Water: A suitable medium for the Petasis borono-Mannioh reaction

Article abstract of DOI:10.1002/ejoc.200900056

Water was used as the solvent in the Petasis borono-Mannich reaction. With the use of salicylaldehyde, secondary amines and boronic acids, several alkylaminophenols were obtained in considerably high yields in water. By using the same methodology, 2H-chro

Full text of DOI:10.1002/ejoc.200900056

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200900056
Water: A Suitable Medium for the Petasis Borono-Mannich Reaction
Nuno R. Candeias,[a] Luís F. Veiros,[a] Carlos A. M. Afonso,[a] and Pedro M. P. Gois*[b]
Keywords: Boron / Water chemistry / Multicomponent reactions / Amines / Solvent effects
Water was used as the solvent in the Petasis borono-Mannich
reaction. With the use of salicylaldehyde, secondary amines
and boronic acids, several alkylaminophenols were obtained
in considerably high yields in water. By using the same meth-
odology, 2H-chromenes were prepared with the use of vinyl
boronic acids. The reaction mechanism was studied by DFT
calculations, and the results obtained corroborate the solvent
effect experimentally observed.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
relevance, as it quite often exerts a remarkable influence
over the chemical transformations performed in this me-
dia.[4] Therefore, it is with no surprise that we witness the
efforts of numerous research groups to introduce water as
solvent in many organic transformations, namely, multi-
component transformations.[5] Hence, it is rather surprising
that the Petasis borono-Mannich reaction has never been
reported in water. This is the aim of this communication.[6]
Introduction
Multicomponent transformations have recently gathered
considerable attention in synthetic organic chemistry.[1] The
one-pot combination of several organic molecules is an
open door to molecular diversity, which can be achieved, in
some cases, with high atom efficiency.[1] Among the re-
ported multicomponent transformations, the Mannich-type
condensation involving boronic acids developed by Petasis
and coworkers is quite remarkable, because the boronic acid
component is inert towards the aldehyde functionality,
though it quite efficiently traps the imine or iminium double
bond.[2] As a result of this exquisite reactivity, the Petasis
reaction (Scheme 1) has become an attractive method for
the preparation of an assortment of compounds, among
which amino acids, heterocycles and alkylaminophenols are
the most easily accessible.[3]
Results and Discussion
To test the possibility of using water as the reaction me-
dium for the Petasis borono-Mannich reaction (Scheme 2)
we combined salicylaldehyde, morpholine and phenyl bo-
ronic acid. To our delight, the reaction afforded the desired
product in 75% yield after 24 h at 80 °C (Table 1, Entry 1).
Extending the protocol to other aldehydes the reaction pro-
ceeded equally efficiently. Electron-donating substituents on
the boronic acid moiety appeared to promote the reaction
(Table 1, Entries 6 and 7), whereas the aryl substituents of
the aldehydes had almost no observable influence on the
reaction outcome (Table 1, Entries 1–3). Ethanol proved to
be a less efficient solvent for this transformation and af-
forded the product in only 63% yield (Table 1, Entry 8).
Scheme 1. Example of a Petasis borono-Mannich reaction.
Water is certainly one of the most desirable solvents
available, because it is abundant, inexpensive and safe.[4]
Nevertheless, water notoriety does not end with this greener
[a] Centro de Química-Física Molecular, Institute of Nanosciences
and Nanotechnology, and Centro de Química Estrutural, De-
partamento de Engenharia Quıímica e Biológica, Instituto Su-
perior Técnico,
1049-001 Lisboa, Portugal
Scheme 2. Petasis borono-Mannich reaction with salicylaldehyde.
[b] iMed.UL, Faculdadade de Farmácia da Universidade de Lis-
boa,
Encouraged by these results, we extended the scope of
this protocol to a variety of secondary amines and boronic
acids (Scheme 3). The reaction proceeded mostly in high
yields whether cyclic or acyclic secondary amines were used.
Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal
Fax: +351-21-7946476
E-mail: pedrogois@ff.ul.pt
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Eur. J. Org. Chem. 2009, 1859–1863
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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N. R. Candeias, L. F. Veiros, C. A. M. Afonso, P. M. P. Gois
SHORT COMMUNICATION
Table 1. Substituent effects in the Petasis borono-Mannich reaction
with salicylaldehyde.
Table 2. Petasis borono-Mannich reaction in water – scope of the
reaction.
Entry R1
R2
Conditions
Product Yield [%][a]
1
2
3
4
5
6
7
8
H
H
H
H
H
24 h, H2O
24 h, H2O
24 h, H2O
4.5 h, H2O
4.5 h, H2O
4.5 h, H2O
4.5 h, H2O
24 h, EtOH
1
2
3
1
4
5
6
1
75
70
72
54
75
85
81
63
Me
OMe
H
H
H
H
H
F
Me
OMe
H
[a] Isolated yield by preparative thin-layer chromatography (hex-
ane/AcOEt).
For those cases in which phenyl boronic acid was used
(Table 2, Entries 1 and 8), slightly lower yields were ob-
tained, as previously observed (Table 1). Amines such as
dibenzylamine and diallylamine[7] performed extremely well
in water (Table 2, Entries 5, 8 and 9).
Scheme 3. Petasis borono-Mannich reaction in water – scope of the
reaction.
Expanding the usefulness of this multicomponent reac-
tion, Finn and coworkers reported the preparation of 2H-
chromenes by using salicylaldehydes, a resin-bounded
amine and vinylic boronic acids.[8] In this reaction
(Scheme 4), after condensation of the three components, an
intramolecular cyclisation promoted by the phenol hydroxy
group with consequent ejection of the amine moiety occurs.
On the basis of this precedent, we tested this transformation
in water with the use of different amines as cyclisation pro-
moters.
Different from the method reported by Finn and co-
workers, in water a stoichiometric amount of amine is nec-
essary to achieve an efficient transformation (Table 3, En-
tries 3 and 4). Among the amines tested, diethylamine was
the most competent, affording the cyclised product in 92%
yield. Under the optimized reaction conditions, satisfying
yields of 2H-chromenes 17 and 18 were obtained
(Scheme 5).
[a] Isolated yields by preparative thin-layer chromatography (hex-
ane/AcOEt).
Careful observation of the reaction mixture revealed that
the salicylaldehyde formed an oil phase when added to
water even at 80 °C, whereas the phenyl boronic acid was
completely solubilised. When the secondary amine is added
to the heterogeneous mixture, the iminium species is readily
formed, which partitions to the aqueous phase. The imin-
ium species can then react with the solubilised boronic acid
to yield the Petasis borono-Mannich reaction product,
which then cyclises to give the hydrophobic chromene prod-
uct that precipitates. This was the case for product 11,
which completely precipitated from the aqueous phase once
formed.
Scheme 4. Preparation of 2H-chromene in water by using the Pet-
asis borono-Mannich reaction.
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Eur. J. Org. Chem. 2009, 1859–1863

Water: A Suitable Medium for the Petasis Borono-Mannich Reaction
Table 3. 2H-Chromene synthesis in water by using the Petasis bo-
rono-Mannich reaction.
The mechanism generally assumed for the Petasis bo-
rono-Mannich involves the activation of the boronic acid
by the hydroxy group to generate what has been referred to
as the “ate complex”, which is able to transfer the aryl moi-
ety to the imine or iminium bond. The evidence that
strongly supports this proposal is the fact that no reaction
takes place in the absence of such an activating hydroxy
group. Despite the general agreement around this proposal,
as far as our knowledge goes, no theoretical analysis was
ever performed for this system.
Entry
1
Conditions
Yield [%][a]
79
Dimethylamine·HCl (1.2 equiv.) and
NaOH (2 equiv.)
Dibenzylamine (1.2 equiv.)
Diethylamine (1.2 equiv.)
Diethylamine (20 mol-%)
2
3
4
58[b]
92
49
[a] Isolated yield by preparative thin-layer chromatography (hex-
ane/AcOEt). [b] Along with the 2H-chromene, 15% of a product
that did not undergo cyclisation was isolated.
The mechanism of the Petasis reaction was studied by
density functional theory (DFT)[10] by using dimeth-
ylamine, phenylboronic acid and salicylaldehyde as model
reactants (see Supporting Information for computational
details). The effect of solvent (water in the following dis-
cussion) was accounted for by the polarisable continuum
model (PCM).[11] The reaction was studied starting from
the iminium formed after condensation of dimethylamine
with salicylaldehyde. Two different sets of reactants were
tested: a positive iminium reactant (keeping the hydroxy
group) and a zwitterionic species with the phenol group de-
protonated. Equivalent mechanisms were obtained in both
cases, corresponding to a one-step path from the “ate com-
plex” to the tertiary amine. However, the mechanism ob-
tained for the positive iminium reactant (keeping the OH
group) is less favourable than the one calculated for the
zwitterionic reagent, as demonstrated by the energy calcu-
lated for the corresponding transition states: 36 and 23 kcal/
mol, respectively. Thus, the following discussion will refer to
the reaction of the zwitterionic iminium. The energy profile
calculated for the positive iminium reactant is presented in
the Supporting Information. It is interesting to note that
despite a positive value obtained for the free energy of the
“ate complex” in water (4.0 kcal/mol), in comparison to the
isolated reagents, the corresponding electronic energy is
negative (–2.8 kcal/mol), which reflects the stabilization that
results from the formation of the B–O bond.
Scheme 5. Preparation of 2H-chromenes under the optimized con-
ditions.
In line with recent reports regarding the water accelera-
tion effect over reactions where at least one of the reactants
forms an oil phase with water, we decided to compare the
water system with other organic solvents (Scheme 6).[9] The
results shown in Table 4 suggest that water does not appear
to have a favourable acceleration effect over the reaction,
and solvents such as 1,2-dichloroethane (DCE) and toluene
promoted the reaction slightly more efficiently.
The transition state obtained (TS) has an intermediate
geometry between the “ate complex” (ATE) and the tertiary
amine (TA). In TS, the phenyl group is clearly migrating
from the boron atom to the carbon atom of the iminium
group. The B–C(Ph) bond is weakened (d = 1.81 Å, WI =
0.51) relative to the one present in the “ate complex” (d =
1.62 Å, WI = 0.77), and the new C–C bond is starting to
form. However, the long distance and small Wiberg index
associated with this interaction (d = 2.00 Å, WI = 0.47)
indicate an early transition state with only incipient C–C
bond formation.
Scheme 6. Petasis borono-Mannich reaction with salicylaldehyde in
different solvent systems – solvent comparison.
The influence of the para substituent in the boronic acid
phenyl group (R2 in Scheme 2) was also investigated com-
putationally. In the energy profile obtained for R2 = MeO
(dashed lined in Figure 1) the corresponding transition state
is more stable than the one calculated for R2 = H (solid
line) by 5.1 kcal/mol, indicating a significantly more facile
reaction in the former case, in excellent agreement with the
experimental results (Table 1, Entries 1 and 6).
Table 4. Petasis borono-Mannich reaction with salicylaldehyde –
solvent comparison.
Entry
Solvent
Yield [%][a]
1
2
3
4
5
H2O
DME
DMF
Toluene
DCE
53
69
41
75
77
Finally, the influence of the solvent was also investigated
through comparison of energy calculations with the PCM
[a] Isolated yield of product 1 by preparative thin-layer chromatog-
raphy (hexane/AcOEt).
Eur. J. Org. Chem. 2009, 1859–1863
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1861

N. R. Candeias, L. F. Veiros, C. A. M. Afonso, P. M. P. Gois
SHORT COMMUNICATION
Figure 1. Energy profiles calculated for the Petasis reaction between dimethylamine, salicylaldehyde and phenyl boronic acid (solid lines)
or 4-methoxyphenyl boronic acid (dashed lines). The geometries optimized for the reaction with phenyl boronic acid (solid lines) are
presented. The relevant bond lengths (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] are referred to the isolated reagents, zwitterionic 2-[(dimethyliminio)-
methyl]phenolate (ZW) and boronic acid (BA). H atoms on the phenyl and methyl substituents are omitted for clarity.
model for dimethyl formamide and 1,2-dichloroethane with
those calculated for water, discussed above. The results ob-
Experimental Section
General Procedure: A round-bottomed flask equipped with a con-
tained (see Figure 1) indicate that the reaction should be
denser and magnetic stirrer and under an argon atmosphere was
slightly less favourable in DMF than in water and, more
charged with boronic acid (1.2 equiv.) and distilled water (1.0 mL).
importantly, that DCE should be the better solvent for the
reaction, in good accordance with the experimental findings
(see Table 4). In fact, the energy of the transition state, cal-
culated for DCE, is 5 kcal/mol lower than the equivalent
one obtained for water.
This suspension was stirred at 80 °C for 3 min, after which the sali-
cylaldehyde (0.41 mmol) and the amine (1.2 equiv.) were sub-
sequently added. The mixture was stirred at 80 °C for 24 h (or 4.5 h
for 4–6), after which the product was filtered or the water was evap-
orated under reduced pressure. The product was further purified
by preparative thin-layer chromatography.
Supporting Information (see footnote on the first page of this arti-
cle): Full characterisation of all new compounds; tables with atomic
coordinates for all optimized species.
Conclusions
Water was successfully used as the solvent in the Petasis
borono-Mannich reaction. An assortment of alkylamino-
phenols was obtained in yields up to 99% by using different
secondary amines, salicylaldehydes and boronic acids. By
combining vinyl boronic acids with salicylaldehydes and di-
ethylamine, 2H-chromenes were obtained in up to 92%.
DFT mechanistic calculations were performed, and the re-
sults obtained corroborate the generally accepted mecha-
nism for this multicomponent transformation and the sol-
vent effect experimentally observed.
Acknowledgments
We thank the Fundação para a Ciência e Tecnologia (POCI 2010)
and FEDER (SFRH/BPD/46589/2008PTDC/QUI/66695/2006,
PTDC/QUI/66015/2006,
58791/2004) for financial support.
POCI/QUI/60175/2004,
POCI/QUI/
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Received: January 19, 2009
Published Online: March 5, 2009
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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