A novel precipitating auxiliary approach to the purification of
Baylis–Hillman adducts†
Todd Bosanac and Craig S. Wilcox*
Department of Chemistry and The Combinatorial Chemistry Center, University of Pittsburgh, Pittsburgh,
PA 15260, USA. E-mail: daylite@pitt.edu
Received (in Cambridge, UK) 3rd May 2001, Accepted 27th June 2001
First published as an Advance Article on the web 9th August 2001
Diaryl alkene alcohol 1 is a ‘precipiton’, a precipitating
auxiliary that is used to aid the isolation of Baylis–Hillman
adducts.
The precipiton Baylis–Hillman reactions were performed on
a 0.52 to 2.43 mmol scale with respect to the acrylate. The
acrylate 2Z was treated with a catalytic amount of DABCO and
an excess of aldehyde at room temperature.11 Upon completion
of the reaction (depending upon the nature of the aldehyde,
reactions were complete in 1 to 10 days) the crude mixture was
diluted with a suitable solvent and treated with I2 and dibenzoyl
peroxide or PhSSPh.12 The isomerization process was mon-
There is a need for new methods of product isolation which rely
on simple purification procedures, eliminate the need for
distillation or chromatography, and can be easily automated and
used for parallel chemical syntheses.1 While solid-phase
organic synthesis (SPOS) remains the most popular method,
there are several disadvantages associated with SPOS: the
supports can be expensive; loading capacities can be low
(0.1–1.0 mmol g21); solid-phase reactions often require
extensive optimization of reaction conditions; and monitoring
of reaction progress is difficult. To address the shortcomings of
SPOS, molecules can be attached to ‘phase-tags’. Fluorous
synthesis,2 soluble polymer-supported organic synthesis
(SPSOS),3 dendrimer-supported organic synthesis,4 and acid/
base tags5 are examples of this approach. With these methods,
tagged compounds can be easily separated from untagged
compounds by a phase-transfer event (precipitation or liquid–
liquid partition).
1
itored by H NMR (isomerizations were complete in 4–24 h).
Upon completion of the isomerization event, the crude reaction
mixture was diluted with CHCl3. Aqueous work-up with
bisulfite, followed by evaporation of the organic layer, gave a
crude product, that was then purified simply by trituration with
hexanes, ether, or MeOH, followed by filtration. This protocol
afforded Baylis–Hillman adducts in good yields and with
purities of !95% (Table 1).13
The precipiton-bound products were cleaved from the
precipiton by hydrolysis (LiOH in THF–H2O).14 These reac-
tions were performed on a 22 to 188 mmol scale. The acids were
isolated by filtration of the insoluble precipiton, acidification of
the solution, followed by extraction with EtOAc. Removal of
the EtOAc furnished the desired acids in good yields and with
purities of !95% (Table 2).13 Several other conditions,
We recently introduced an approach to product isolation
based on a solubility switch activated by structural isomeriza-
tion.6 Diaryl alcohol 1 is a ‘precipiton’, a group of atoms
Table 1 Precipiton Baylis-Hillman reaction with acrylate 2Z
(1)
(molecular fragment) that is purposefully attached to a reactant
molecule and that can be activated {in this case isomerized
[equilibrium (1)]} after the reaction in order to cause precipita-
tion of the attached product. Our method has been applied to the
synthesis and isolation of isoxazolines6 and a-substituted b-
ketoesters.7 In this communication, we describe the precipiton
approach for the synthesis of pure Baylis–Hillman adducts.
The Baylis–Hillman reaction8 is a C–C bond forming
reaction between an activated alkene and an aldehyde in the
presence of a tertiary amine, tertiary phosphine, or chalcoge-
nide.9 This reaction provides useful multifunctional inter-
mediates that can be used for subsequent transformations. One
of the drawbacks associated with the Baylis–Hillman reaction is
that one of the components must be used in an excess to drive
the reaction to completion.10 This often leads to a need to use
chromatography to separate the desired product from the excess
reactant. In order to avoid chromatography we sought to use our
methodology to isolate pure Baylis–Hillman adducts.
Isomerization
catalyst(s)
Yield
Product (%)
Entry
R
Time/d
1
2
20
5
I2/BzOOBz
I2/BzOOBz
3E
4E
70
58
3
4
5
5
3
4
I2/BzOOBz
I2/BzOOBz
I2/BzOOBz
5E
6E
7E
78
76
76
Alcohol 1Z was prepared as previously described from
4-biphenylcarbaldehyde and p-bromobenzyl alcohol via a
Negishi coupling.7 Acrylate 2Z was then readily prepared by
treatment of 1Z with acryloyl chloride in the presence of
NEt3.6
6
7
1
2
I2/BzOOBz
Ph2S2
8E
8E
81
75
† Electronic supplementary information (ESI) available: full experimental
1618
Chem. Commun., 2001, 1618–1619
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b103969p
Bosanac
