Probing the Mechanism of Classical and the Supramolecular CoCatalyzed Baylis-Hillman Reactions via ESI(+)-MS and MS/MS
L. S. Santos,* C. H. Pavam, C. S. Consorti, B. A. S. Neto, F. Coelho, J. Dupont and M. N. Eberlin
*University of Oldenburg, Department of Chemistry, D-26111 Oldenburg, Germany
*leonardo@iqm.unicamp.br
The Baylis–Hillman reaction has recently emerged as extremely versatile method for the
synthesis of highly complex systems. The reaction leads to the straightforward formation of
new  C-C bonds in a single step, and yields functionalized molecules (-methylene-hydroxy derivatives), which are then conveniently manipulated as key synthons in the
synthesis of a variety of natural and nonnatural products. In the current work, the proposed
intermediates for the catalytic cycle of the Baylis–Hillman reaction (Scheme 1) have been
successfully intercepted and structurally characterized for the first time using electrospray
ionization with mass and tandem mass spectrometry. Strong evidence for the currently
accepted mechanism has been collected, thus confirming the proposals initially made by
Isaacs and Hill.1 Herein, attempts to intercept key cationic intermediates of Baylis–Hillman
reactions performed in ionic liquids have been obtained. Several H-bonded cationic species
formed by ion pairing of the aldehyde and zwiterionic intermediates with ionic liquid
cations and anions have been transferred from solution to the gas-phase, detected and
characterized. These supramolecular species indicate therefore that ionic liquids improve
overall reaction rates by activating the aldehyde toward nucleofilic attack and by stabilizing
the zwitterionic species that acts as the main Baylis-Hillman intermediates.2
+
+
N
N + OH
N
N+
H
BMI.Y
OCH 3
[5 + H]+
m/z 199
[3 + H]+
m/z 113
BMI+
Y+
N
S
6
N
O
H
N
O
S
2
S
H
1
+
+
8
m/z 252
BMI.Y
N
+
N
OH
N
N+ O
OCH 3
O
OCH 3
BMI
10c+, Y- = CF3CO2-, m/z 511
N
N+ O
5
O
HO
7
OCH 3
N
N
HO
S
S
12+
m/z 338
BMI.Y
N
N + OH
BMI+
Y-
OCH 3
N
HO
S
S
[7 + H]+
11a+, Y- = BF4-, m/z 538
m/z 312
11b+, Y- = PF6-, m/z 596
OH
CO 2CH 3
N
+
BMI.Y
OCH 3
OH
BMI+
OCH 3
10b+, Y- = PF6-, m/z 543
9c+, Y- = CF3CO2-, m/z 451
OCH 3
-
10a+, Y- = BF4-, m/z 485
-
H
N
+
N
OH
Y
H3CO
9b+, Y- = PF6-, m/z 483
N
N+ O
N
N
DABCO
3
-
N
N+
OH
+
OCH 3
9a , Y = BF4 , m/z 425
H+
H+
N
N + OH
CO 2CH 3
N
S
4
Baylis-Hillman
Adduct
+
N
N
H
H+
11c+, Y- = CF3CO2-, m/z 564
H+
O
O
N
OCH 3
S
[4 + H]+
m/z 200
DABCO
3
Scheme 1: Baylis-Hillman reaction of methyl acrylate (1) and thiazolecarboxaldehyde 2 co-catalyzed by both DABCO (3) and ionic
liquids BMI.Y (Y-=BF4-, PF6-, CF3CO2-) showing both the protonated and supramolecular H-bonded cationic species gently transferred
from solution to the gas phase by ESI, detected and structurally characterized by MS and MS/MS analysis, with their respective m/z
ratios.
[1] Hill, J. S., Isaacs, N. S. J. Phys. Org. Chem. 1990, 3, 285.
[2] (a) Santos, L. S., Pavam, C. H., Almeida, W. P., Coelho, F., Eberlin, M. N Angew. Chem. Int. Ed. 2004,
43, 4330. (b) Santos, L. S., Pavam, C. H., Consorti, C. S., da Silveria Neto, B. A., Coelho, F., Dupont, J.,
Eberlin, M. N. Chemistry- A European Journal 2005, submmited.