TMS, 25 °C): δ = 2.410–2.466 (m, 2 H,
C3HC4H2C5), 2.494–2.560 (br. m, 2 H, C4C5H2C=O), 3.688–3.698
(d, J = 4 Hz, 1 H, C2CHOH), 5.723 (s, 1 H, C2CHOH), 7.271–
7.276 (t, 1 H, C2C3HC4H2), 7.464–7.484 (d, J = 8 Hz, 3 H, βCH,
Ar), 7.8.15–7.939 (m, 4 H, αCH, Ar) ppm. 13C NMR (400 MHz,
CDCl3, TMS, 25 °C):
δ =
26.780, (C3HC4H2C5), 35.348
(C4H2C5H2C=O), 69.994 (C2CHOH), 124.462, 125.249, 126.131,
126.304 (βArCH), 127.772, 128.176, 128.391 (αAr CH), 133.142,
133.348, 138.802 (Ar C), 147.742 (C=OC2CH2), 159.794
(C2C3HC4H2), 209.798 (C=O) ppm. Spectral data were assigned on
the basis of 2D HMQC and 2D COSY NMR spectroscopy.
syn-2,5-Bis[hydroxy(4-nitrophenyl)methyl]cyclopent-2-enone (17-vi):[9b]
Pale yellow solid, m.p. 81–83 °C, Rf = 0.39 (silica; EtOAc/hexane,
1:2). 1H NMR (400 MHz, CDCl3, TMS, 25 °C): δ = 2.252–2.482
(m, 1 H, C3HHC4HC5), 2.636–2.689 (m, 1 H, 1 H, C3HHC4HC5),
2.785–2.803 (m, 1 H, C4H2C5HC=O), 3.444–3.478 (t, 1 H, OH),
3.502–3.698 (br. m, 1 H, OH), 5.481–5.512 (d, J = 12.4 Hz, 1 H,
C5HCHCAr), 5.675, (s, 1 H, C2CHCAr), 7.402–7.420 (m, 1 H,
C2C3HC4H2), 7.481–7.585 (m, 4 H, Ar), 8.135–8.196 (m, 4 H,
Ar) ppm. 13C NMR (400 MHz, CDCl3, TMS, 25 °C): δ = 27.673
(C3HC4H2C5H), 53.421 (C4H2C5HC=O), 69.023, (C5HCHCAr),
70.806 (C2CHCAr), 123.929, 126.375, 127.224, 127.368 (4 CH Ar),
146.632, 146.945, 147.458, 148.249 (4 C Ar), 149.665 (C=OC2C3H),
161.323 (C2C3HC4H2), 208.489 (C=O) ppm. The spectroscopic
data were assigned on the basis of 2D HMQC and 2D COSY
NMR spectroscopy.
Supporting Information (see footnote on the first page of this arti-
1
cle): Chromatograms of the reaction optimization experiments, H
1
NMR spectral details of the tandem reaction, and H and 13C 2D
NMR spectroscopic data of all isolated compounds together with
GS–MS spectra.
Acknowledgments
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2000, 41, 1–5; b) M. Shi, Y.-M. Xu, G.-L. Zhao, X.-F. Wu, Eur.
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The authors are grateful to Fundação para a Ciência e a Tecnolo-
gia [Programa Operational Ciência e Inovação (POCI) 2010] and
2378
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 2372–2379

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