Water as the reaction medium for multicomponent reactions based on boronic acids

Article abstract of DOI:10.1016/j.tet.2010.01.084

Water is a suitable medium for the Petasis-borono-Mannich multicomponent reaction. Salicylaldehyde, glyoxalic acid, glycoaldehyde and glyoxal were reacted with several boronic acids and different amines affording alkylaminophenols, 2H-chromenes, α-amino a

Full text of DOI:10.1016/j.tet.2010.01.084

Tetrahedron 66 (2010) 2736–2745
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Water as the reaction medium for multicomponent reactions based
on boronic acids
a
a
b
b
ˆ
´
Nuno R. Candeias , Pedro M.S.D. Cal , Vania Andre , M. Teresa Duarte ,
b
a,
*
´
Luıs F. Veiros , Pedro M.P. Gois
a
´
iMed.UL, Faculdade de Farmacia da Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal
b Centro de Qu´ımica Estrutural, Departamento de Engenharia Quı´ımica e Biolo´gica, Instituto Superior Te´cnico,1049-001 Lisboa, Portugal
a r t i c l e i n f o
a b s t r a c t
Article history:
Water is a suitable medium for the Petasis-borono-Mannich multicomponent reaction. Salicylaldehyde,
glyoxalic acid, glycoaldehyde and glyoxal were reacted with several boronic acids and different amines
affording alkylaminophenols, 2H-chromenes, a-amino acids, a-amino alcohols and 2-hydroxylmorpho-
lines in good to high yields. An efficient new one-pot method for the assembly of boron-heterocycles
based on amino-acids, boronic acids and salicylaldehyde using water as the reaction media is pre-
sented. The mechanisms of these reactions were studied by means of DFT calculations, and the effect of
solvent on the calculated energy barriers was addressed, for different aldehydes.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 11 December 2009
Received in revised form 14 January 2010
Accepted 26 January 2010
Available online 1 February 2010
Keywords:
Boron
Multicomponent reactions
Petasis reaction
Boron heterocycles
1. Introduction
have a negative transition molar volume and for that reason may be
accelerated due to the hydrophobic effect.5–7
The emerging of high-throughput screening of drug candidates
in pharmaceutical industries has brought the concept of Multi-
component reactions (MCR) into the limelight of organic synthe-
sis.1 MCRs are one of the best tools available for the preparation of
large libraries of diverse and structurally distinct molecules in
a time and cost effective way.1
Boronic acids are ideal partners in MCR as they are generally
stable and soluble in aqueous media. Furthermore, many different
molecular structures are commercially available, which is particu-
larly noteworthy when designing reactions targeting high levels of
molecular diversity. Considering MCRs in which the boronic acids is
used as a potential nucleophilic species generated without the use
of metal catalysts, Petasis and co-workers developed a protocol in
which the irreversible step is the formation of a new C–C bond.8
The reaction proceeds via the formation of an imine or an imi-
nium species, which reacts with the boronic acid to yield secondary
or tertiary amines (Scheme 1). The success of this protocol resides
in the fact that the boronic acid is completely inert towards the
aldehyde though it efficiently traps the iminium or the imine bond.
This process depends on the existence of an adjacent hydroxyl
group that reacts with the boronic acid to form a more nucleophilic
tetrahedron boronate species (‘ate complex’), which is able to
transfer the boron substituent to the imine or iminium bond.
The use of water as solvent in organic reactions has been suc-
cessfully reported for several examples. The low cost, the lack of
inflammability, explosive, mutagenic, and carcinogenic properties
are some of the economic and environmental benefits that have
been associated to this solvent. In addition to this, the network of
hydrogen bonds, the large surface tension, the high specific heat
capacity, the high cohesive energy and the high polarity have been
highlighted as some of the unique properties of water that can
dramatically influence the transformations performed in this me-
dia.2,3 In addition the necessity of exploring alternatives to con-
ventional organic solvents, have lead, over the last decade, to
a considerable increment in the number of reactions that may use
water as solvent.4 Conceptually, multicomponent reactions are
potential candidates for the use of water as solvent since the
multiple hydrophobic reactants are brought in closer proximity due
to hydrophobic interactions. Furthermore these reactions typically
* Corresponding author.
Scheme 1. Example of a Petasis-borono-Mannich reaction.
E-mail address: pedrogois@ff.ul.pt (P.M.P. Gois).
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.01.084

N.R. Candeias et al. / Tetrahedron 66 (2010) 2736–2745
2737
Table 1
Following our preliminary report on the use of water as solvent
for the Petasis-BMR,9 we now present a detailed synthetic and
mechanistic study on this topic.
2H-Chromene synthesis via the Petasis-BMR
Entry
Amine
Yielda (%)
1
2
3
4
5
Dimethyl amine$HCl (1.2 equiv) and NaOH (2 equiv)
Dibenzylamine (1.2 equiv)
Diethyl amine (1.2 equiv)
Diethyl amine (20 mol %)
Diethyl amine (40 mol %)
79
58
92
49
71
2. Results and discussion
Depending on the aldehyde (aldehydeþactivating group), the
Petasis-BMR may be used to prepare several synthetic valuable
a
Isolated yield.
compounds such as
a , a
-amino acids8a,10 -amino alcohols8b,11, 2H-
chromenes12 -hydrazinocarboxylic acids13, 2-hydroxymorpholines
,
a
and aminodiols14, 2-aminomorpholines15 among others. Therefore in
our first communication on the use of wateras solvent for the Petasis-
BMR we disclosed the preparation of alkylaminophenols in yields up
to 96% based on the combination of different salicylaldehydes with
a variety of secondary amines and boronic acids (Scheme 2).
entries 2 and 3). Using the optimized reaction conditions 2H-chro-
menes 2 and 3 were obtained in 92% and 78% yield, respectively.
Almost simultaneously with our first communication on this
topic, Petasis and co-workers reported the use of water as solvent in
the preparation of 2H-chromenes.12b In this study was shown that
dibenzylamine was the best amine to promote the cyclisation. Dif-
ferently, in our hands the same reaction afforded only 58% of com-
pound 1 (Table 1, entry 2). This lower yield may be related with the
reaction stirring as in our reaction conditions the stirring stopped
frequently due to product 1 precipitation (Scheme 4 and Scheme 5).
R1
R2
R3
OH
O
H
N
R3
B
N
H2O
R1
R2
+
H
HO
OH
24 h,80 ºC
+
OH
10 examples; yields 75-96%
OH
O
Scheme 2. Petasis-borono-Mannich reaction with salicylaldehydes.
H
N
H
Despite the success achieved when using salicylaldehyde, we
became interested in understanding if water could be used as
a general solvent for the Petasis-BMR. Therefore, different alde-
hydes were tested in the MCR using water as solvent (Scheme 3).
Accompanying this synthetic study, the efficiency of the different
activating groups (phenol, carboxylic acid and alcohol) was evalu-
ated using DFT calculations.
H2O
+
24 h, 80 ºC
O
Ph
B(OH)2
Ph
O
2 - 92 % (a)
74 % (b)
OH
H
N
H
OH
O
H2O
O
O
+
O
Ph
OH
24 h, 80 ºC
H
O
H
H
OH
H
B(OH)2
H
Ph
O
O
3 - 78 % (a)
75 % (b)
glycolaldehyde
glyoxalic acid
salicylaldehyde
glyoxal
Scheme 5. 2H-Chromenes preparation using the optimized reaction conditions using
1.2 equiv of amine (a) and using 40 mol % of amine (b).
In 2005 Pirrung and co-workers described an Ugi four-centre
three-component reaction (U-4C-3CR) to construct b-lactams in
R1
R3
R2
O
O
OH
R2
R1
R3
R2
N
N
OH
OH
which a considerable acceleration effect was detected when using
water as solvent. This observation was rationalized considering the
hydrophobic effect and the negative activation volume of the cyc-
lisation step leading to the heterocyclic formation.6c Taking this
precedent in consideration, we envisioned that water could exert
a similar effect over the synthesis of 2H-chromenes as it involves an
intramolecular cyclisation step as well. Therefore water, 1,2-di-
chloroethane and dioxane were evaluated in the preparation of
compound 1 (Scheme 6, Table 2). When comparing with the other
N
R1
O
R
amino alcohols 2-hydroxymorpholines
2H-chromenes
amino acids
Scheme 3. Petasis-BMR using different aldehydes.
Among the methodologies described in the literature, the one
disclosed by Finn and co-workers, which combines an amine, sali-
cylaldehydes and vinylboronic acids remains as one of the most ef-
ficient protocols to prepare 2H-chromenes.12a In this reaction after
the three components condensation, occurs an intramolecular cyc-
lisation promoted by the phenol hydroxyl group with consequent
ejection of the amine moiety. In water the desired 2H-chromenes
were obtained in good yields using 40 mol % of amine (Scheme 4,
Table 1, entries 4 and 5) though when using 1.2 equiv of amine the
yields of 2H-chromenes 1 and 2 were improved up to 92%. Among
the amines tested, diethyl amine was the most competent, (Table 1,
Scheme 6. 2H-Chromene preparation in different solvents using the Petasis-BMR.
Table 2
Solvent comparison in the preparation of 2H-chromene via the Petasis-BMR
OH
O
H
N
Entry
Solvent
Temperature (ꢀC)
Yielda (%)
H
R1
R2
H2O
1
2
3
4
Water
Water
1,2-DCE
Dioxane
80
50
80
80
66
58
62
60
+
24 h, 80 ºC
O
Ph
B(OH)2
1
Ph
a
Scheme 4. 2H-Chromene preparation using the Petasis-BMR.
Isolated yields.

2738
N.R. Candeias et al. / Tetrahedron 66 (2010) 2736–2745
organic solvents typically used for this transformation, water
exerted only a modest acceleration effect over the synthesis of
2H-chromene 1 (Scheme 6,Table 2).
afforded product 9 in 72% yield at the same time that the
water soluble ethanolamine afforded the corresponding amino
acid in 67% yield.
The two proposedmechanismsfortheformationof2H-chromene
using the Petasis-MCR involve either an intramolecular nucleophilic
displacement of an ammonium leaving group12a (Scheme 7,
O
OH
H
OH
B
H2O
HN
H2N
+
pathway a) or an 6p-electrocyclisation (Scheme 7, pathway b). Bear-
O
+
OH
24 h, 80 ºC
Ph
OH
Ph
Ph
ing this in mind, we envisioned that if the reaction proceeds via
pathway a we could probably induce some enantioselectivity in the
process using a chiral amine. Therefore we attempted the enantio-
O
9
- 72 %
selectivity synthesis of 1 using half equivalent of (S)-a,a-diphenyl-
O
prolinol at 80 ꢀC for 24 h. A racemic mixture of 2H-chromene 1 was
obtained in 36% yield, which indicates that, at least in water, the re-
action probably proceeds via pathway b.
OH
OH
OH
H
H2O
OH
HN
OH
+
+
O
B
24 h, 80 ºC
Ph
OH
H2N
O
OH
O
R1
R2
H
N
10
N
- 67 %
H
R1 R2
a
Scheme 9. Petasis borono-Mannich with glyoxalic acid and primary amines, with
+
b
reaction products purified by precipitation.
O
Ph
O
a
Ph
B(OH)2
1
Ph
Once established the synthesis of amino acids, the preparation
of amino alcohols was studied. Hence, glycolaldehyde (dimer) was
reacted with secondary amines and trans-2-phenylvinylboronic
Scheme 7. Possible pathways for the preparation of 2H-chromenes.
Regarding the efficiency of salicylaldehyde to promote the
Petasis-BMR in water, we extend the protocol to the preparation of
acid. This methodology afforded the expected a-amino alcohols at
room temperature in yields up to 69% (Scheme 10, Table 4, entries
1–3). Interestingly 1,2,3,4-tetrahidroquinoline proved to be a very
useful amine for this reaction affording the amino alcohols in good
yields despite using vinyl or phenylboronic acid (Scheme 10, Table
4, entries 4 and 5).
a
-amino acids using glyoxalic acid as the carbonyl component. The
reaction of glyoxalic acid with stoichiometric amounts of boronic
acids and secondary amines afforded the corresponding amino
acids in yields up to 86%. These results are comparable with those
described when using ethanol as solvent.8a The products obtained,
were simply isolated via filtration after precipitation from the re-
action media (Scheme 8, Table 3).
R3 OH
R1 R2
N
HO
+
R2
O
O
B
H2O
+
OH
OH
R3
OH
R1
N
H
R3 OH
R1
R2
B
R1 R2
N
Scheme 10. Petasis borono-Mannich with glycolaldehyde dimer.
N
H
H2O
OH
O
OH
R3
OH
Table 4
Petasis borono-Mannich with glycolaldehyde dimer
H
O
O
Entry
Boronic Acid
Amine
Reaction conditions Product Yielda (%)
Scheme 8. Petasis borono-Mannich with glyoxalic acid.
Ph
Ph
OH
25 ꢀ
48 h
C
B
1
11
12
13
14
62
64
69
75
N
H
OH
Table 3
Petasis borono-Mannich with glyoxalic acid
Ph Ph
Ph
Ph
Ph
OH
25 ꢀ
C
B
Entry
Boronic Acid
Amine
Reaction conditions Product Yielda (%)
2
3
4
N
H
48 h
OH
Ph
OH
50 ꢀ
24 h
C
B
1
4
67
OH
25 ꢀ
C
N
H
OH
B
48 h
N
H
OH
O
Ph
Ph
OH
50 ꢀ
24 h
C
B
2
3
4
5
6
7
8
75
77
86
65
OH
50 ꢀ
C
B
N
H
OH
24 h
N
H
OH
Ph
OH
50 ꢀ
36 h
C
OH
B
N
H
B
50 ꢀ
C
48 h
OH
5
OH
15
74
N
H
MeO
OH
Ph
Ph
Ph
50 ꢀ
24 h
C
B
a
Isolated yields, except entry 2 where the product was extracted from the re-
action medium with Et2O.
OH
N
H
OH
B
80 ꢀ
36 h
C
2-Hydroxymorpholines are important synthetic motifs present
in a variety of biologically active molecules. This structure can be
assessed reacting glyoxal with substituted ethanolamine in the
presence of boronic acids (Scheme 11).14
5
OH
N
H
a
Isolated yield after precipitation in water and filtration.
In water this protocol proved to be quite efficient affording the
2-hydroxymorpholines in high yields at room temperature conve-
niently using an aqueous solution of glyoxal and benzyl-
ethanolamine (Scheme 12, Table 5). Interestingly, when the
As shown in Scheme 9, the reaction also proceeds satisfy-
ingly when using primary amines regardless their hydrophobic
nature. For instance, the bulky hydrophobic adamantylamine

N.R. Candeias et al. / Tetrahedron 66 (2010) 2736–2745
2739
O
Several boronate complexes similar to 20 and generated from
N,O,O-tridentate ligands may be found in the literature including
those resulting from the combination of boronic acids with salicy-
laldehydes and amino-alcohols, amino-phenols or N-(2-hydroxy-
OH
HN
OH
B
R
H
O
O
O
N
OH
R
H
R
OH
+
-
Ph
O
+
OH
B
N
benzyl)-a
-amino-acids.16 Though their synthesis generally involves
OH
Ph
Ph
a multistep approach and organic solvents as the reaction media.17
As far as our knowledge goes these complexes have never been
prepared in one-pot using water as the reaction media. Therefore,
and encouraged by the high yield obtained in the synthesis of
complex 20, as well as the complex high thermal and hydrolytic
stability we extend the protocol to the preparation of different
Scheme 11. Preparation of 2-hydroxymorpholines in water.
reaction products were isolated by preparative TLC, the yields
obtained were similar to those reported by Berree and co-workers
14
´
(35–67%). Though, simply extracting the reaction mixture with ethyl
ether led to a remarkable improvement of the isolated yields (89–
97%). When using water as solvent no chromatographic steps were
required to purify the products as they were extracted almost se-
lectively, considering their 1H and 13C NMR (Table 5).
boron-complexes. Hence, combining L-phenylalanine with different
salicylaldehydes and boronic acids afforded complexes 21–27 in
yields up to 96%. Rather surprising, and despite our attempts, we
were unable to improve the yield of complex 26 prepared using
4-metoxy-phenylboronic acid. Apart from this case, the substitutions
either in the salicylaldehyde or the boronic acid had little effect on
the overall good yields obtained (Scheme 14).
O
OH
HN
OH
R
O
N
H
+
H2O
25 ºC
H
R
Ph
O
OH
B
-
OH
Ph
Scheme 12. Preparation of 2-hydroxymorpholines in water.
Table 5
Preparation of 2-hydroxymorpholines by Petasis borono-Mannich in water
Entry
R
Time (h) Product Diastereoisomeric ratio Yielda (%)
1
2
3
4
Ph
4-MeC6H4
4-MeOC6H4 24
CH]CHPh 48
24
48
16
17
18
19
1:0.3
1:0.2
1:0.24
1:0.9
97
93
94
89
a
Isolated yields after extraction of the reaction product with Et2O.
Finally we decided to extend this protocol to the use of amino
acids as the source of the amino component. Therefore we perform
the reaction of L-phenylalanine and salicylaldehyde with phenyl-
boronic acid in water. Rather surprisingly after 20 h reacting at
90 ꢀC instead of the expected product we obtained the boron-
complex 20 in 86% yield and with 99% de. Very conveniently, the
complex isolation was considerably facilitated because it com-
pletely precipitated from the reaction mixture (Scheme 13).
O
Scheme 14. Scope of the methodology using L-phenylalanine, different salicylalde-
hydes and boronic acids.
OH
HO
H2N
N
B
H2O
20 h, 90 ºC
Suitable crystals for X-ray analysis were obtained for complexes
20, 21, 25 and 26. Despite the different boronic acids used to pre-
pare 20, 21 and 25 they all display similar N–B dative bond dis-
tances (1.577(2) Å (20), 1.574(3) Å (21) and 1.569(4) Å (25)) and this
fact most probably results from stereo constrains imposed by the
tridentate ligand (Fig. 1).
O
OH
O
B
+
O
O
H
86 % yield
99 % de
20
OH
Scheme 13. Self assembly of boron-complexes in water.
Figure 1. Molecular diagrams of the complexes 20, 26, 25 and 21 (from left to right) obtained by X-ray diffraction.

2740
N.R. Candeias et al. / Tetrahedron 66 (2010) 2736–2745
The structural features of selected boron-complexes were
studied by means of DFT calculations,18 with emphasis on the na-
ture of the B–N bond. All complexes with determined X-ray
structure were addressed, and the corresponding optimised ge-
ometry calculated (see Computational details). The calculated B–N
distance is similar for all complexes (1.58 Å), in good agreement
with the experimental bond lengths determined for complexes 20,
21 and 25 (within 0.01 Å), and ca. 0.05 Å longer than the experi-
mental B–N separation observed in the X-ray structure of complex
26 (1.530(7) Å). The similarity observed in the B–N bond lengths
calculated for all species is reinforced by the corresponding Wiberg
indices,19 with a value of 0.61 in all cases, indicating comparable
bond strength. In addition, the atomic charge (NPA,20 see
Computational details) calculated for the B-atom is also equal for all
species (1.02) showing, once again, a general equivalence between
the electronic structure of the complexes studied. These results
indicate that the significantly shorter B–N bond distance observed
in the X-ray structure of complex 26, when compared with the
remaining species, is most probably due to a solid-state effect. The
relative positioning of the different B substituent implies a different
conformational geometry, noticed in the angle between the planes
sharing the B–N edge (36.05(6), 33.28(7), 38.79(8) and 41.1(3)ꢀ for
complexes 20, 21, 25 and 26, respectively) thus entailing distinct
crystal packing arrangements.(see Fig. in Supplementary data).
The mechanism generally assumed for the Petasis-borono-
Mannich reaction involves the formation of a tetrahedric boron
complex, denominated as ate complex, after the activation of the
boron atom by the hydroxyl functional group. This complex then
transfers the aryl moiety to the iminium or imine bond. The aryl
transfer does not occur in the absence of such hydroxyl group, sup-
porting the need of a boronic acid activating agent in the molecule.
After our previous work based on Density Functional Theory (DFT)18
calculations for the reaction of salycilaldehyde,9 we now report
a comparative study including the reactions of glyoxalic acid and
glycoaldehyde.
The DFT calculations on the mechanism of the Petasis reaction
used dimethylamine, phenylboronic acid and three aldehydes
(salicylaldehyde, glyoxalic acid and glyoxaldehyde) as model re-
actants. The effect of solvent was accounted for by means of the
polarisable continuum model PCM (see Computational details). The
corresponding results are presented as Supplementary data, but,
for simplification sake, the following discussion will be based on
the results obtained for water. For the three reactions studied, the
phenyl migration step was investigated in two different conditions:
starting from a boronic acid activated through the formation of an
ate complex, or in the absence of such activation. In all cases, the ate
complexes lead to lower energy barriers and, thus, these will be the
mechanisms discussed here. The energy profiles associated with
the alternative pathways, without previous activation of the bo-
ronic acid, are presented as Supplementary data.
Figure 2. Energy profile calculated for Petasis reaction between dimethylamine, sali-
cylaldehyde and phenylboronic acid. The relevant bond distances (Å) are indicated, as
well as the respective Wiberg indices (WI, italics). The minima and the transition state
were optimized and the energy values (kcal/mol) are referred to ate complex. H-atoms
on the phenyl and methyl substituents are omitted for clarity.
study was performed (Fig. 3). The ate complex formed from
glyoxalic acid is equivalent to the previous one, derived from sali-
cylaldehyde, as shown by a comparison of the relevant B–O bond,
i.e, the one that links together the iminium and the boronic acid:
d¼1.63 Å, WI¼0.46 for salicylaldehyde and d¼1.66 Å, WI¼0.46 for
Concerning the reaction of salicylaldehyde, it was previously
found9 that the ate complex formation should occur by the in-
teraction of the boronic acid with a zwiterionic species resultant from
the deprotonation of the iminium (Fig. 2). The transition state for the
migration of phenyl (TS1) demands an energetic barrier of 18.9 kcal/
mol and corresponds to an intermediate geometry between the ate
complex (ATE1) and the tertiary amine (TA1). The long distance and
the Wiberg index (WI)19 associated with the formation of the new
C–C bond (d¼2.00 Å, WI¼0.47), as well as the values relative to the C–
B bond break (d¼1.81 Å, WI¼0.51), indicate an early transition state
with only incipient C–C bond formation and C–B bond breaking.
Interestingly, the energy barrier was calculated to be ca. 2 kcal/
mol smaller for dichloroethane, than for the other two solvent
tested (water and dimethylformamide).
Figure 3. Energy profile calculated for Petasis reaction between dimethylamine,
glyoxalic acid and phenylboronic acid. The relevant bond distances (Å) are indicated, as
well as the respective Wiberg indices (WI, italics). The minima and the transition state
were optimized and the energy values (kcal/mol) in water (PCM) are referred to the ate
complex. H-atoms on the phenyl and methyl substituents are omitted for clarity.
Analogously to the previous mechanism, glyoxalic acid was
considered as the aldehyde component and a new mechanistic

N.R. Candeias et al. / Tetrahedron 66 (2010) 2736–2745
2741
glyoxalic acid. Again, the transition state determined for this
mechanism (TS2) has an intermediate geometry between the ate
complex (ATE2) and the tertiary amine (TA2). In TS2, the process of
C–B bond breaking is incipient (d¼1.74 Å, WI¼0.57), while the new
C–C bond is almost formed (d¼1.53 Å, WI¼0.57). Comparing both
mechanisms, the smaller energetic barrier to achieve the transition
state for the reaction of glyoxalic acid (10.2 kcal/mol) is in good
agreement with the experimental results. For the case of the acid,
the reaction can be performed at 50 ꢀC, while a temperature of
80 ꢀC is needed for the case of the aromatic aldehyde.
In the case of glycoaldehyde it was not possible to optimize the
geometry of free deprotonated iminium alkoxide. All attempts
leaded to alternative undesired geometries, reflecting the in-
stability of that intermediate. However, both the corresponding ate
complex, as well as the mechanism of phenyl migration from the
ate complex to the amine, could be calculated (Fig. 4), similarly to
what happened with the two former substrates, salicylaldehyde
and glyoxalic acid, allowing, this way, the comparison between all
three calculated paths.
investigated in which there is no deprotonation of the initial imi-
nium reactant, and the ate complex is formed via dehydration of
the boronic acid. This hypothesis was also tested for the other al-
dehydes and the corresponding profiles are presented as
Supplementary data.
In the mechanism represented in Figure 5, there are two con-
secutive steps. The first step corresponds to the formation of an ate
complex and, thus, to the activation of the boronic acid, while in the
second step, there is phenyl migration from the boron to the
C-atom of the iminium, with formation of the product. In the first
step, proton transfer from the OH group in the iminium to one OH
group of the boronic acid, allows to the formation of the B–O bond
between the two reagents and the formation of the ate complex
with one water molecule coordinating the B-atom (ATE4). In the
second step phenyl migration occurs, in the ate complex, yielding
the final product, the O-protonated tertiary amine TA4. This second
step is equivalent, in its general features, to the mechanisms dis-
cussed above, based on the deprotonated ate complexes.
In the mechanism of Figure 5 the rate limiting step is the for-
mation of the ate complex, with a very high activation energy of
30.4 kcal/mol. In addition, the energy barrier associated with
phenyl migration (13.9 kcal/mol), is significantly higher than the
one calculated for the mechanism involving the deprotonated ate
complex (Fig. 4). This indicates that the mechanism depicted in
Figure 4 is not competitive and hints that the reaction should
proceed via a deprotonated ate complex.
Figure 4. Energy profile calculated for Petasis reaction between dimethylamine, gly-
coaldehyde acid and phenylboronic acid. The relevant bond distances (Å) are indicated,
as well as the respective Wiberg indices (WI, italics). The minima and the transition
state were optimized and the energy values (kcal/mol) in water (PCM) are referred to
the ate complex. H-atoms on the phenyl and methyl substituents are omitted for
clarity.
Comparing the ate complex (ATE3) with the ones previously
obtained, the relevant B–O bonddarising from the formation of the
ate complexdis stronger (d¼1.53 Å, WI¼0.51) than the B–O bonds
of the other ate complexes, ATE1 and ATE2 (see above). This bond
strengthening is a direct consequence of the increased O-basicity in
the case of glycoaldehyde, compared to the former two substrates.
In other words, the O-atom belonging to the stronger base (glyco-
aldehyde) binds more strongly to the acidic boron center in the ate
complex. In the calculated mechanism (Fig. 4), the transition state
(TS3) is an early one since both the formation of the new C–C bond
(d¼2.27, WI¼0.23), as well as the breaking of the C–B bond (d¼1.72,
WI¼0.63), are only starting, once TS3 is reached. This is a ground
state effect, reflecting a weaker B–C(Ph) bond in the case of ATE3,
compared with ATE1 and ATE2, as shown by the corresponding
distances and Wiberg indices (Figs. 2–4). As a consequence, the
energy barrier calculated for this reaction is quite small (3.7 kcal/
mol), in good agreement with the experimental results, since this
kind of reaction proceeds at room temperature.
Figure 5. Energy profiles calculated for Petasis reaction between dimethylamine,
glycoaldehyde and phenylboronic acid via dehydration. The geometries optimized are
presented, and the relevant bond distances (Å) are indicated, as well as the respective
Wiberg indices (WI, italics). The minima and the transition states were optimized and
the energy values (kcal/mol) in water (PCM) are referred to the dimethyliminium and
phenylboronic acid reactants. H-atoms on the phenyl and methyl substituents are
omitted for clarity.
3. Conclusions
Water was successfully used as solvent for the Petasis-borono-
Mannich reaction, using structurally different aldehydes such as
salicylaldehyde, glyoxalic acid and glycoaldehyde. The products low
solubility generally allowed simple isolation protocol based on ex-
tractions or filtrations. Therefore 2H-chromenes (78–92% yields),
Considering that the deprotonation of the alcohol and sub-
sequent formation of the ate complex should be a difficult process,
due to the alcohol pKa high value, an alternative mechanism was
a
-amino acids (65–86% yields), a-amino alcohols (62–75% yields)
and 2-hydroxymorpholines (89–97% yields) have been prepared in
good to excellent yields. In addition, we established a new

2742
N.R. Candeias et al. / Tetrahedron 66 (2010) 2736–2745
methodology for the one-pot assembly of boron heterocycles based
on boronic acids, salicylaldehydes and aminoacids. Most of the
complexes were obtained in good to excellent yields (up to 96%). The
isolation protocol for these boron-heterocycles was considerably
facilitated due to complex precipitation fromwater. DFTcalculations
were performed in order to establish the Petasis-BMR mechanism
and the results obtained corroborate the generally accepted
mechanism for this multicomponent transformation.
collected, 3576 were independent (Rint¼0.1268); final R indices
R1¼0.0547, wR2 (all data)¼0.1246, GOF¼0.856.
4.3.4. Crystallographic data for complex 26. C22H20BNO4, fw¼385.21,
monoclinic, space group P21/n, a¼16.444(6)(12) Å, b¼5.923(4) Å,
c¼21.162(3) Å, b¼109.378(8)ꢀ, V¼1944.4(15) Å3, Z¼4, dcalcd
¼
1.316 mg mꢁ3, m¼0.089 mmꢁ1, F(000)¼808. Of 9358 reflections
collected, 3362 were independent (Rint¼0.2346); final R indices
R1¼0.0669, wR2 (all data)¼0.1494, GOF¼0.670. Crystallographic
data for the above mentioned compounds have been deposited in
the Cambridge Crystallographic Data Centre with deposition
numbers CCDC 766931 to CCDC 766934.
4. Experimental section
4.1. General information
The energy values reported result from single point energy
calculations using a 6-311þG(d,p)26 basis set and the geometries
optimised at the PBE1PBE/6-31G(d,p) level. Solvent effects were
considered in the PBE1PBE/6-311þþG(d,p)//PBE1PBE/6-31G(d,p)
energy calculations using the Polarizable Continuum Model
(PCM) initially devised by Tomasi and co-workers27 as imple-
mented on Gaussian 03,28 and, thus, the energy barriers can be
taken as free energy.29 The molecular cavity was based on the
united atom topological model applied on UAHF radii, optimized
for the HF/6-31G(d) level.
Dichloromethane (DCM), 1,2-dimethoxyethane (DME) were
freshly distilled over calcium hydride prior to use. Ethyl acetate was
distilled over potassium carbonate. All reactions were performed in
oven-dried glassware under nitrogen atmosphere. Preparative thin
layer chromatography plates were prepared with silica gel 60 GF254
Merck (Ref. 1.07730.1000). Reaction mixtures were analysed by TLC
using ALUGRAMÒ SIL G/UV254 from MN (Ref. 818133, silica gel 60),
and visualisation of TLC spots was effected using UV and phos-
phomolybdic acid solution. NMR spectra were recorded in a Bruker
AMX 300 or 400 using CDCl3 as solvent and (CH3)4Si (1H) as in-
ternal standard. All coupling constants are expressed in hertz. The
aldehydes and boronic acids were purchased from Aldrich and used
without further purification. The amines were distilled prior to use.
4.4. Experimental procedure for the Petasis-Borono-Mannich
reactions with glyoxalic acid
A round bottom flask equipped with a magnetic stirrer was
charged with boronic acid (1.0 equiv), glyoxalic acid (1.0 equiv) and
distilled water (2.0 mL). This suspension was stirred at 50 or 80 ꢀC for
5 min after which the amine (0.41 mmol) was added. The mixture
was stirred at 50 or 80 ꢀC for 24 h or 36 h after which the reaction
mixture was cooled at 4 ꢀC and the reaction product filtered and
washed with water. Products 9 and 10 were obtained with the same
spectral characterization as previously described in Ref. 6a, product 7
as described in Ref. 10b, and products 4–6 as described in Ref. 10c.
Compound 8 was obtained in 65% after 36 h at 80 ꢀC (0.068 g);
4.2. Computational details
All calculations were performed using the Gaussian 03 software
package,21 and the PBE1PBE functional, without symmetry con-
straints. That functional uses a hybrid generalised gradient approxi-
mation (GGA), including 25% mixture of Hartree-Fock22 exchange
with DFT18 exchange-correlation, given by Perdew, Burke and Ern-
zerhof functional (PBE).23 The optimised geometries were obtained
with a standard 6-31G(d,p)24 basis set. Transition state optimisations
were performed with the Synchronous Transit-Guided Quasi-New-
ton Method (STQN) developed by Schlegel et al.25 Frequency calcu-
lations were performed to confirm the nature of the stationary
points, yieldingone imaginary frequency for the transition states and
none for the minima. Each transition state was further confirmed by
following its vibrational mode downhill on both sides, and obtaining
the minima presented on the energy profile. A Natural Population
Analysis (NPA)20 and the resulting Wiberg indices19 were used to
study the electronic structure and bonding of the optimised species.
1H NMR (400 MHz, DMSO-d6):
NCH3), 3.49–3.63 (m, 2H, NCH2Ph),
7.69 (m, 5H, Ph),
8.20 (br s, 1H, CO2H); 13C NMR (125 MHz, CDCl3):
d
2.09 (s, 3H, CH3),
d 2.30 (s, 3H,
d
d
4.20 (s, 1H, NCHCO2), 7.13–
d
21.19 (CH3), 21.64 (NCH3), 58.22 (NCH2Ph), 72.21 (NCHCO2), 127.59,
128.50, 128.68, 129.13, 129.21, 129.42, 134.31, 134.66 (Ph), 137.68
(Ph, quaternary), 138.74 (Ph, quaternary), 139.81 (Ph, quaternary),
172.90 (CO2H). MS (EI): m/z¼224, 132, 91. HMRS (EI): m/z calcd
[Mþ1H] 270.1494, found [Mþ1H] 270.1495.
4.5. Experimental procedure for the Petasis-Borono-Mannich
reactions with glycolaldehyde dimer
4.3. Crystallographic details
4.3.1. Crystallographic data for complex 20. C22H18BNO3, fw¼355.18,
monoclinic, space group P21/c, a¼15.3476(8) Å, b¼5.9084(4) Å,
A round bottom flask equipped with a magnetic stirrer was
charged with glycolaldehyde dimer (0.5 equiv), boronic acid
(1.0 equiv) and distilled water (2.0 mL). This suspension was stirred
at room temperature or 50 ꢀC for 5 min after which the amine
(0.41 mmol) was added. The mixture was stirred at room temper-
ature or 50 ꢀC for 24 h or 48 h after which the water was evapo-
rated under reduced pressure and the reaction product isolated by
preparative thin layer chromatography (AcOEt/Hexane). Product 13
was obtained pure by extraction of the reaction mixture with ethyl
ether (3ꢂ3 mL), with no need of further purification. Product 11
was obtained with the same spectral characterization as previously
described in Ref. 8b.
c¼19.1585(12) Å,
b¼90.983(2)ꢀ,
V¼1737.03(18) Å3,
Z¼4,
dcalcd¼1.358 mg mꢁ3, m¼0.089 mmꢁ1, F(000)¼744. Of 16,270 re-
flections collected, 3565 were independent (Rint¼0.0654); final R
indices R1¼0.0445, wR2 (all data)¼0.1057, GOF¼0.985.
4.3.2. Crystallographic data for complex 21. C20H16BNO3S, fw¼361.21,
orthorhombic, space group P212121, a¼9.8260(2) Å, b¼10.9220(2) Å,
c¼16.5660(3) Å, V¼1777.86(6) Å3, Z¼4, dcalcd¼1.349 mg mꢁ3
,
m¼0.202 mmꢁ1, F(000)¼752. Of 16,804 reflections collected, 4342
were independent (Rint¼0.0445); final R indices R1¼0.0602, wR2 (all
data)¼0.1868, GOF¼1.069.
Compound 12 was obtained in 64% after 48 h at room temper-
ature and isolated by PTLC, AcOEt/Hex (1:1) (0.091 g); 1H NMR
4.3.3. Crystallographic data forcomplex 25. C22H17BFNO3, fw¼373.18,
monoclinic, space group P21/n, a¼10.470(1) Å, b¼9.715(1) Å,
(400 MHz, CDCl3):
2H, NCHCH2OH),
d
3.33 (d, J¼13.3, 2H, NCH2Ph),
d 3.38–3.43 (m,
d
4.03 (d, J¼9.4, 1H, NCHCO2), 3.84 (d, J¼13.3, 2H,
c¼18.653(2) Å, b¼93.322(4)ꢀ, V¼894.1(4) Å3, Z¼4, dcalcd
¼
NCH2Ph), 6.09–6.15 (m, 1H, CHCHPh), 6.44 (d, J¼16.0, NCHCHPh),
1.309 mg mꢁ3, m¼0.093 mmꢁ1, F(000)¼776. Of 16,174 reflections
7.14–7.35 (m, 5H); 13C NMR (125 MHz, CDCl3): 53.56 (NCH2Ph),

N.R. Candeias et al. / Tetrahedron 66 (2010) 2736–2745
2743
61.05 (NCHCH2OH2), 61.71 (NCHCH2OH), 123.26 (CHCHPh), 126.52,
127.35,128.07, 128.62, 128.75, 129.04 (Ph), 135.83 (CHCHPh),136.48,
139.04 (Ph, quaternary). MS (EI): m/z¼312, 220, 91. HMRS (EI): m/z
calcd [Mþ1H] 344.2014, found [Mþ1H] 344.2006.
Compound 18 was obtained in 94% and a 1:0.2 trans:cis di-
astereoisomeric ratio after 24 h at room temperature (0.116 g);
trans diasterioisomer: 1H NMR (400 MHz, CDCl3):
d
2.72 (d, J¼16.0,
2H, NCH2CH2O),
d
2.94 (d, J¼17.6, 2H, NCH2CH2O), 3.09 (d, J¼9.6,1H,
Compound 13 was obtained in 69% after 48 h at room temper-
ature and isolated extraction of the reaction medium (0.084 g); 1H
NCHCHOH), 3.74–4.08 (m, overlapped signals, 5H, NCH2Ph, OCH3),
4.72 (d, J¼9.6, NCHCHOH), 6.96 (d, J¼11.2, 2H, Ph), 7.26–7.48 (m,
NMR (400 MHz, CDCl3):
3.49 (m, 2H, NCH2CHCH2),
5.27 (m, 4H, NCH2CHCH2),
d
3.00–3.06 (m, 2H, NCH2CHCH2),
d
3.48–
5.21–
7H); 13C NMR (125 MHz, CDCl3):
d 50.42 (NCH2CH2O), 55.19 (OCH3),
d
3.60–3.70 (m, 1H, NCHCH2OH),
d
58.54 (NCH2CH2O), 64.05 (NCH2Ph), 72.00 (NCHCHOH), 97.64
(NCHCHOH), 113.96 (Ar), 127.27, 128.29, 128.54, 128.71, 128.93,
128.96, 129.87 (Ar), 135.50, 138.26, 159.23 (Ar, quaternary); Rele-
vant signals for the cis diasterioisomer: 1H NMR (400 MHz, CDCl3):
d
5.82–5.92 (m, 2H, NCH2CHCH2), 6.12
(dd, J¼16.0, J¼7.3, 1H, CHCHPh), 6.54 (d, J¼16.0, 1H, CHCHPh), 7.27–
7.42 (m, 5H, Ph); 13C NMR (125 MHz, CDCl3): 52.54 (NCH2CHCH2),
61.03 (NCHCH2OH), 62.67 (NCHCH2OH), 118.17 (NCH2CHCH2),
123.38 (CHCHPh), 126.38, 128.02, 128.68 (Ph), 135.35 (NCHCHCH2),
135.69 (CHCHPh), 136.40 (Ph, quaternary). MS (EI): m/z¼244, 212,
172, 129, 115, 91. HMRS (EI): m/z calcd [Mþ1H] 244.1701, found
[Mþ1H] 244.1702.
d
5.31 (br s, 1H, NCHCHOH); 13C NMR (125 MHz, CDCl3):
d 70.06
(NCHCHOH), 93.46 (NCHCHOH). MS (EI): m/z¼252, 149, 135, 91.
[Mþ1H] 300.1600, found [Mþ1H] 300.1592.
Compound 19 was obtained in 89% and a 1:0.9 diastereoisomeric
ratio after 48 h at room temperature (0.109 g); trans diasterioisomer:
Compound 14 was obtained in 75% after 24 h at 50 ꢀC and iso-
lated by PTLC, AcOEt/Hex (1:4) (0.086 g); 1H NMR (400 MHz,
1H NMR (400 MHz, CDCl3):
d
2.30–2.39 (m, 2H, NCH2CH2O),
d 2.75–
2.85 (m, 2H, NCH2CH2O),
d3.04–3.41(m,1H,NCHCHOH),3.88–4.13(m,
CDCl3):
NCH2CH2CH2),
2H, NCHCH2OH),
d
1.94–2.01 (m, 2H, NCH2CH2CH2),
3.31 (t, J¼5.6, 2H, NCH2CH2CH2),
4.71–4.73 (m,1H, NCHCH2OH), 6.22–6.27 (m,1H,
d
2.81–2.86 (m, 2H,
2H, NCH2Ph), 4.84–4.85 (m, 1H, NCHCHOH), 4.98 (m, 1H, NCHCHOH),
6.31–6.48 (m, 1H, NCHCHCHPh), 6.69–6.71 (m, 1H, NCHCHCHPh),
d
d
3.88–4.00 (m,
d
7.28–7.53 (m, 10H, Ph); 13C NMR (125 MHz, CDCl3):
d 48.27, 50.02
CHCHPh), 6.58 (dd, J¼16.2, J¼5.8, 1H, CHCHPh), 6.70–7.34 (m, 9H,
Aryl); 13C NMR (125 MHz, CDCl3): 23.50 (NCH2CH2CH2), 28.21
(NCH2CH2CH2), 42.63 (NCH2CH2CH2), 60.96 (NCHCH2OH), 61.79
(NCHCH2OH), 112.40, 117.22 (Ar), 124.31 (CHCHPh), 124.81, 126.41,
127.18, 127.85, 128.63, 129.52, 132.79 (Ar), 136.52 (CHCHPh), 145.76
(Ar). MS (EI): m/z¼279, 248, 170, 91. HMRS (EI): m/z calcd [Mþ1H]
280.1701, found [Mþ1H] 280.1697.
(NCH2CH2O), 59.04, 60.00 (NCH2Ph), 60.64, 60.74 (NCH2CH2O), 67.81,
68.84 (NCHCHOH), 93.76, 94.52 (NCHCHOH), 126.50, 126.55, 127.19,
128.00, 128.29, 128.34, 128.57, 128.96, 129.02, 135.71, 135.94, 136.14,
136.35,137.71 (NCHCHCHPh, Ph). MS (EI): m/z¼277, 249, 204,158,115,
91. [Mþ1H] 295.1651, found [Mþ1H] 296.1646.
4.7. Experimental procedure for the reactions for the
preparation of boron heterocycles
Compound 15 was obtained in 74% after 48 h at 50 ꢀC and iso-
lated by PTLC, AcOEt/Hex (1:4) (0.086 g); 1H NMR (400 MHz,
CDCl3):
NCH2CH2CH2),
1H, NCH2CH2CH2),
NCHCH2OH),
d
1.83–1.87 (m, 2H, NCH2CH2CH2),
3.13–3.16 (m, 1H, NCH2CH2CH2),
3.83 (s, 3H, OCH3),
4.13 (d, J¼7.8, 2H,
d
2.81 (t, J¼6.3, 2H,
A round bottom flask equipped with a magnetic stirrer was
charged with amino acid (2.0 equiv), aldehyde (1.5 equiv) and dis-
tilled water (2.0 mL). This suspension was stirred at 90 ꢀC for 1 h,
after which the boronic acid (0.41 mmol) was added. The mixture
was stirred at 90 ꢀC for 20 h and the product was filtered and washed
with water, hexane and was recovered with dichloromethane.
Compound 20 was obtained in 86% after 20 h at 90 ꢀC (0.125 g);
d
d
3.27–3.32 (m,
d
d
d
5.15 (t, J¼7.3, 1H, NCHCH2OH), 6.69 (t, J¼7.3, 1H, Ar),
6.89–7.24 (m, 7H, Ar); 13C NMR (125 MHz, CDCl3): 22.33
(NCH2CH2CH2), 28.46 (NCH2CH2CH2), 42.83 (NCH2CH2CH2), 55.29
(OCH3), 61.42 (NCHCH2OH), 61.78 (NCHCH2OH), 111.91, 114.05,
116.58, 123.57, 127.20, 128.48, 129.04, 129.51, 129.70, 130.07, 146.14,
158.89 (Ar). MS (EI): m/z¼281, 252, 161, 132, 121. HMRS (EI): m/z
calcd [Mþ1H] 284.1651, found [Mþ1H] 284.1656.
1H NMR (400 MHz, CDCl3, 25 ꢀC, TMS):
d 2.71 (t, 1H, JH: 13.2,
–CHCH2Ph), 3.41 (dd, 1H, JH: 3.6, 14.0, –CHCH2Ph), 4.34 (dd, 1H, JH:
3.6, 12.4, –NCHCOCH2–), 6.87–6.95 (m, 3H), 7.02–7.05 (m, 1H), 7.11–
7.16 (m, 2H), 7.27–7.34 (m, 6H), 7.43–7.55 (m, 3H); 13C NMR
(100 MHz, CDCl3, 25 ꢀC, TMS):
d 37.73 (–CHCH2Ph), 66.92
4.6. Experimental procedure for the Petasis-Borono-Mannich
reactions with glyoxal and amino alcohols
(–NCHCOCH2–), 117.57, 120.19, 120.32, 127.79, 127.90, 128.58, 129.16,
129.21, 130.55, 131.45, 135.11, 139.04 (Ph), 159.95 (ArCHN–),
160.43(Ar, quaternary), 170.22 (–CHCOO–). HMRS (EI): m/z calcd
[Mþ1H] 356.1458, found [Mþ1H] 356.1466.
A round bottom flask equipped with a magnetic stirrer was
charged with boronic acid (1.0 equiv) distilled water (2.0 mL) and
glyoxal 40% aqueous solution (1 equiv). To this suspension was
added the amino alcohol (0.41 mmol) and mixture stirred at room
temperature for 24 or 48 h. The reaction products were extracted
from the reaction media with ethyl ether extraction (3ꢂ3 mL) and
after the evaporation of the solvent under reduced pressure, the
products were obtained with no need of further purification.
Product 16 was obtained with a diasterioisomeric ratio 1:0.3 with
the same spectral characterization as previously described in Ref.14.
Compound 17 was obtained in 93% and a 1:0.2 trans:cis di-
astereoisomeric ratio after 48 h at room temperature (0.109 g); trans
Compound 21 was obtained in 96% after 20 h at 90 ꢀC (0.142 g); 1H
NMR (400 MHz, CDCl3, 25 ꢀC, TMS):
d 2.76 (t, 1H, JH: 13.2, –CHCH2Ph),
3.49 (dd, 1H, JH: 3.6, 14.0, –CHCH2Ph), 4.33 (dd, 1H, JH: 3.6, 12.4,
–NCHCOCH2–), 6.82–7.59 (m, 13H); 13C NMR (100 MHz, CDCl3, 25 ꢀC,
TMS): d38.22 (–CHCH2Ph), 66.45(–NCHCOCH2–),117.66,120.39,120.43,
125.83, 127.88, 128.02, 129.20, 129.32, 129.71, 131.35 (Aryl), 135.00 (Ar,
quaternary), 138.97 (Aryl), 159.63 (ArCHN–), 170.38 (–CHCOO–). HMRS
(EI): m/z calcd [Mþ1H] 362.1022, found [Mþ1H] 362.1035.
Compound 22 was obtained in 78% after 20 h at 90 ꢀC (0.125 g),
1H NMR (400 MHz, CDCl3, 25 ꢀC, TMS):
d 2.73 (t, 1H, JH: 13.0,
diasterioisomer: 1H NMR (400 MHz, CDCl3):
d
2.43 (s, 3H, CH3), 2.74
–CHCH2Ph), 3.44 (dd, 1H, JH: 3.6, 14.0, –CHCH2Ph), 3.85 (s, 3H,
–ArOCH3). 4.31 (dd, 1H, JH: 3.4, 12.2, –NCHCOCH2–), 6.47–6.52 (m,
2H), 6.95–7.04 (m, 5H), 7.28–7.40 (m, 5H); 13C NMR (100 MHz,
(d, J¼11.8, 1H, NCH2CH2O), 2.95 (d, J¼7.6, 1H, NCH2CH2O), 3.14 (d,
J¼7.1,1H, NCHCHO), 3.77–3.95 (m, 4H, NCH2CH2O, NCH2Ph), 4.77 (d,
J¼7.2, 1H, NCHCHO), 7.24–7.48 (m, 9H, Ph); 13C NMR (125 MHz,
CDCl3): 21.23 (CH3), 50.56 (NCH2CH2O), 58.76 (NCH2CH2O), 64.49
(NCH2Ph), 72.58 (NCHCHO), 97.83 (NCHCHO),127.03,128.26,128.31,
128.91, 129.37 (Ar), 135.84, 137.61, 138.55 (Ar, quaternary); Relevant
CDCl3, 25 ꢀC, TMS):
d 38.22 (–CHCH2Ph), 55.89 (–ArOCH3), 66.02
(–NCHCOCH2–), 102.72, 110.19, 111.50, 125.71, 127.70, 127.75, 129.11,
129.34, 129.80, 132.82, 135.32 (Aryl), 158.24 (ArCHN–), 162.34 (Ar,
quaternary), 168.70 (Ar, quaternary), 171.05 (–CHCOO–). HMRS (EI):
m/z calcd [Mþ1H] 392.1128, found [Mþ1H] 392.1138.
signals for the cis diasterioisomer: 1H NMR (400 MHz, CDCl3):
d 5.03
(br s,1H, NCHCHOH). MS (EI): m/z¼265, 236, 208,192,118, 91. HMRS
Compound 23 was obtained in 88% after 20 h at 90 ꢀC (0.133 g), 1H
(EI): m/z calcd [Mþ1H] 284.1651, found [Mþ1H] 284.1651.
NMR (400 MHz, CDCl3, 25 ꢀC, TMS):
d 2.69 (t,1H, JH: 13.0, –CHCH2Ph),

2744
N.R. Candeias et al. / Tetrahedron 66 (2010) 2736–2745
3. (a) Narayan, S.; Muldoon, J.; Finn, M. G.; Fokin, V. V.; Kolb, H. C.; Sharpless, K. B.
Angew. Chem., Int. Ed. 2005, 44, 3275–3279; (b) Jung, Y. S.; Marcus, R. A. J. Am.
Chem. Soc. 2007, 129, 5492–5502.
4. (a) Chanda, A.; Fokin, V. V. Chem. Rev. 2009, 109, 725–748; (b) Herrerias, C. I.;
Yao, X.; Li, Z.; Li, C. J. Chem. Rev. 2007, 107, 2546–2562; (c) Lindstrom, U. M.
Chem. Rev. 2002, 102, 2751–2771; (d) Li, C. J.; Chen, L. Chem. Soc. Rev. 2006, 35,
68–82; (e) Lindstro¨m, U. M. Organic Reactions in Water: Principles, Strategies and
Applications; Blackwell.: Oxford, 2007.
5. Lindstrom, U. M.; Andersson, F. Angew. Chem., Int. Ed. 2006, 45, 548–551.
6. (a) Pirrung, M. C.; Sarma, K. D. Synlett 2004,1425–1427; (b) Pirrung, M. C.; Sarma,
K. D. J. Am. Chem. Soc. 2004, 126, 444–445; (c) Pirrung, M. C.; Sarma, K. D. Tet-
rahedron 2005, 61, 11456–11472; (d) Pirrung, M. C. Chem.dEur. J. 2006, 12, 1312–
1317; (e) Pirrung, M. C.; Sarma, K. D.; Wang, J. J. Org. Chem. 2008, 73, 8723–8730.
7. (a) Candeias, N. R.; Branco, L. C.; Gois, P. M. P.; Afonso, C. A. M.; Trindade, A. F.
Chem. Rev. 2009, 109, 2703–2802; (b) Shapiro, N.; Vigalok, A. Angew. Chem., Int.
Ed. 2008, 47, 2849–2852; (c) Shi, L. D.; Niu, L. H.; Yao, H.; Jiang, H. J. Heterocycl.
Chem. 2009, 46, 237–242; (d) Alizadeh, A.; Rostamnia, S.; Zohreh, N.; Hos-
seinpour, R. Tetrahedron Lett. 2009, 50, 1533–1535; (e) Shanthi, G.; Perumal, P. T.
Synlett 2008, 2791–2794; (f) Teimouri, M. B.; Abbasi, T.; Mivehchi, H. Tetrahe-
dron 2008, 64, 10425–10430; (g) Vasuki, G.; Kumaravel, K. Tetrahedron Lett.
2008, 49, 5636–5638; (h) Kanizsai, I.; Gyonfalvi, S.; Szakonyi, Z.; Sillanpaa, R.;
Fulop, F. Green Chem. 2007, 9, 357–360.
8. (a) Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc. 1997, 119, 445–446; (b) Petasis,
N. A.; Zavialov, I. A. J. Am. Chem. Soc. 1998, 120, 11798–11799.
9. Candeias, N. R.; Veiros, L. F.; Afonso, C. A. M.; Gois, P. M. P. Eur. J. Org. Chem.
2009, 1859–1863.
10. (a) Kaiser, P. F.; Churches, Q. I.; Hutton, C. A. Aust. J. Chem. 2007, 60, 799–810; (b)
McLean, N. J.; Tye, H.; Whittaker, M. Tetrahedron Lett. 2004, 45, 993–995; (c)
Jourdan, H.; Gouhier, G.; Van Hijfte, L.; Angibaud, P.; Piettre, S. R. Tetrahedron
Lett. 2005, 46, 8027–8031.
11. Prakash, G. K. S.; Mandal, M.; Schweizer, S.; Petasis, N. A.; Olah, G. A. Org. Lett.
2000, 2, 3173–3176.
3.39 (dd,1H, JH: 3.6,14.0, –CHCH2Ph), 3.84 (s, 3H, –ArOCH3), 4.31 (dd,
1H, JH: 3.2,12.4, –NCHCOCH2–), 6.45–6.50 (m, 2H), 6.97–7.09 (m, 4H),
7.28–7.48(m, 6H),7.49–7.50(m, 2H);13CNMR(100 MHz,CDCl3, 25 ꢀC,
TMS):
d 37.78 (–CHCH2Ph), 55.87 (–ArOCH3), 66.54 (–NCHCOCH2–),
102.62, 110.12, 111.47, 127.65, 127.88, 128.42, 129.10, 129.24, 130.57,
132.88,135.47 (Aryl),158.98 (ArCHN–),162.65(Ar, quaternary),168.80
(Ar, quaternary), 170.91 (–CHCOO–). HMRS (EI): m/z calcd [Mþ1H]
386.1564, found [Mþ1H] 386.1571.
Compound 24 was obtained in 63% after 20 h at 90 ꢀC (0.095 g), 1H
NMR (400 MHz, CDCl3, 25 ꢀC, TMS):
d 2.35 (s, 3H, –ArCH3), 2.70 (t,1H,
JH: 12.0, –CHCH2Ph), 3.41 (dd, 1H, JH: 2.0, 14.0, –CHCH2Ph), 4.34 (dd,
1H, JH: 4.0,12.0, –CHCH2Ph), 6.73 (d,1H, JH: 8.0 Hz), 6.85 (s,1H), 6.97–
7.03 (m, 3H), 7.12 (s, 1H), 7.28–7.38 (m, 6H), 7.45–7.47 (m, 2H); 13C
NMR (100 MHz, CDCl3, 25 ꢀC, TMS):
d 22.50 (–ArCH3), 37.75(–
CHCH2Ph), 66.75(–NCHCOCH2–),115.41,120.38,121.74,127.74,127.88,
128.48, 129.14, 129.24, 130.58, 131.23, 135.28 (Aryl), 151.41 (Ar, qua-
ternary),159.95 (Ar, quaternary),159.99 (ArCHN–), 170.58 (–CHCOO–
). HMRS (EI): m/z calcd [Mþ1H] 370.1614, found [Mþ1H] 370.1615.
Compound 25 was obtained in 80% after 20 h at 90 ꢀC (0.122 g),
1H NMR (400 MHz, CDCl3, 25 ꢀC, TMS):
d 2.68 (t, 1H, JH: 13.2,
–CHCH2Ph), 3.45 (dd, 1H, JH: 3.4, 13.8, –CHCH2Ph), 4.36 (dd, 1H, JH:
3.2, 12.4, –NCHCOCH2–), 6.80–7.71 (m, 14H); 13C NMR (100 MHz,
CDCl3, 25 ꢀC, TMS):
d 37.79 (–CHCH2Ph), 66.87 (–NCHCOCH2–),
114.74, 114.94, 117.47, 120.32, 120.38, 127.91, 129.16, 129.24,
131.53,132.34, 132.41, 134.97, 139.23 (Aryl), 159.84 (Ar, quaternary),
160.56 (Ar, quaternary), 170.13 (–CHCOO–). HMRS (EI): m/z calcd
[Mþ1H] 374.1364, found [Mþ1H] 374.1367.
12. (a) Wang, Q.; Finn, M. G. Org. Lett. 2000, 2, 4063–4065; (b) Petasis, N. A.;
Butkevich, A. N. J. Organomet. Chem. 2009, 694, 1747–1753.
13. Portlock, D. E.; Naskar, D.; West, L.; Li, M. Tetrahedron Lett. 2002, 43, 6845–6847.
´
F.; Debache, A.; Marsac, Y.; Collet, B.; Girard-Le Bleiz, P.; Carboni, B.
14. Berree,
Compound 26 was obtained in 31% after 20 h at 90 ꢀC (0.048 g),
Tetrahedron 2006, 62, 4027–4037.
1H NMR (400 MHz, CDCl3, 25 ꢀC, TMS):
d 2.72 (t, 1H, JH: 13.0,
15. Regnier, T.; Berree, F.; Lavastre, O.; Carboni, B. Green Chem. 2007, 9, 125–126.
16. Selected examples: (a) Barba, V.; Rodrı´guez, A.; Ochoa, M. E.; Santillan, R.;
Farfa´n, N. Inorg. Chim Acta 2004, 357, 2593–2601; (b) Abreu, A.; Alas, S. J.;
Beltra´n, H. I.; Santillan, R.; Farfa´n, N. J. Organomet. Chem. 2006, 691, 337–348; (c)
Braun, M.; Schlecht, S. M.; Engelmann, M.; Frank, W. Eur. J. Org. Chem. 2008,
5221–5225; (d) Kaiser, P. F.; White, J. M.; Hutton, C. A. J. Am. Chem. Soc. 2008,
130, 16450–16451; (e) Christinat, N.; Croisier, E.; Scopelliti, R.; Cascella, M.;
Ro¨thlisberger, U.; Severin, K. Eur. J. Inorg. Chem. 2007, 5177–5181; (f) Christinat,
N.; Scopelliti, R.; Severin, K. J. Org. Chem. 2007, 72, 2192–2200; (g) Christinat, N.;
Scopelliti, R.; Severin, K. Angew. Chem., Int. Ed. 2008, 47, 1848–1852; (h) Farfa´n,
–CHCH2Ph), 3.42 (dd, 1H, JH: 3.2, 13.6, –CHCH2Ph), 3.81 (s, 3H,
–ArOCH3), 4.34 (dd, 1H, JH: 3.2, 12.4, –NCHCOCH2–), 6.80–7.35 (m,
14H); 13C NMR (100 MHz, CDCl3, 25 ꢀC, TMS):
d 37.87 (–CHCH2Ph),
55.04 (–ArOCH3), 66.82 (–NCHCOCH2–), 113.42, 117.55, 120.15,
120.27, 127.80, 129.16, 129.28, 131.48, 131.96, 135.14, 138,92 (Ph),
159.94 (ArCHN–), 159.98, 160.22 (Ar, quaternary), 170.42 (–CHCOO–
). HMRS (EI): m/z calcd [Mþ1H] 386.1564, found [Mþ1H] 386.1556.
Compound 27 was obtained in 83% after 20 h at 90 ꢀC (0.126 g),
´
´
N.; Ho¨pfl, H.; Barba, V.; Ochoa, M. E.; Santillan, R.; Gomez, E.; Gutierrez, A.
J. Organomet. Chem. 1999, 581, 70–81.
1H NMR (400 MHz, CDCl3, 25 ꢀC, TMS):
d 2.34 (s, 3H, –ArCH3), 2.73
´
´
17. Beltran, H. I.; Zamudio-Rivera, L. S.; Mancilla, T.; Santillan, R.; Farfan, N. J. Or-
ganomet. Chem 2002, 657, 194–204.
(t, 1H, JH: 12.0, –CHCH2Ph), 3.42 (dd, 1H, JH: 4.0, 14.0, –CHCH2Ph),
4.35 (dd, 1H, JH: 4.0, 12.0, –NCHCOCH2–), 6.91 (t, 1H, JH: 8.0), 6.99–
7.04 (m, 3H), 7.12–7.16 (m, 4H), 7.28–7.38 (m, 5H), 7.50–7.56 (m,
18. Parr, R. G.; Yang, W. Density Functional Theory of Atoms and Molecules; Oxford
University Press: New York, 1989.
19. (a) Wiberg, K. B. Tetrahedron 1968, 24, 1083–1096; (b) Wiberg indices are
electronic parameters related to the electron density between atoms. They can
be obtained from a Natural Population Analysis and provide an indication of
the bond strength.
20. (a) Carpenter, J. E.; Weinhold, F. J. Mol. Struct. (Theochem) 1988, 169, 41–62; (b)
Carpenter, J.E. PhD Thesis, University of Wisconsin (Madison WI), 1987. (c)
Foster, J. P.; Weinhold, F. J. Am. Chem. Soc. 1980, 102 7211–7118; (d) Reed, A. E.;
Weinhold, F. J. Chem. Phys. 1983, 78, 4066–4073; (e) Reed, A. E.; Weinhold, F. J.
Chem. Phys. 1985, 78, 1736–1740; (f) Reed, A. E.; Weinstock, R. B.; Weinhold, F. J.
Chem. Phys. 1985, 83, 735–746; (g) Reed, A. E.; Curtiss, L. A.; Weinhold, F. Chem.
Rev. 1988, 88, 899–926; (h) Weinhold, F.; Carpenter, J. E. The Structure of Small
Molecules and Ions; Plenum: New York, 1988; p. 227.
1H); 13C NMR (100 MHz, CDCl3, 25 ꢀC, TMS):
d 21.44 (–ArCH3), 37.78
(–CHCH2Ph), 66.90 (–NCHCOCH2–), 117.62, 120.14, 120.32, 127.80,
128.67, 129.16, 129.28, 130.61, 131.46, 135.21, 138.19, 138.94 (Aryl),
159.94 (Ar, quaternary), 160.35 (ArCHN–), 170.35 (–CHCOO–).
HMRS (EI): m/z calcd [Mþ1H] 370.1614, found [Mþ1H] 370.1620.
Acknowledgements
ˆ
We thank the Fundaça˜o para a Ciencia e Tecnologia (POCI 2010)
21. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.;
Cheeseman, J. R.; Montgomery, J. A., Jr.; Vreven, T.; Kudin, K. N.; Burant, J. C.;
Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci, B.; Cossi, M.;
Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.;
Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao,
O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Adamo, C.;
Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.;
Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G. A.; Salvador, P.;
Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels, A. D.; Strain, M. C.;
Farkas, O.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Ortiz, J.
V.; Cui, Q.; Baboul, A. G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.;
Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-
Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.;
Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian 03, Re-
vision C.02; Gaussian: Wallingford CT, 2004.
and FEDER (SFRH/BPD/46589/2008, PTDC/QUI/66695/2006, PTDC/
QUI/66015/2006, POCI/QUI/60175/2004, POCI/QUI/58791/2004) for
financial support.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tet.2010.01.084.
References and notes
22. Hehre, W. J.; Radom, L.; Schleyer, P. v. R.; Pople, J. A. Ab Initio Molecular Orbital
Theory; John Wiley & Sons: New York, 1986.
23. (a) Perdew, J. P.; Burke, K.; Ernzerhof, M. Phys. Rev. Lett. 1997, 78, 1396; (b)
Perdew, J. P. Phys. Rev. B 1986, 33, 8822–8824.
24. (a) Ditchfield, R.; Hehre, W. J.; Pople, J. A. J. Chem. Phys. 1971, 54, 724–728; (b)
Hehre, W. J.; Ditchfield, R.; Pople, J. A. J. Chem. Phys. 1972, 56, 2257–2261; (c)
´
1. (a) Zhu, J.; Bienayme, H. Multicomponent Reactions; Wiley-VCH: Weinheim,
2005.
2. (a) Breslow, R.; Maitra, U. Tetrahedron Lett. 1984, 25, 1239–1240; (b) Breslow, R.;
Maitra, U.; Rideout, D. Tetrahedron Lett. 1983, 24, 1901–1904; (c) Rideout, D. C.;
Breslow, R. J. Am. Chem. Soc. 1980, 102, 7816–7817.

N.R. Candeias et al. / Tetrahedron 66 (2010) 2736–2745
2745
Hariharan, P. C.; Pople, J. A. Mol. Phys. 1974, 27, 209–214; (d) Gordon, M. S. Chem.
Phys. Lett. 1980, 76, 163–168; (e) Hariharan, P. C.; Pople, J. A. Theor. Chim. Acta
1973, 28, 213–222.
J. Chem. Phys. 1977, 66, 4377–4384; (e) Raghavachari, K.; Trucks, G. W. J. Chem.
Phys. 1989, 91, 1062–1065; (f) Binning, R. C.; Curtiss, L. A. J. Comput. Chem. 1995,
103, 6104–6113; (g) McGrath, M. P.; Radom, L. J. Chem. Phys. 1991, 94, 511–516.
`
25. (a) Peng, C. Y.; Ayala, P. Y.; Schlegel, H. B.; Frisch, M. J. J. Comp. Chem. 1996, 17,
49–56; (b) Peng, C.; Schlegel, H. B. Israel J. Chem. 1993, 33, 449–454.
26. (a) McClean, A. D.; Chandler, G. S. J. Chem. Phys. 1980, 72, 5639–5648; (b)
Krishnan, R.; Binkley, J. S.; Seeger, R.; Pople, J. A. J. Chem. Phys. 1980, 72, 650–
654; (c) Wachters, A. J. H. J. Chem. Phys. 1970, 52, 1033–1036; (d) Hay, P. J.
27. (a) Cances, E.; Mennucci, B.; Tomasi, J. J. Chem. Phys. 1997, 107, 3032–3041;
(b) Cossi, M.; Barone, V.; Mennucci, B.; Tomasi, J. Chem. Phys. Lett. 1998, 286,
253–260; (c) Mennucci, B.; Tomasi, J. J. Chem. Phys. 1997, 106, 5151–5158.
28. Tomasi, J.; Mennucci, B.; Cammi, R. Chem. Rev. 2005, 105, 2999–3093.
29. Cossi, M.; Scalmani, G.; Rega, N.; Barone, V. J. Chem. Phys. 2002, 117, 43–54.