An efficient and simple Morita-Baylis-Hillman reaction based on the N-methylpyrrolidine-Ba(OH)2 catalytic system

Article abstract of DOI:10.1016/j.tet.2011.02.020

By using of precise catalytic amount of N-methylpyrrolidine (5 mol %) and Ba(OH)₂ (1.5 mol %) in H₂O/CH₃OH 5/1 or CH ₃OH/CH₂Cl₂ 3/1 solvent mixtures at T=0 °C a Morita-Baylis-Hillman derivatives could be obtained in good to excellent yield from 2-cyclopenten-1-one, 2-cyclohexen-1-one and formaldehyde and diverse aryl aldehydes after suitable reaction time.

Full text of DOI:10.1016/j.tet.2011.02.020

Tetrahedron 67 (2011) 2562e2569
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
An efficient and simple MoritaeBayliseHillman reaction based on the
N-methylpyrrolidineeBa(OH)2 catalytic system
,b,
Krassimira P. Guerra b, Carlos A.M. Afonso a
*
a
ꢀ
i-Med.UL, Faculdade de Farmacia da Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal
CQFM, Centro de Química-Física Molecular, INdInstitute of Nanosciences and Nanotechnology, Instituto Superior Tecnico, 1049-001 Lisboa, Portugal
b
ꢀ
a r t i c l e i n f o
a b s t r a c t
Article history:
By using of precise catalytic amount of N-methylpyrrolidine (5 mol %) and Ba(OH)2 (1.5 mol %) in H2O/
CH3OH 5/1 or CH3OH/CH2Cl2 3/1 solvent mixtures at T¼0 ꢀC a MoritaeBayliseHillman derivatives could
be obtained in good to excellent yield from 2-cyclopenten-1-one, 2-cyclohexen-1-one and formaldehyde
and diverse aryl aldehydes after suitable reaction time.
Received 1 September 2010
Received in revised form 3 February 2011
Accepted 8 February 2011
Available online 12 February 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Water
Cooperative catalysis
Enone
Formaldehyde
N-Methylpyrrolidine
MBH reaction
1. Introduction
of forward methodologies for multicomponent reactions and ra-
tionalized syntheses of important natural and medicinal products
The MoritaeBayliseHillman reaction (MBH) has been recog-
nized as important coupling protocol between the electrophiles
and activated alkenes promoted generally by nucleophilic cata-
lysts.1,2 Enormous scientific efforts have been made to develop
a number of effective promoters and physical methods enlarging
the substrate scope.3 The striking challenges to find the optimal
catalysts and conditions for MBH reaction with cyclic enones have
motivated many remarkable investigations.4e7
become more discernible.16
Our motivation to investigate the classical MBH reaction with
cyclic enones becomes from the requirement of a large amount of
the 2-(hydroxymethyl)-2-cyclopenten-1-one, key starting material
for the synthesis of particular medicinal compounds with carbo-
cyclic ring.17 The simple but demanding reaction between
2-cyclopenten-1-one and aqueous HCHO could offer rapidly direct
access to 2-(hydroxymethyl)-derivative in aqueous media. The
application of this MBH protocol increases even under difficult
synthetic circumstances and a high yield of MBH hydroxymethyl
derivative is a prerequisite for feasible and successful realization of
various total synthetic routes.18,19 The particular industrial scale-up
processes for a preparation of important drugs, such as sampatrilat
claimed for a simple, economical, efficient and environmentally
The MBH reaction allowed an atom economy and a formation of
chemospecific functional groups in closeness to the a-alkylene-b-
hydroxyl product. Newly the popularity of MBH protocol was
growing due to a broad range of reaction scope, cost-effective
starting materials and a facility to be applied on complex synthetic
routes exploring the reactivity of formed allylic alcohols.8 The
modern development of asymmetric and aza-MBH reactions was
investigated the stereoselective CeC bond formation under mild
conditions with a main array of alkenes and imines, tosylimines,
clean catalytic system promoting
a formation of 2-(hydrox-
ymethyl)-enone derivatives.20 In fact the reported MBH methods
based on the different catalysts reveal a number of deficiencies, for
example: a low yield and or long reaction time21e24 or use of
hazardous and expensive catalysts such as the phosphine de-
rivatives and others.25,26 The historical background call attention to
the important unsolved problems correlated with MBH reaction
between activated cyclic enones and formaldehyde. Here we de-
scribed the development of capable, low-costing, and environ-
mentally friendly methodology for the MBH reaction with activated
a
-ketoesters, fluoroesters, and p-deficient olefins in addition to
aldehydes.3e,9ꢁ11 Recently the intrinsic mechanism of MBH reaction
was disclosed successfully.12e15 The new frontiers for the evolution
* Corresponding author. Tel.: þ351 933111611; fax: þ351 21 7946470. e-mail
address: carlosafonso@ff.ul.pt (C.A.M. Afonso).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.02.020

K.P. Guerra, C.A.M. Afonso / Tetrahedron 67 (2011) 2562e2569
2563
Table 2
alkenes as a 2-cyclopent-1-one and 2-cyclohexen-1-one and 36%
aqueous solution of HCHO.
Initial optimization of the reaction conditionsa
O
O
O
promoter (30 mol%)
25 oC
+
2. Result and discussion
OH
H
H
2.1. Screening of various additives for promoters
1
2
Entry
Promoter
Solvent
36% HCHO
(mol equiv)
Time
Yieldb (%)
1R
3.4
Initially we selected more of 50 inorganic and organic envi-
ronmentally clean and available compounds (Lewis acids and bases,
nucleophilic amines, cinchona derivatives, etc.) that could act as
efficient and unexplored promoters of the MBH reaction between
2-cyclopenten-1-one (1) and 36% aqueous solution of HCHO. The
DMSO was used as polar aprotic medium exploring its property to
accelerate the MBH reaction by stabilization of the ionic transition
states.12,27 The additives were tested by TLC studies and the
obtained yield of 2-(hydroxymethyl)-2-cyclopenten-1-one (2) with
every single one additive was calculated from following HPLC
analysis. All results are listed on the Table S1 of Supplementary data
(SD). The best ones are shown on the Table 1.
2
1c
2
3
4
5
Ba(OH)2
NMP
CH3OH
CH3OH
CH3OH
DMSO
H2O
1.2
1.2
5
1.2
1.2
1.2
20 min
15 h
4 h
4 h
40 min
3 h
24
c
41
38
NMP
NMP
NMP
NMP
31.4
2.8
23.4
25
11.5
38
14.6
13.8
6
H2O
1R Unconverted substrate.
a
Reaction conditions: see footnote (a) of Table 1.
Calculated from HPLC analysis.
Precipitate formation.
b
c
conditions. The inferior yields of 2 and 1R were observed when
5 mol equiv of 36% HCHO were used (compare entries 3 and 2).
These results could due to the formation of side products created by
the excess of formaldehyde. The optimal enone/formaldehyde ratio
for production of 2 was 1:1.2 mol equiv. The precipitate formation
in water was observed on the reactions with 30 mol % Ba(OH)2 (see
Table S2 of SD). The reaction with promoter NMP was faster in
water (entries 5 and 6) than in CH3OH (entry 2) although the yield
of 1R found on the reaction mixture after 40 min or 3 h was lower
than this after 15 h (entry 2). We understand that NMP at 30 mol %
in water might promote also other non MBH reaction pathways and
a substrate 1 was spent on the formation of side products.
The experimental data at this point of investigation revealed an
increment of yield of 2 (from 21% to 41%) in protic media (H2O,
CH3OH) using the following MBH reaction conditions: 1.2 mol equiv
of 36% HCHO, 30 mol % of promoter, at T¼25 ꢀC and reaction time
from 20 min to 15 h.
Table 1
Selected promoters of studied MBH reactiona (TLC and HPLC analysis)
Entry
Additive
Time (h)
Yieldb (%) of 2
1
2
3
4
NMP
Li2CO3
25 h
21.3
7.6
17 days
0.5 h
48 h
c
Ba(OH)2
6.2d
6.0
CH3ONae
a
Reaction conditions: 2-cyclopenten-1-one (1) (10.5
m
L, 0.12 mmol), 36% aque-
ous HCHO (11
m
L, 0.144 mmol), additive (30 mol %) in 0.25 mL of DMSO, T¼25 ꢀC.
b
Based on HPLC analysis.
Solvent CH3OH/CHCl3, 3/1.
Precipitate formation.
T¼25e40 ꢀC.
c
d
e
Table 1 provided the vital initial information: from all tested
additives an NMP (N-methylpyrrolidine) revealed superior pro-
moter’s activity of studied MBH reaction and furnished the product 2
in 21.3% yield (entry 1). Li2CO3 was inefficient as promoter (entry 2)
while the reaction with Ba(OH)2 ran faster but in fact a precipitate
formation at the beginning of the reaction (half hour) apparently
suppressed an increase of yield of 2 with the time (entry 3). The
additive CH3ONa which is a known catalyst for MBH reaction in
CH3OH4e was ineffective in our experimental conditions. We de-
cided to carry on the studies with NMP and Ba(OH)2 as potential
promoters of investigated MBH reaction.
2.3. Fine tuning of the catalytic system
With these results in the hands we investigated how the
quantity of promoter influenced the modification of yield of 2 and
1R testing the mixtures of NMP and Ba(OH)2 in H2O/CH3OH 5/1,
H2O/CH3OH 1/3, H2O/CH3OH 1/1, and respectively in each solvent
alone. The MBH reaction was carried out at T¼25 ꢀC for 2 h varying
a mol % of promoter (s) on an individual system or a promoter
alone. To each reaction mixture was added a reaction rate accel-
erator NaI28 in different concentrations. Full data of the experi-
mental results is listed on Table S3, SD while the selected ones are
presented on Table 3 to help the discussion. After a careful exam-
ination of the obtained data at this point of studies, we accom-
plished the following conclusions:
The best yield of 2 was attained in H2O/CH3OH 5/1 reaction
medium (see Table 3, entries 1e3). The promoter system NMP/Ba
(OH)2, 5/1.5 mol %, (III) was a superior (entry 3) achieving 65% yield
of 2 with 26.4% of 1R for 2 h reaction time. The substrate 1 was
almost completely spent only on the MBH derivative formation. The
catalytic amount of Ba(OH)2 in system III was optimal. For example
a promoting MBH reaction system NMP/Ba(OH)2 5/3 mol % attained
only 51% yield of 2 (entry 5). Most likely Ba(OH)2 acted as a base
and/or a nucleophile.29
2.2. Tuning of a solvent and a mole equivalent of 36%
aqueous HCHO
Then a type of solvent and amount of 36% HCHO used on the
MBH reaction, promoted by each of two selected previously addi-
tives, were investigated. The total data of realized experiments is
given on the Table S2 of SD while the selected ones are presented
on Table 2.
The MBH reaction was performed in three different solvents
namely CH3OH, H2O, and DMSO, keeping the amount of promoters
at 30 mol %. CH3OH and H2O were selected for the reaction solvents
taken into account their properties. A protic media (H2O) could help
to reduce the barrier for the proton transfer and accelerate the
reaction moreover the hydrogen-bond donors as a H2O and CH3OH
activate the reaction allowing the proton-transfer step from the
Apparently, the system NMP/NaI/Ba(OH)2 50/22/3 mol %, (I),
(entry 1) was able to get 70% yield of 2 nevertheless almost 20% of
initial substrate amount was depleted and only 10% of 1R was found
in the reaction mixture after 2 h reaction time. A precipitate was
observed on the reactions with system I in all solvent mixtures or
a
-position to the alkoxide of intermediate.12,14,27 After a compari-
son of evolution of yields of 2 and 1R (unconverted substrate)
depicted on Table 2 (entries 2, 5 and 6) with (entry 4), H2O and
CH3OH were selected as solvents of choice in studied reaction

2564
K.P. Guerra, C.A.M. Afonso / Tetrahedron 67 (2011) 2562e2569
Table 3
Table 4
Final fine tuning of the studied catalytic systems: promoters and additive (mol %) in
Preparative syntheses of 2a
varied solvent mixtures proportionsa
Entry
Catalytic system
or individual
promoter (mol %)
1, g (mmol)
Time
(h)
T
ꢀC
Isolated yield
(%) of 2
O
O
O
catalytic systems I-III
+
OH
50b,c
48b,c
57b
H
H
1
2
3
I
I
II
0.20 (2.4)
0.20 (2.4)
0.30 (3.6)
0.20 (2.4)
0.20 (2.4)
0.40 (4.8)
0.30 (3.6)
0.20 (2.4)
0.20 (2.4)
0.60 (7.3)
0.20 (2.4)
1.00 (12.0)
3.00 (36.5)
5.00 (60.9)
10.00 (121.8)
0.30 (3.6)
0.20 (2.4)
0.20 (2.4)
0.20 (2.4)
2
16
9
2
2
6
18
5
6
8
10
8
8
9
8.5
15
25
25
25
25
25
25
25
0
0
0
0
0
0
0
0
25
25
25
25
solvent
2 h, 25 oC
1
(1.2 eq.)
2
4
5
6
7
8
9
10
11
12
13
14
15
16h
17h
18
19
II
III
III
III
III
III
III
III
III
III
III
III
63b
Entry
Catalytic
system
NMP
NaI
Ba(OH)2
Yieldb (%)
53b
67b
2
1R
59b
88b
H2O/CH3OH 5/1
1c
2
3
4
5
I
II
III
50
5
5
5
5
22
5
d
d
d
3
70
69
65
64
51
10
93d
94d,e
90d
1.5
1.5
d
3
17.5
26.4
24
94d,f
93g(90)d
91g(88)d
90g(87)d
49b
12
H2O/CH3OH 1/3
6
II
III
I
5
5
50
5
d
1.5
1.5
3
49
46.4
41
18
17
13
NMP (30)
NMP (30)
NMP (5)
NMP (5), Ba(OH)2
(0.75)
42b
7
10 days
2
2.5
8c
22
49b
61b
H2O/CH3OH 1/1
9
II
I
5
50
5
22
1.5
3
52
40
24.6
11
a
Unchanged reaction conditions were: 1.2 mol equiv of 36% HCHO and H2O/
CH3OH, 5/1 as solvent.
10c
b
Isolated yield after chromatographic purification.
Precipitate formation.
c
H2O
11
d
III
II
I
5
5
50
d
5
22
1.5
1.5
3
21.5
14.6
9.5
24.1
15.3
12.5
Isolated yield without using chromatography.
e
The degree of purity determined by 1H NMR and 13C NMR spectra and HPLC
12
13c
chromatography(see Fig. 2).
f
a
See footnote (a) of Table 1, 2 h reaction time at T¼25 ꢀC.
Using formaldehyde aqueous solution, containing precipitate of para-
b
c
formaldehyde, 2 was isolated in 86% yield.
Determined by HPLC analysis.
g
Overall yield (see procedure C, Experimental section).
CH3OH as solvent was used.
Precipitate formation.
h
solvents alone. The system NMP/NaI/Ba(OH)2 5/5/1.5 mol %, (II),
(entry 2) showed better than the system III performance with 69%
yield of 2 but about 14% of the total substrate amount was
employed in the formation of side products. And finally, the addi-
tive NaI does not induce significant acceleration of the reaction or
(and) enhance of yield of 2.
2.4. Preparative synthetic studies
Three promising values of the yield of 2 in solvent mixture H2O/
CH3OH, 5/1: (70%) using system I, (69%) with system II and (65%)
attained by system III were achieved by the presented above HPLC
optimization of studied MBH reaction. The following step was to
employ preparative synthetic studies using these three catalytic
system and others for comparison in order to validate or discard
some of provided by HPLC results.
Full data of all fulfilled independently preparative syntheses of 2
at different substrate scales’ employing the catalytic system I, II,
and III and others was presented on Table 4.
Fig. 1. Correlation between yield (%) of 2, 1R and a time of reaction at T¼0 ꢀC (HPLC
The best isolated yield of 2 at T¼25 ꢀC was 67%, using system III
(Table 4 entry 6). Next the MBH reaction was carried out at T¼0 ꢀC to
validate the temperature control on a formation of 2 under our
reaction conditions. In the initial synthetic experiment we isolated
88% yield of 2 after 5 h reaction time (entry 8). The fine tuning of the
reaction time was done by carefully performed HPLC studies of six
individual samples provided from separated MBH reactions carried
out at diverse times at T¼0 ꢀC. The correlation of calculated from
HPLC yields of 2 and 1R in function of reaction time is presented on
Fig.1 showing a non linear relationship with max of yield of 2 at 8 h.
During the described HPLC improvement of the reaction con-
ditions we observed the formation of unknown side products under
MBH conditions (see Fig. S5, SD). There are seen two anonymous
peaks at 7.98 (7.47) and 9.63 (9.35) min. Their intensities at T¼25 ꢀC
are stronger than these at T¼0 ꢀC. In fact, the last temperature
data).
suppressed a formation of side products thus increases the possi-
bility of realization of MBH reaction pathway.
The isolated yield of 2 with 6 h reaction time was 93% and re-
spectively 94% at 8 h, without using chromatographic purification
(Table 4, entries 9 and 10) and (Fig. 2).
A number of preparative synthetic experiments in substrate
scale 0.60e10.00 g (7.3e121.8 mmol) with catalytic system III were
performed exploring optimized from HPLC studies data (8 h re-
action time and T¼0 ꢀC) and the obtained results are presented on
Table 4 (entries 10, 12e15). About 100% conversation of 1 were
observed using different scales. For our gratefulness the in-
vestigated MBH reaction exhibited very good reproducibility when
1 was employed in gram scale. A principal amount of 2 (87e94%)

K.P. Guerra, C.A.M. Afonso / Tetrahedron 67 (2011) 2562e2569
2565
Table 5
MBH reaction of cyclopentenone 1 with representative aryl and alkyl aldehydes
O
O
OH
O
NMP (5 mol%),
+
Ba(OH)2 (1.5 mol%)
R
R
H
CH3OH/CH2Cl2 3/1
0 oC
(1.2 eq.)
BH product
1
3-9
Entry
1
Time (h)
Yield (%)
73
9
2
3
50
4
83
65
Fig. 2. Typical 1H and 13C NMR spectra of 2 obtained devoid of chromatographic
purification (Table 4, entry 9e15).
4
5
6
18
2a
6
85
46
40
was achieved devoid of chromatography (entries 12e15), see also
Fig. 2. The purification of remaining after extraction aqueous layers
furnished about 3% of MBH adduct (see Procedure 3 of Experi-
mental part). The new miscellaneous catalytic system III in our
experimental MBH conditions took the equal reaction time (8e9 h)
to transform 0.60 g or 10.00 g of substrate to MBH adduct and also
could work well with relatively uncertain formaldehyde concen-
tration (see Table 4, entry 12, footnote (f)). Truly the cooperative
catalytic system III in our adjusted MBH conditions demonstrated
robustness on the preparative synthetic experiments in large scale.
The better results reached at T¼0 ꢀC might due to the higher
efficiency of catalytic system III as catalyst of desirable MBH re-
action at this temperature range in detriment to other reaction
pathways. Leahy et al. observed enormous acceleration of MBH
reaction with methyl acrylate and different aldehydes at T¼0 ꢀC
using DABCO or Bu3P catalysts.30 The phenomenon was explained
with the existence of different populations of purported
intermediates enolate species at room temperature and T¼0 ꢀC.
At the best of our knowledge only two methods reported the
similar yields of an MBH adduct obtained on the reaction between 1
and 36% HCHO: 86% for 17 days, using 5 mol % imidazole22 and 97%
for 1 h employing 5 mol % Me2PhP25 as catalysts.
The verification of a reproducibility of the reported methods in
our conditions and the results of these experiments together with
a data from the literature are presented on (Table S4, SD). The re-
action with a phosphine catalyst was shown a good reproducibility
however this type of catalyst has an intrinsic chemical instability
(it’s difficult to manipulate and maintain) and is harmful. Due to the
last reason the scope of its application in a total synthesis of
medicinal drugs is very limited and required the use of chroma-
tography thus increasing the anticipated high cost of this catalyst in
scale-up processes.
7
14a
67
a
T¼25 ꢀC.
less active than HCHO electrophiles, such as aryl aldehydes even in
CH3OH/CH2Cl2 3/1 solvent mixture. The achieved yields with the
different types of aldehydes are similar to the best reported on the
literature. However some important differences were observed. For
instance, system III exhibited the selective behavior under employed
working reaction conditions with p-nitrobenzaldehyde, p-methox-
ybenzaldehyde, and 2-furylaldehyde (Table 5, entries 2e4). The MBH
derivative of p-nitrobenzaldehyde (5) was attained in 65% yield
which was a bit lower compared with the reported ones (Table S5
of SD). Contrary, the p-methoxybenzaldehyde containing the elec-
tron-donating group reacted slowly but 4 was furnished in 83% as
a sole product (Table 5, entry 2). The 2-furylaldehyde reacted rela-
tively fast with 1 at T¼0 ꢀC (18 h, Table 5, entry 4) and the obtained
good yield of 6 (85%) could be compared with the best reported using
imidazole as catalyst (84%), obtained for longer reaction time
(70 h)24 also see Table S5, SD. Interestingly, with the hindered 2-
naphthylaldehyde after 14 h at T¼25 ꢀC from the reaction mixture
was isolated the MBH product 9 in 67% yield, (Table 5, entry 7) and
also unconverted substrate in 24% yield. The catalytic system III was
fairly efficient with the aliphatic aldehydes providing 7 and 8 in 46%
and 40% yields, respectively (Table 5, entries 6 and 7 and Table S5, SD)
for comparison.
2.5. Preparative synthesis of aryl MBH derivatives
The optimal catalytic system III in H2O/CH3OH, 5/1, worked very
well under MBH conditions with 1 and 36% HCHO. Besides the cat-
alytic system III was developed and attuned for the preparation of
the important building block 2, we explored the possibility to apply
this methodology to aryl and alkyl aldehydes (Table 5). All details and
the comparison of our results with reported methods are listed on
Table S5, SD. The reaction scope of catalytic system III included also
2.6. MBH reaction with other cyclic enones
The preparative synthetic experiments with selected cyclic
enones were carried out in the solvent mixture H2O/CH3OH 5/1

2566
K.P. Guerra, C.A.M. Afonso / Tetrahedron 67 (2011) 2562e2569
to determine the substrate scope of optimum catalytic system III.
The system III promoted satisfactorily MBH reaction with 10 and
at T¼0 ꢀC and 11 was produced at 89% yield (Table 6, entry 1A)
well-matching with a number of reported results (see Table S6
of SD).
2.7. MBH reaction with acyclic Michael acceptors
We studied also the MBH reaction between activated acyclic
alkenes, such as acrylonitrile (15), ethylacrylate (16), and methyl
vinyl ketone (17) and 36% HCHO under catalytic action of system III
in H2O/CH3OH, 5/1 and CH3OH/CH2Cl2 3/1 (see details in Table 6,
entries 4e6).
The MBHproducts of 15,16, and17 were not observed. Compound
15 underwent 1e4 addition in CH3OH/CH2Cl2 (3/1) originating 98%
yield of respective 3-methoxypropanenitrile (18) (entry 4B).
The experiments with activated acyclic alkenes identified III as
a specific catalytic system for MBH reaction involving cyclic enones.
However this type of limitation of the substrate catalytic scope
corresponding to the acyclic alkenes was observed also for the
catalytic mixed system DMAP/TMEDA/MgI2.7 In this context our
catalytic system might address the longstanding problem of addi-
tion to acyclic enones and enoates. Recently have been published
some work in this field.32
Table 6
MBH reaction with different cyclic enones and acyclic Michael receptors and
formaldehyde, using NMP/Ba(OH)2 mixed catalytic systema
Entry Substrate Catalytic
Time
(h)
Products
Isolated yield (%)
system
(mol %)
11,
Recovered
substrate
14
1Aa
1Ba
2
III
III
24
16
12
89c
73
d
d
d
80
11
NMP
(15),
Ba(OH)2
(7.5)
3. Conclusions
d
The classical MBH reaction involving aqueous 36% HCHO and
a number of cyclic enones was explored. The discovery and fine
tuning of the new miscellaneous catalytic system NMP/Ba(OH)2
5/1.5 mol % (III) was supported by detailed analytic HPLC and pre-
parative synthesis studies. The efficiency of the novel system is
strongly dependent of a precise catalysts loading, solvents media,
the temperature and the reaction time. The system III promotes
very efficiently MBH reaction with 2-cyclopenten-1-one (1) and
36% HCHO at T¼0 ꢀC in H2O/CH3OH 5/1 solvent mixture in range
0.20e10.00 g of 1 and 2-(hydroxymethyl)-2-cyclopent-1-one (2)
was isolated in 90e94% total yield. The catalytic system III pro-
motes well the MBH reaction with other cyclic enones, such as
2-cyclohexen-1-one and some low reactive aryl aldehydes.
The resourceful, cost-effective and environmentally sustainable
synthetic methodology for the preparation of MBH hydroxymethyl
adducts of cyclic enones exploring a new mixed catalytic system
NMP/Ba(OH)2 was described. The methodology could consist of
benefit for the synthetic organic chemists37 to be applied on the
total syntheses of pharmaceutical drugs and biologically active
natural compounds.
NMP
(15),
Ba(OH)2
(7.5)
3Ab
3Bb
30
30
42
36
15
17
NMP
(30),
Ba(OH)2
(3)
14
4A
4B
III
III
15
7
d
d
dd
d
98
5
III
III
72
8
d
d
d
d
100
100
6
In our present work we are studied the asymmetric function-
alization of 2-hydroxymethyl cyclopentenone derivative (2), which
is a key step of the synthesis of important pharmacologically active
molecules.
a
Reaction conditions: 36% aqueous HCHO (1.5 mol equiv), H2O/CH3OH 5/1,
T¼25 ꢀC.
b
c
Aqueous HCHO (2.0 mol equiv, 36%).
T¼0 ꢀC.
d
Decomposition of the substrate.
4. Experimental
The 4,4-dimethyl-2-cyclohexen-1-one (13) reacted slowly with
4.1. General remarks
2 mol equiv HCHO and 14 was isolated in 42% yield. Luo et al. also
reported moderate yields (17e37%) of aryl derivatives of 13.4e Other
researcher group has been investigated the MBH reaction with 5,5-
dimethyl-2-cyclohexen-1-one and HCHO employing DMAP and
SDS as co-catalytic system. They attained fairly good (53e63%) yield
of MBH derivative.31 Both groups imputed a sluggishness of the
reaction and reached yields of MBH derivatives to the relatively
hindered structure of cyclic alkenes.
The MBH reaction did not work with 3-methyl-2-cyclopenten-
1-one (12) and 1.5 equiv HCHO employing the catalytic system
NMP/Ba(OH)2 (Table 6, entry 2). This absence of reactivity was in
line with the reported data observed for 2-cyclohexen-1-one ana-
logs.21 The lack of a formation of MBH product derived from 12
indicated that the MBH pathway was interrupted by steric effect at
Dichloromethane (CH2Cl2), ethyl ether (Et2O), and methanol
(CH3OH) were freshly distilled prior to use. Ethyl acetate (EtOAc)
was distilled over potassium carbonate. The water used for HPLC
studies was a Mili-Q grade and the acetonitrile was HPLC grade. The
preparative thin layer chromatography plates were prepared with
silica gel 60 GF254 Merck (Ref. 1.07730.1000) while the flash chro-
matography were carried out on silica gel 60 M purchased from MN
(Ref. 815381). Reaction mixtures were analyzed by TLC using
ALUGRAMÒ SIL G/UV254 from MN (Ref. 818133, silica gel 60), and
visualization of TLC spots was effected using UV and ninhydrine
(2,2-dihydroxyindane-1,3-dione) or phosphomolybdic acid (PMA)
solutions. The additives used on TLC and HPLC scanning studies
were purchased from Aldrich, Merck and Fluka and used without
further purification. The 36% aqueous solution of HCHO with
methanol as stabilizer was purchased from Fluka and Merck. The
2-cyclopenten-1-one and 2-cyclohexen-1-one were obtained from
b-position of 3-methyl-2-cyclopenten-1-one. Thus the nucleophilic
tertiary amine catalyst (NMP) could not undergo a 1e4 addition as
a first step of MBH reaction.12e14

K.P. Guerra, C.A.M. Afonso / Tetrahedron 67 (2011) 2562e2569
2567
Aldrich and Alfa Aesar while 4,4-dimethyl-2-cyclohexen-1-one,
N-methylpyrrolidine, Ba(OH)2.8H2O, 4-nitrobenzaldehyde, furan-
2-carbaldehyde, 2-naphthylaldehyde, and propionaldehyde were
purchased from Aldrich. Acetaldehyde was obtained from Merck
and used as received. The benzaldehyde, 4-methoxybenzaldehyde,
2-furylaldehyde, acrylonitrile, ethylacrylate, and methyl vinyl ke-
tone, were obtained from Aldrich and used after purification by
distillation under vacuum. NMR spectra were recorded in a Bruker
AMX 400 using CDCl3 as a solvent. All coupling constants are
expressed in Hz. The HPLC studies were done on the Shimadzu
5/1 mixture of H2O/CH3OH (9 mL) were added sequentially 36%
aqueous solution of HCHO (0.460 mL, 6 mmol) and 2-cyclopenten-
1-one (1) (0.410 mL, 4.9 mmol) (entry 6). The resultant mixture was
stirred at T¼25 ꢀC (water bath). Upon completion of 6 h reaction
time the reaction was quenched with 1 N HCl until pH 3. To the
mixture was added NaCl (10 g) and stirred about half hour. Then
aqueous layer was extracted four times with EtOAc/CH2Cl2 (1/1).
The combined organic layers were dried over anhydrous MgSO4,
filtered, and concentrated under reduced pressure. The residue was
purified by silica gel preparative TLC eluted with (1/1) mixtures of
EtOAc/CH2Cl2 or Et2O/CH2Cl2. The organic extracts containing the
desired product 2 were concentrated carefully under reduced
pressure.
Prominence system apparatus using the C18 Kromasil 100 5 mm
column, 250ꢂ4.6 mm and 5% of CH3CN in Mili-Q water to mobile
phase. The SPD-20A UVevIS detector was used with sensitivity to
the limit (Noise level 0.5ꢂ10(-5) AU), wide linearity (2.5AU), and
Wavelength range: 190e700 nm.
Procedure B (Table 4, entries 9e15): To a mixture of Ba(OH)2
(0.0114 g, 1.5 mol %) and N-methylpyrrolidine (12.5 mL, 5 mol %) in
5 mL of H2O/CH3OH (5/1) were added sequentially 36% aqueous
solution of HCHO (0.220 mL, 2.88 mmol) and 2-cyclopenten-1-one
(1) (0.200 mL, 2.4 mmol). The resulting mixture was stirred at
T¼0 ꢀC. After 8 h, (Table 4, entry 9) the reaction was quenched with
1 N HCl until pH 3. To the reaction mixture was added NaHCO3 until
pH about 7 and then was extracted with CH2Cl2. The combined
organic layers were dried over anhydrous MgSO4, filtered, and
concentrated under reduced pressure to give the desired product 2
as crystals.
Procedure C (Table 4, entries 13e15). To a mixture of Ba(OH)2
(0.580 g, 1.5 mol %) and N-methylpyrrolidine (0.633 mL, 5 mol %) in
250 mL of H2O/CH3OH (5/1) were added sequentially 36% aqueous
solution of HCHO (11.70 mL, 152.2 mmol) and 2-cyclopenten-1-one
(1) (10.10 mL, 121.8 mmol) (entry 15). The resulting mixture was
stirred at T¼0 ꢀC. When the TLC silica gel analysis (eluent EtOAc/
hexane, 9/1) indicated the lack of the spot of 1 (after 8.5 h) the
reaction mixture was quenched with 1 N HCl until pH 3. The
NaHCO3 was added until pH about 7 to neutralize the acid excess
and then the aqueous reaction mixture was extracted with CH2Cl2
and after that with CH2Cl2/Et2O (1/1). The combined organic layers
were dried over anhydrous MgSO4, filtered, and concentrated un-
der reduced pressure to give the desired product 2 (11.83 g, 87%
yield) as translucent crystals. The remaining aqueous layer was
checked by TLC, which indicated the presence of trace of 2 together
with small more polar spot. The aqueous part was evaporated un-
der reduced pressure to slurry residue. The residue was dissolved in
1 mL of EtOAc and purified by thin layer chromatography using
CH2Cl2/Et2O/EtOAc, 2/1/1 as eluent. The organic extracts containing
the desired product 2 were concentrated under reduced pressure to
white crystalline powder (0.41 g, 3% yield). The total yield of 2 was
90%, 12.24 g.
4.2. General procedure for the MBH reaction by TLC screening
(Table 1 and Table S1, SD)
The MBH reactions were performed on the home-made carousel
reaction station apparatus in respective size reaction-flasks using
0.12 mmol (10 mg, 10.5
mL) of 2-cyclopenten-1-one (1) and 0.14
mmol (11 L) of aqueous formaldehyde in 0.250 mL of different
m
solvents. For every one reaction a 30 mol % catalytic amount of each
respective additive was employed. The vials were emerged in oil bath
with controlled temperature. The reaction time varied from minutes
to 2e3 h or more as the major amount of substrate was disappeared
and the formation of the MBH product was considerable, observed by
TLC using the mixture of EtOAc/hexane 9/1 as eluent.
4.3. General procedure for the MBH reaction by HPLC
screening (Tables 1 and 2, Tables S2 and S3, SD)
Those experiments were performed on the basis of prior TLC
screening. Then from each reaction were taken 10
solution and dissolved in 1 mL H2O (Mili-Q)/acetonitrile, 95/5. From
these solutions 20 L were injected on the Shimadzu Prominence
system apparatus with the C18 Kromasil 100 column,
mL of reaction
m
5 mm
250ꢂ4.6 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 employed was 0.7 mL/min. In these experimental condi-
tions the retention time (tR) observed for the MBH product (2) was
between 17 and 18.5 min and respective one for the 2-cyclopenten-
1-one (1) was between 23 and 24.5 min depending of the column
equilibrium and temperature. The column temperature was room
temperature (approximately 25 ꢀC). To obtain the reproductive
results before HPLC analysis daily was done ‘black’ flush with the
used working solvent gradient. The daily work was slighter than
10 h and at a finish of the work the column was cleaned with used
as eluent solvent gradient of Mili-Q water and acetonitrile. The time
between each injection was 10e15 min. The routine sample cal-
culations were based on the comparison of peak areas of MBH
product and 2-cyclopenten-1-one, with external standard peak
area from previously obtained calibration curves at equal working
conditions. Six samples with the concentration from 0.0036 to
0.0001 mg of the 2-cyclopent-1-one 1 were used while the samples
for the BH product 2 were seven with the concentration between
0.005 and 0.0003 mg. Each calibration curve was obtained based of
the ratio area of respective peak and concentration on the sample.
4.4.1. Known compound 2-(hydroxymethyl)-2-cyclopenten-1-one
(2). C6H8O2, translucent crystals. Yields: 25 ꢀC (365 mg, 67%) 0 ꢀC
(254 mg, 93%). The BH product 2 was obtained in very comparable
yield (770 mg, 94%) when 1 was employed in 600 mg (entry 9) and
(12.24 g, 90%) from 10.00 g of 1 (entry 15). Rf¼0.36 (silica, AcOEt/
hexane, 9/1). 1H NMR (400 MHz, CDCl3): dH 2.16 (br, 1H), 2.44e2.46
(m, 2H), 2.62e2.65 (m, 2H), 4.36e4.37 (d, J¼4.0 Hz, 2H), 7.52e7.53
(m, 1H); 13C NMR (CDCl3, 400 MHz): dC 26.86, 35.01, 57.57, 144.91,
159.05, 209.98. NMR spectral properties were consistent with those
previously reported.22,25
4.5. General procedure for the preparative synthetic MBH
reaction between 2-cyclopenten-1-one (1) and representative
aryl and alkyl aldehydes (Table 5). Spectral data for known
compounds (3e9)
4.4. General procedures for the preparative synthetic MBH
reaction between 2-cyclopenten-1-one (1) and 36% aqueous
solution of HCHO (Table 4). Spectral data for (2)
To a mixtures of Ba(OH)2 (0.0057 g, 1.5 mol %) and N-methyl-
Procedure A (Table 4, entries 1e7): To a mixture of Ba(OH)2
pyrrolidine (6.2
mL, 5 mol %) in 2.5 mL of CH3OH/CH2Cl2 (3/1) or
(0.023 g, 1.5 mol %) and N-methylpyrrolidine (25.5 mL, 5 mol %) in
H2O/CH3OH (5/1) were added 1.46 mmol of RCHO (R¼phenyl,

2568
K.P. Guerra, C.A.M. Afonso / Tetrahedron 67 (2011) 2562e2569
4-methoxyphenyl, 4-nitrophenyl, 2-furanyl, 2-naphthyl, 1-ethyl
and 1-propyl) and 2-cyclopenten-1-one 1 (0.100 mL,1.2 mmol). The
resulting mixtures were stirred at T¼0ꢀ or 25 ꢀC (water bath). Upon
completion of the time indicated in the Table 5, the reactions were
quenched with minimum quantity of 1 N HCl. To the mixtures was
added NaHCO3 until pH about 7 and they were concentrated under
reduced pressure to slurry residues. The residues were purified by
silica gel column or preparative thin layer chromatography using
2/1 to 1/1 mixtures of EtOAc/hexane, or Et2O/CH2Cl2 (depending of
the aldehyde employed). The combined organic layers with the
presence of the desired BH derivative (tested by silica TLC using the
particular mixtures of eluents) were concentrated under reduced
pressure to solids. The respective known compounds were dried
under vacuum and characterized by 1H and 13C spectral analysis.
2H), 2.43 (s, 1H), 4.36 (s, 1H), 7.44e7.45 (m, 1H); 13C NMR (CDCl3,
400 MHz): dC 9.88, 26.72, 2858, 35.37, 69.25, 147.61, 158.21, 158.21,
210.38. NMR spectral properties were consistent with those pre-
viously reported.4c
4.5.7. Known compound 2-[(hydroxy(naphthalen-1-yl)methyl)]-2-
cyclopent-1-one (9). C16H14O2 colorless crystalline oil, yields: 25 ꢀC:
(207 mg, 67%). Rf¼0.725 (silica, Et2O/CH2Cl2 1/1). 1H NMR
(400 MHz, CDCl3, 25 ꢀC, TMS): dH 2.41e2.46 (m, 2H, C3HC4H2C5),
2.49e2.56 (m, br 2H, C4C5H2C]O), 3.68e3.69 (d, J¼4 Hz, 1H,
C2CHOH), 5.72 (s, 1H, C2CHOH), 7.271e7.276(t, 1H, C2C3HC4H2),
7.46e7.48 (d, J¼8 Hz, 3H,
NMR (CDCl3, 400 MHz, TMS): dC 26.78, (C3HC4H2C5), 35.34
(C4H2C5H2C]O), 69.99 (C2CHOH), 124.46, 125.24, 126.13, 126.30 (
b CH, Ar), 7.81e7.93 (m, 4H, a C
CH, Ar); 13
b
Ar CH), 127.77, 128.17, 128.39 (a Ar CH), 133.14, 133.34, 138.80 (Ar C),
4.5.1. Known compound 2-(hydroxyphenylmethyl)-2-cyclopenten-1-
147.74 (C]OC2CH2), 159.79 (C2C3HC4H2), 209.79 (C]O). Spectral
data are assigned based of 2D HMQC and 2D COSY NMR studies.
NMR spectral properties were consistent with those previously
reported.7
one (3). C12H12O2, pale yellow solid, yields: 25 ꢀC: (160 mg, 70%);
0
ꢀC: (167 mg, 73%). Rf¼0.31 (silica, EtOAc/hexane, 1/1). 1H NMR
(400 MHz, CDCl3): dH 2.43e2.45 (m, 2H), 2.57 (m, 2H), 3.56e3.57 (d,
J¼4.0 Hz, 1H), 5.54 (s, 1H), 7.26e7.38 (m, 6H); 13C NMR (CDCl3,
400 MHz): dC 26.73, 35.32, 69.86, 126.42, 127.93, 128.57, 141.41,
147.80, 159.59, 209.77. 13C NMR spectral properties were consistent
with those previously reported.4e,24,25,33,34
4.6. General procedure for the preparative synthetic MBH
reaction between 2-cyclohexen-1-one (10) and 36% aqueous
solution of HCHO (Table 6, entry 1A,B). Spectral data for
known compound (11)
4.5.2. Known compound 2-[hydroxy(4-methoxyphenyl)methyl]-2-
cyclopenten-1-one (4). C13H14O3, colorless yellow crystalline solid,
yields: 25 ꢀC: (151 mg, 57%); 0 ꢀC: (220 mg, 83%). Rf¼0.25 (silica,
EtOAc/hexane, 1/1). 1H NMR (CDCl33, 400 MHz): dH 2.41e2.43 (m,
2H), 2.57 (s, 2H), 3.46 (br, 1H), 3.78 (s, 3H), 5.47 (s, 1H), 6.85e6.87
(d, J¼8.0 Hz, 2H), 7.23e7.29 (m, 3H); 13C NMR (CDCl3, 400 MHz): dC
26.67, 35.35, 55.34, 69.52, 113.84, 127.74, 133. 66,148. 05, 159.28,
209.69. NMR spectral properties were consistent with those pre-
viously reported.4e,24,33,34
To the mixtures of Ba(OH)2 (0.0050 g, 1.5 mol %) and N-meth-
ylpyrrolidine (5.5 mL, 5 mol %) in 2.5 mL of H2O/CH3OH (5/1) were
added sequentially 36% aqueous solution of HCHO (0.120 mL,
1.56 mmol) and 2-cyclohexen-1-one (10) (0.102 mL, 1.04 mmol).
The resulting mixtures were stirred at T¼0 ꢀC and 25 ꢀC (water
bath). Upon completion of 16 h at T¼25 ꢀC and 24 h at T¼0 ꢀC the
reactions were quenched with 1 N HCl until pH 3. To the mixtures
was added NaHCO3 until pH about 7 and was extracted with CH2Cl2.
The combined organic layers were dried over anhydrous MgSO4,
filtered, and concentrated under reduced pressure. The residues
were purified by silica gel column chromatography using EtOAc/
hexane, 1/1 and Et2O/CH2Cl2 1/1 as eluents. The organic layers that
include the desired derivative 11 were concentrated under reduced
pressure to solids.
4.5.3. Known compound (5) 2-[hydroxy(4-nitrophenyl)methyl]-2-
cyclopenten-1-one. C12H11NO4, slightly yellow crystalline solid,
Yields: 25 ꢀC: (173 mg, 61%); 0 ꢀC: (184 mg, 65%). Rf¼0.44 (silica,
EtOAc/hexane, 1/1). 1H NMR (400 MHz, CDCl3): dH 2.46e2.48 (m,
2H), 2.61e2.63 (m, 2H), 3.72 (br,1H), 5.66 (s,1H), 7.30e7.30 (m, 1H),
7.56e7.58 (d, J¼8.0 Hz, 2H), 8.18e8.19 (d, J¼4.0 Hz, 2H); 13C NMR
(CDCl3, 400 MHz): dC 26.96, 35.26, 69.06, 123.84, 127.21, 146.81,
147.57, 148.65, 160.06, 209.47. NMR spectral properties were con-
sistent with those previously reported.4e,33ꢁ35
4.6.1. Known compound 2-(hydroxymethyl)-2-cyclohexen-1-one
(11). C7H10O2 white powder, yields: 25 ꢀC: (0.096 mg, 73%) and
respectively 0 ꢀC: (118 mg, 89%). Rf¼0.28 (EtOAc/hexane, 1/1). 1H
NMR (400 MHz, CDCl3): dH 1.97e2.03 (m, 2H), 2.37e2.41, (m, 4H),
2.41e2.44, (t, 1H), 4.22e4.24, (d, J¼8.0 Hz, 2H), 6.92e6.94, (t, 1H);
13C NMR (CDCl3, 400 MHz): dC 22.81, 25.72, 38.31, 62.17, 138.35,
147.10, 200.78. NMR spectral properties were consistent with those
previously reported.21,25,34
4.5.4. Known compound 2-[1-hydroxy(2-furyl)methyl]-2-cyclo-
penten-1-one (6). C10H10O3, yellow solid, yields: 25 ꢀC: (167 mg,
77%); 0 ꢀC: (184.5 mg, 85%). Rf¼0.28 (silica, EtOAc/hexane, 1/1). 1H
NMR (400 MHz, CDCl3): dH 2.47e2.50 (m, 2H), 2.65 (m, 2H),
3.45e3.46, (d, J¼4.0 Hz, 1H), 5.58 (s, 1H), 6.28e6.29 (d, J¼4.0 Hz,
1H), 6.33e6.34 (d, J¼4.0 Hz,1H), 7.38 (m,1H), 7.52 (m,1H); 13C NMR
(CDCl3, 400 MHz): dC 26.92, 35.21, 64.01, 107.48, 110.52, 142.63,
144.84, 153.82, 160.27, 209.38.25
4.7. General procedure for the preparative synthetic MBH
reaction between 4,4-dimethyl-2-cyclohexen-1-one (13) and
36% aqueous solution of HCHO (Table 6, entry 3A,B). Spectral
data for (14)
4.5.5. Known compound 2-(1-hydroxyethyl)-2-cyclopenten-1-one
(7). C7H10O2, white solid, Yields: 25 ꢀC: (68 mg, 46%); 0 ꢀC: (61 mg,
40%). Rf¼0.38 (silica, EtOAc/CH2Cl2, 1/1). 1H NMR (400 MHz, CDCl3):
dH 1.39e1.41 (d, J¼8 Hz, 3H), 1.61, (s, 1H), 2.44e2.46 (m, 2H),
2.60e2.63 (m, 2H), 4.63e4.64 (q, 1H), 7.44e7.45 (m, 1H); 13C NMR
(CDCl3, 400 MHz): dC 21.60, 26.67, 35.37, 63.87, 149.03, 157.36,
210.77. NMR spectral properties were consistent with those pre-
viously reported.36
To the mixtures of Ba(OH)2 (0.0033 g, 3 mol % or 0.0082 g,
7.5 mol %) and N-methylpyrrolidine (25.1 mL, 30 mol % or 12.5 mL,
15 mol %) in 2.5 mL H2O/CH3OH (5/1) were added sequentially 36%
aqueous solution of HCHO (0.123 mL,1.61 mmol) and 4,4-dimethyl-
2-cyclohexen-1-one (13) (0.109 mL, 0.805 mmol). The resulting
mixtures were stirred at T¼25 ꢀC (water bath) and upon completing
30 h the reactions were quenched with 5 mL of brine. The mixtures
were extracted with CH2Cl2. The combined organic layers were
dried over anhydrous MgSO4, filtered, and concentrated under re-
duced pressure. The residues were purified by silica gel column or
preparative thin layer chromatography using as eluent gradient
EtOAc/hexane, (2/1 to 1/1). The organic layers that include the
4.5.6. Known compound 2-(1-hydroxypropyl)-2-cyclopenten-1-one
(8). C8H12O2 white solid, yield 25 ꢀC: (65 mg, 38%) 0 ꢀC: (68 mg,
40%). Rf¼0.41 (silica, EtOAc/CH2Cl2, 1/1). 1H NMR (400 MHz, CDCl3):
dH 0.92e0.99 (m, 3H), 1.64e1.70 (m, 2H), 1.72e1.75 (m, 2H), 2.16 (m,

K.P. Guerra, C.A.M. Afonso / Tetrahedron 67 (2011) 2562e2569
2569
5. Aggarwal, V. K.; Mereu, A.; McCague, R. J. Org. Chem. 1998, 63, 7183e7189.
6. Kawamura, M.; Kobayashi, S. Tetrahedron Lett. 1999, 40, 1539e1542.
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solids.
8. (a) Hoveyda, A. N.; Evans, D. A.; Fu, G. C. Chem. Rev. 1993, 93, 1301e1370; (b)
Banwell, M. G.; Crasto, C. F.; Easton, C. J.; Karoli, T.; March, D. R.; Nairn, M. R.;
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4.7.1. Known compound (14): 2-(hydroxymethyl)-4,4-dimethyl-2-
cyclohexen-1-one, C9H14O2. White powder. Yields: (52 mg, 42%,
entry 3A) and (44 mg, 36%, entry 3B). Rf¼0.72 (EtOAc/hexane, 1/2).
1H NMR (400 MHz, CDCl3): dH 1.17 (s, 6H), 1.84e1.87, (t, 2H),
2.47e2.50, (m, 2H), 4.20e4.21, (d, J¼4.0 Hz, 2H), 6.58, (s, 1H); 13C
NMR (CDCl3, 400 MHz): dC 22.89, 33.02, 34.75, 36.06, 62.48, 133.73,
156.18, 201.03. NMR spectral properties were consistent with those
previously reported.31
Guan, Y.; Wenkert, E. Helv. Cˇ him. Acta 2005, 88, 330e338; (d) Hanessian, S.;
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The authors are Fundac¸ ao para a Ciencia e a Tecnologia, (POCI
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and PTDC/QUI-QUI/099389/2008) and the Portuguese Nuclear
Magnetic Resonance Network (Instituto Superior Tecnico) for NMR
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Supplementary data
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Full experimental data of a fine optimization of the reaction
conditions including TLC and HPLC details for a formation of
product 2 and representative chromatograms, complete list of
preparative synthetic experimental results and comparison with
reported examples, copies of 1H and 13C NMR spectra of all isolated
MBH derivatives. Supplementary data associated with this article
can be found in online version at doi:10.1016/j.tet.2011.02.020.
These data include MOL files and InChiKeys of the most important
compounds described in this article.
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