A new interpretation of the Baylis-Hillman mechanism

Article abstract of DOI:10.1021/jo050202j

On the basis of reaction rate data, we have proposed a new mechanism for the Baylis-Hillman reaction involving the formation of a hemiacetal intermediate. We have determined that the rate-determining step is second order in aldehyde and first order in DAB

Full text of DOI:10.1021/jo050202j

A New Interpretation of the Baylis-Hillman Mechanism
Kristin E. Price, Steven J. Broadwater, Brian J. Walker, and D. Tyler McQuade*
Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York 14853
dtm25@cornell.edu
Received February 1, 2005
On the basis of reaction rate data, we have proposed a new mechanism for the Baylis-Hillman
reaction involving the formation of a hemiacetal intermediate. We have determined that the rate-
determining step is second order in aldehyde and first order in DABCO and acrylate. We have
shown that this mechanism is general to aryl aldehydes under polar, nonpolar, and protic conditions
using both rate data and two isotope effect experiments.
SCHEME 1. The Published Baylis-Hillman
Mechanism
The Baylis-Hillman (BH) reaction, also known as the
Morita-Baylis-Hillman reaction,1 is an attractive method
for forming carbon-carbon bonds and yields highly
functionalized products with a new stereocenter.2-4 The
reaction became popular in the early 1980s with the first
application to synthesis,5 the first “arrow-pushing” mech-
anism,6 and the first physical organic studies.7 Since
these original reports, the reaction has spawned an
immense body of literature. One exemplar of the reac-
tion’s utility is Pfizer’s ∼40-kg synthesis of tert-butyl
2-(hydroxymethyl)propenoate, a key intermediate en
route to the Zn-metalloprotease inhibitor Sampatrilat.8
The significance of the BH reaction has prompted a
number of mechanistic investigations. These studies
provide some insight into the reaction, but leave many
unanswered questions. On the basis of pressure depen-
dence, rate, and kinetic isotope effect (KIE) data, Hill and
Isaacs, using acrylonitrile,7,9 suggested a mechanism
similar to that in Scheme 1. The focus of their work was
the pressure dependence of the BH reaction and, as such,
they did not provide experimental or graphical informa-
(1) Morita, K.; Suzuki, Z.; Hirose, H. Bull. Chem. Soc. Jpn. 1968,
41, 2815.
tion concerning the rate data. The authors observed a
KIE of 1.03 ( 0.1 for the R-position, from which they
concluded that no R-proton cleavage occurs in the rate-
determining step (RDS).9 Later, Bode and Kaye, using
acrylates, supported the Hill and Isaacs mechanism
(Scheme 1) with rate data and a rate law (eq 1 ).10 Even
(2) Basavaiah, D.; Rao, A. J.; Satyanarayana, T. Chem. Rev. 2003,
103, 811-891.
(3) Ciganek, E., Ed. In Organic Reactions; Paquette, L. A., Ed.; John
Wiley & Sons: New York, 1997; Vol. 51, pp 201-350.
(4) Basavaiah, D.; Rao, P. D.; Hyma, R. S. Tetrahedron 1996, 52,
8001-8062.
(5) Drewes, S. E.; Emslie, N. D. J. Chem. Soc., Perkin Trans. 1 1982,
2079-2083.
rate ) K1k2[1][2][4]
(1)
(6) Hoffmann, H. M. R.; Rabe, J. Angew. Chem., Int. Ed. Engl. 1983,
22, 795-796.
(7) Hill, J. S.; Isaacs, N. S. Tetrahedron Lett. 1986, 27, 5007-5010.
(8) Dunn, P. J.; Hughes, M. L.; Searle, P. M.; Wood, A. S. Org. Proc.
Res. Dev. 2003, 7, 244-253.
with these mechanistic studies, a number of observations
(9) Hill, J. S.; Isaacs, N. S. J. Phys. Org. Chem. 1990, 3, 285-288.
(10) Bode, M. L.; Kaye, P. T. Tetrahedron Lett. 1991, 32, 5611-5614.
10.1021/jo050202j CCC: $30.25 © 2005 American Chemical Society
Published on Web 04/14/2005
3980
J. Org. Chem. 2005, 70, 3980-3987

A New Interpretation of the Baylis-Hillman Mechanism
SCHEME 2. Dioxanone Baylis-Hillman Product
appear in the literaturesincluding slow reaction rates,2
dioxanone formation,11-13 difficulty controlling stereo-
chemistry,3 autocatalysis,14 and rate acceleration with
protic additives15-19sthat cannot be fully explained.
BH reactions are often sluggish, and methods to
increase the reaction rate are numerous.2 If eq 1 was
valid, the reaction merely being third order does not
explain why typical BH reactions are slow. Many third-
order reactions are fast, including the Mitsunobu, Aldol-
Tischencko, and Pd cross-coupling reactions. In general,
electron-poor aldehydes and acrylates tend to provide
faster reactions.2 Even in cases in which additives are
reported to accelerate the rate, the reaction still takes
many hours to days to complete. For example, lanthanide
salts in combination with triethanolamine are known to
accelerate the reaction.20 This method works well with
p-nitrobenzaldehyde (pNBA) and methyl acrylate, yield-
ing 90% product in 3 h, but it takes considerably longer
with electron-rich anisaldehyde (2 days, 65%) and cyclo-
hexanecarboxaldehyde (5 days, 37%).21
SCHEME 3. Leahy’s Enantioselective
Baylis-Hillman Reaction
SCHEME 4. Hatakeyama’s Dioxanone Kinetic
Resolution
The dioxanone diastereomer was also present in the
few cases in which optically active Lewis bases provided
high enantiomeric excess. Hatakeyama reported a modi-
fied quinidine that provided modest yields of nearly
optically pure BH products.25 As shown in Scheme 4, a
significant fraction of the byproduct was the other
enantiomer trapped as a dioxanone, so in essence the
reaction was a kinetic resolution. Hatakeyama’s example
contrasts the many chiral Lewis bases that provide only
modest enantioselectivity.3
In addition to normal acyclic products, the BH reaction
yields a dioxanone byproduct for which the published
mechanism offers no clear explanation. This byproduct
was first reported in 1990 by Drewes et al. and typically
results when the acrylate ester is a reasonable leaving
group and the aldehyde concentration is high (Scheme
2).12,13,22
The only example of a highly enantioselective BH
reaction that does not rely on dioxanone formation uses
an optically active 1,1′-bi-2-naphthol (BINOL). Schaus
demonstrated that a modified BINOL catalyst in tandem
with triethyl phosphine could react with 2-cyclohexenone
and a range of aldehydes to provide BH products with
high enantioselectivity.26 Using the old mechanism, the
authors suggested that the BINOL interacts with inter-
mediate 3, thus controlling the face of the enolate
attacked by the aldehyde.
Dioxanone formation was, surprisingly, an essential
part of most successful asymmetric BH reactions. Given
the published mechanism, the BH reaction should re-
spond similarly to an aldol reaction.23 In practice, how-
ever, chiral auxiliaries provide poor enantioselectivities
except when dioxanones are the sole product.4 For
example, Leahy demonstrated high enantioselectivity
using Oppolzer’s sultam, as depicted in Scheme 3.24 In
this case, the reaction produced only the dioxanone, with
both good yield and high enantioselectivity.
The BINOL catalysis is related to the observation that
protic solvents accelerate BH reactions. Early on, 3-hy-
droxyquinuclidine (3-Hq) was found to be a more active
catalyst than diazabicyclo[2.2.2]octane (DABCO).10,27-29
The activity of 3-Hq was attributed to the formation of a
3-Hq-enolate hydrogen bond. Later, a number of groups
reported that other protic additives such as ethylene
glycol, formamide, and water also accelerate the reac-
tion.9,15 Auge suggested that the acceleration was due to
stabilization of the 1,2 addition (k2) or an increase in K1
(11) Perlmutter, P.; Puniani, E.; Westman, G. Tetrahedron Lett.
1996, 37, 1715-1718.
(12) Drewes, S. E.; Emslie, N. D.; Karodia, N.; Khan, A. A. Chem.
Ber. 1990, 123, 1447-1448.
(13) Khan, A. A.; Emslie, N. D.; Drewes, S. E.; Field, J. S.; Ramesar,
N. Chem. Ber. Recl. 1993, 126, 1477-1480.
(14) Aggarwal, V. K.; Fulford, S. Y.; Lloyd-Jones, G. C. Angew.
Chem., Int. Ed. 2005, 44, 1706-1708.
(15) Auge, J.; Lubin, N.; Lubineau, A. Tetrahedron Lett. 1994, 35,
7947-7948.
(16) Basavaiah, D.; Krishnamacharyulu, M.; Rao, A. J. Synth.
Commun. 2000, 30, 2061-2069.
(17) Aggarwal, V. K.; Dean, D. K.; Mereu, A.; Williams, R. J. Org.
Chem. 2002, 67, 510-514.
(18) Yu, C. Z.; Liu, B.; Hu, L. Q. J. Org. Chem. 2001, 66, 5413-
5418.
(24) Brzezinski, L. J.; Rafel, S.; Leahy, J. W. J. Am. Chem. Soc. 1997,
119, 4317-4318.
(19) Cai, J. X.; Zhou, Z. H.; Zhao, G. F.; Tang, C. C. Org. Lett. 2002,
4, 4723-4725.
(25) Iwabuchi, Y.; Nakatani, M.; Yokoyama, N.; Hatakeyama, S. J.
Am. Chem. Soc. 1999, 121, 10219-10220.
(20) Aggarwal, V. K.; Tarver, G. J.; McCague, R. Chem. Commun.
1996, 2713-2714.
(26) McDougal, N. T.; Schaus, S. E. J. Am. Chem. Soc. 2003, 125,
12094-12095.
(21) Aggarwal, V. K.; Mereu, A.; Tarver, G. J.; McCague, R. J. Org.
Chem. 1998, 63, 7183-7189.
(27) Ameer, F.; Drewes, S. E.; Freese, S.; Kaye, P. T. Synth.
Commun. 1988, 18, 495-500.
(22) Drewes, S. E.; Emslie, N. D.; Field, J. S.; Khan, A. A.; Ramesar,
N. S. Tetrahedron Lett. 1993, 34, 1205-1208.
(23) Palomo, C.; Oiarbide, M.; Garcia, J. M. Chem.-Eur. J. 2002, 8,
37-44.
(28) Drewes, S. E.; Freese, S. D.; Emslie, N. D.; Roos, G. H. P. Synth.
Commun. 1988, 18, 1565-1572.
(29) Bailey, M.; Marko, I. E.; Ollis, W. D.; Rasmussen, P. R.
Tetrahedron Lett. 1990, 31, 4509-4512.
J. Org. Chem, Vol. 70, No. 10, 2005 3981

Price et al.
SCHEME 5. A New Mechanism for the Baylis-Hillman Reaction
(k1/k-1) (Scheme 1). Later, more thorough reports by
Aggarwal, Hu, and Tang confirmed the acceleration of
the BH reaction with solvent/water mixtures.17-19 Despite
many hypotheses for each of these phenomena, no
current model can explain them all.
TABLE 1. Aldehyde Order for Different Substrates Run
in DMSO or THF
aldehydea
solvent
aldehyde order
BA
DMSO
THF
DMSO
THF
DMSO
THF
2.4
2.2
1.9
1.9
1.9
1.8
BA
Recently, using p-nitrobenzaldehyde (pNBA) and meth-
yl acrylate as substrates, we showed with rate and
isotope data that the BH reaction is second order in
aldehyde and that the R-position C-H bond breaks in
the RDS.30 On the basis of this order information, we
altered the mechanism to include the second equivalent
of aldehyde (Scheme 5). This mechanism features all of
the intermediates previously proposed (and recently
observed with mass spectroscopy)31 but now includes the
formation of a hemiacetal that subsequently goes on to
eliminate DABCO in the RDS. The mechanism is bol-
stered by a primary KIE at the R-position and a large
inverse secondary isotope effect at the aldehyde proton
of pNBA. In this full paper, we expand the number and
type of substrates studied. We also report the mechanism
in protic solvents. Finally, we discuss how this new
mechanism elucidates some of the unexplained nuances
of BH chemistry.
PYR
PYR
pNBA
pNBA
a BA ) benzaldehyde; PYR ) 4-pyridinecarboxaldehyde; pNBA
) 4-nitrobenzaldehyde.
Using pNBA, we also examined the mechanism of the
BH reaction in a series of protic conditions. The aldehyde
shows a second-order dependence for each protic condi-
tion tested: THF/water, THF/formamide, and THF/
methanol (Table 2). In addition, we examined the order
in water, formamide, and methanol. We found that the
order in each solvent was first order, but all displayed
saturation at high concentration (Figure 2). In the case
of water, the asymptote coincided with reagent insolubil-
ity. Methanol exhibits saturation at much lower concen-
tration compared to formamide and water and showed
the smallest rate enhancement. As such, we explored the
potential of a methanol-aldehyde preequilibrium. NMR
inspection of a solution of MeOH and pNBA reveals a
significant hemiacetal concentration. We also compared
the relative rates of pNBA reacting with methyl acrylate
in DMSO, THF, THF/water, THF/formamide, and THF/
methanol. As shown in Table 2, DMSO provided the
fastest rate followed by THF/formamide.
To support the order results, we collected isotope effect
data for both the R-position of methyl acrylate and the
aldehyde proton (Table 3). All of the reactions run in
DMSO show clear primary KIEs. Reactions run with
pNBA show primary KIEs for all conditions. Unlike
pNBA, the other substrates show KIEs between 1 and 2
in solvents other than DMSO. For the aldehyde proton,
all reactions show large inverse secondary KIEs. To
ensure that the R-position cleavage was still taking place
when protic solvents were used, we measured the KIE
in 2.75 M water in THF and found the value to be
primary (2.07 ( 0.3). In addition to the KIE data, Table
3 contains relative rate data for each aldehyde in multiple
solvents as well as a comparison of the entire data set.
Results
Order plots for each substrate were constructed with
rate data collected by using the method of initial rates.32
Each substrate/solvent combination studied was first
order in acrylate and DABCO, but second order in
aldehyde (Table 1). Previously, we found that DMSO
significantly accelerates the rate of the BH reaction. We
collected order plots using constant DMSO concentration
to avoid any solvent-based changes in rate. DMSO
concentration was held constant by using a small variable
amount of THF to compensate for volume changes due
to reagent concentration. To juxtapose the polar DMSO
cases, order plots were also collected in THF. The
4-pyridinecarboxaldehyde (PYR) order plots featured in
Figure 1 are representative of all order plots (see the
Supporting Information for remaining plots).
(30) Price, K. E.; Broadwater, S. J.; Jung, H. M.; McQuade, D. T.
Org. Lett. 2004, 7, 147-150.
(31) Santos, S.; Pavam, C.; Almeida, W.; Coelho, F.; Eberlin, M.
Angew. Chem., Int. Ed. 2004, 43, 4330-4333.
(32) Connors, K. A. Chemical kinetics: the study of reaction rates in
solution; VCH: New York, 1990.
3982 J. Org. Chem., Vol. 70, No. 10, 2005

A New Interpretation of the Baylis-Hillman Mechanism
FIGURE 1. Order plots for reaction of 4-pyridinecarboxaldehyde, methyl acrylate, and DABCO in DMSO. (A) Rate as a function
of 4-pyridinecarboxaldehyde; (B) rate as a function of methyl acrylate; and (C) rate as a function of DABCO. For raw data and
plot fits, see the Supporting Information.
FIGURE 2. Order plots for reaction of p-nitrobenzaldehyde, methyl acrylate, and DABCO in THF with various protic additives.
(A) Rate as a function of formamide; (B) rate as a function of water (the asymptote coincides with reagent precipitation); and (C)
rate as a function of methanol.
For reference, two solvent polarity scales are also fea-
tured.
The rate law was derived by using either the steady-
state approximation (SSA) or the equilibrium approxima-
tion. The equations describing each intermediate’s con-
centration were derived by hand according to the reaction
mechanism in Scheme 5 and then solved with Math-
ematica v. 5.0. The rate law derived by using the SSA,
J. Org. Chem, Vol. 70, No. 10, 2005 3983

Price et al.
SCHEME 6. The Origin of the EIE and the KIE
TABLE 2. A Comparison of Relative Rates and Solvent
Conditions for Reactions of pNBA, DABCO, and Methyl
Acrylate
solventa protic additive [protic] (M) krel order in pNBA
DMSO
THF
THF
THF
THF
THF
THF
THF
N/A
0
49
1
1.9
N/A
0
1.8
H2O
H2O
formamide
formamide
methanol
methanol
0.083
5.13
0.84
11.62
0.84
1.7
7
2.0
31
9
47
3
4
1.4b
1.8
2.0
N/A
N/A
a All reactions were run under general kinetics conditions (see
the Experimental Methods section). b The intermediate order is
due to aldehyde insolubility (see the Supporting Information for
more details).
TABLE 3. Kinetic Isotope Data for Both r-Position
Labeled Methyl Acrylate and Labeled Aldehydes for
Reactions Run in Different Solvents
generality of the mechanism using a range of solvents.
We found that aldehydes are second order, and methyl
acrylate and DABCO are first order for each aldehyde
examined (Table 1). To ensure that the mechanism was
not an artifact of using DMSO as the solvent, we explored
the order in both DMSO and THF, as polar and nonpolar
solvents, respectively. We have found that the order is
invariant with respect to solvent polarity (Table 1). We
also examined the order in aldehyde under a variety of
protic conditions and found that the reaction remains
second order regardless of protic additive concentration
(Table 2). These data indicate that the RDS stoichiometry
is not influenced by solvent polarity or the presence of
protic additives despite the observation that the rate is
strongly influenced by the medium.
As in the initial communication, we measured isotope
effects using two isotopically sensitive positions, the
R-position on the acrylate and the aldehyde proton
(Scheme 6 and 8).30 The pNBA case, in DMSO, exhibits
the largest R-position KIE (5.2) and provides the fastest
overall rate. We interpret this result as a limiting case,
and as such, 5.2 represents the maximum observable
KIE. With use of the equilibrium approximation, the
KIEobs reduces to eq 4. Since the R-carbon’s geometry only
changes for K2, the KIEobs simplifies further to eq 5.
b
c
aldehydea solvent kH/kD (R) kH/kD (ald) krel krel ET(30) ꢀd
BA
DMSO 2.6 ( 0.1 0.73 ( 0.05
THF 1.0 ( 0.1 0.78 ( 0.10
CHCl3 1.2 ( 0.1 0.69 ( 0.09
DMSO 2.0 ( 0.2 N/A
MeCN 2.1 ( 0.1 N/A
CHCl3 1.4 ( 0.1 N/A
7
1
2
7
1
2
45
37
39
45
46
39
45
46
43
37
39
47
8
BA
BA
5
PYR
PYR
PYR
pNBA
pNBA
pNBA
pNBA
pNBA
54 9969
10 1814
1
47
37
5
184
DMSO 5.2 ( 0.6 0.75 ( 0.05 36 4269
MeCN 4.2 ( 0.1 N/A
47
37
38
8
7
877
DMF
THF
2.9 ( 0.2 N/A
10 1197
2.4 ( 0.1 0.80 ( 0.07
2
1
184
120
CHCl3 2.2 ( 0.2 0.72 ( 0.03
5
a BA ) benzaldehyde; PYR ) 4-pyridinecarboxaldehyde; pNBA
) 4-nitrobenzaldehyde. b These krel values refer to relative rates
for one aldehyde within the series of solvents. c These krel values
refer to the rates of each reaction relative to benzaldehyde in THF,
the slowest reaction we studied. d Dielectric constant. All reactions
were run under general kinetics conditions (see the Experimental
Methods section).
eq 2, can be further simplified to that of the equilibrium
approximation if k4 is assumed to be small (eq 3).
rate )
k1k2k3k4[1][2][4]2
(2)
k2k3k4[4]2 + k-1k3k4[4] + k-1k-2k-3 + k-1k-2k4
(K1HK2HK3H) k4H
KIEobs
)
(4)
(5)
k1k2k3k4[1][2][4]2
k4D
(K1DK2DK3D)
rate )
) K1K2K3k4[1][2][4]2
k-1k-2k-3
K2H k4H
≈
K2D k4D
(3)
KIEobs
The reversibility of the BH reaction was examined by
heating the product of the reaction of methyl acrylate and
pNBA with DABCO in DMSO. The reaction was moni-
tored with gas chromatography (GC) for approximately
100 h, and no aldehyde formation was observed.
Therefore, the KIEobs is a product of the inverse equilib-
rium isotope effect (iEIE; Scheme 6, top) and the KIE
(Scheme 6, bottom). If we assume a value of 0.8 for the
iEIE (typical values are between 0.6 and 0.9), then a true
KIE for bond breaking is calculated by dividing 5.2 by
0.8, which provides 6.4. This value is close to the
theoretical maximum for a primary KIE, 6.9.33
Discussion
We examined the isotope effects for the substrates as
a function of solvent (Table 3). We propose that all of the
KIEs are primary for the R-position in both low- and high-
polarity solvents. We observe that as the solvent polarity
In an initial communication, we showed, using pNBA
as a substrate, that the BH reaction mechanism is second
order in aldehyde.30 On the basis of the order and isotope
data, we proposed the mechanism featured in Scheme 5.
We now report order and isotope effect data for three aryl
aldehydes (BA, PYR, and pNBA), and we investigate the
(33) Melander, L.; Saunders, W. H. Reaction Rates of Isotopic
Molecules; Wiley-Interscience: New York, 1980.
3984 J. Org. Chem., Vol. 70, No. 10, 2005

A New Interpretation of the Baylis-Hillman Mechanism
SCHEME 7. TS Geometry of Bond Breaking May
Dictate KIE
SCHEME 8. The Origin of the Large Inverse
Aldehyde Proton Kinetic Isotope Effect
decreases, the KIE at the R-position decreases and in low-
polarity solvents, PYR and BA provided KIEobs < 2.
Variation in isotope effect as a function of solvent has
been studied.33 Changes in KIEobs are ascribed to the
solvent-dependent change in the ∆pKa between the base
and acidsin this case, the hemiacetal and the R-position
proton. Therefore, we propose that for pNBA in DMSO,
∆pKa ≈ 0 and consequently the KIEobs is maximized.
When comparing one aldehyde within a solvent series,
we suggest that the ∆pKa increases with decreasing
equilibrate. The kobs term has an inverse dependence on
aldehyde concentration (eq 2). For aldehydes whose k2,
k3 ≈ k4 the overall reaction rate is attenuated relative to
aldehydes whose k2, k3 . k4 (eq 2).
For fast BH substrates (electron-poor aldehydes, for
example), we propose that the elimination rate, k4, is slow
relative to the other rate constants. This assumption
simplifies the rate law to eq 3. This simplification
polarity, reducing the magnitude of the KIEobs
.
Comparing one aldehyde to another, we found that
R-proton KIEs vary in the following order pNBA > PYR
> BA. This series correlates well with 13C carbonyl
chemical shifts, indicating that the electronic character
of the carbonyl is important.34 For example, the observed
KIE for PYR in DMSO is 2.0. If we assume that the
compounding iEIE is 0.8 then the real KIE should be
∼2.5. This low value is due to the poor pKa match
between the R-proton and the hemiacetal, 6. Despite the
low KIE, the PYR order in both DMSO and THF remains
2, indicating that the proposed mechanistic model is
valid. Once the iEIE is factored out, BA run in THF is
the only substrate/solvent pair yielding a KIE value less
than 2. Despite the low KIEobs, the aldehyde order
remains 2, supporting the mechanism depicted in Scheme
5. As such, we conjecture that the low KIEobs represents
a primary isotope effect.
For each of the aryl substrates, we also investigated
the KIE associated with the aldehyde proton. As ex-
pected, each substrate yielded an observed KIE consis-
tent with a large inverse secondary isotope effect. This
inverse secondary KIE indicates that the aldehyde
geometry changes from an sp2 to an sp3 center. As
depicted in Scheme 8, because two aldehyde geometry
changes must occur before the RDS, a strong inverse
effect is expected and observed (eq 6).
removes the inverse aldehyde-dependent terms in kobs
.
These terms do not alter the order but do alter the
reaction rate. Alternatively in the case of sluggish
substrates, we suggest that the assumption that k4 is
slow with respect to k2 and k3 becomes invalid, thus
forcing the reaction into the inverse aldehyde-dependent
regime. In addition, this rate law helps to explain why
the reaction appears to equilibrate.35 Since most BH
reactions are run with a 1:1 ratio of aldehyde to methyl
acrylate, as the reaction consumes aldehyde, k2 and k3
decrease, the equilibrium approximation becomes invalid,
and the reaction slows dramatically as a function of
aldehyde consumption.
The new mechanism also provides an explanation for
the formation of dioxanone products. The proposed hemi-
acetal intermediate, 6, can cyclize to yield dioxanone
product (Scheme 9).3 The hemiacetal intermediate does
not provide irrefutable evidence, but it is a plausible
intermediate en route to cyclic products, and others have
proposed 8 as a post-rate-determining intermediate.11,12
We are the first to provide any evidence supporting the
presence of 7.
Our new mechanism can also explain why the BH
stereochemistry is difficult to control. As depicted in
Scheme 10, the elimination is both the RDS and the
product distribution-controlling step. The elimination
proceeds through a diastereometric, hemiacetal transi-
tion state (7). When an optically pure auxiliary or Lewis
base is used, the number of stereocenters in the transi-
tion state increases from two to three, but there are still
only four stereoisomers as the configuration of the base
or auxiliary is fixed. These isomers provide four different
pathways to products. Typically, chiral auxiliaries are
successful in cases where only two pathways must be
distinguished, and thus approaches beyond standard
chiral auxiliaries or Lewis bases will be required to bias
the reaction completely. Cyclization to the dioxanone can
K2H K3H
KIEobs
)
(6)
K2D K3D
The order and isotope effect data indicate that the
mechanism provided in Scheme 5 is general for different
aldehyde substrates when using methyl acrylate as the
electron-poor alkene. We use these data and the proposed
mechanism to resolve four unexplained features of the
BH reaction: sluggish reaction rates, dioxanone forma-
tion, difficult stereocontrol, and acceleration with protic
additives.
The rate law derived from the mechanism in Scheme
5 can be used to explain the dramatic difference in rate
between substrates and why the BH reaction appears to
(35) Fort, Y.; Berthe, M. C.; Caubere, P. Tetrahedron 1992, 48,
6371-6384.
(34) http://www.aist.go.jp/RIODB/SDBS/menu-e.html.
J. Org. Chem, Vol. 70, No. 10, 2005 3985

Price et al.
SCHEME 9. A Hypothesis for the Formation of the Dioxanone Product
SCHEME 10. Stereocenters of the Hemiacetal
can be used to explain the BH reaction’s sluggishness,
the difficulty in controlling its stereochemistry, the
formation of dioxanone products, and the influence of
protic additives.
Experimental Methods
General Procedures. Solvents and aldehydes were puri-
fied by using standard procedures. The purity of each aldehyde
1
was evaluated with GC, H NMR, and 13C NMR. 4-Pyridine-
carboxaldehyde was used immediately after purification.
Solvent was used as the internal reference for both 1H and
13CNMR. GC analyses were carried out with a CP-Sil regular
phase column (15.0 m × 0.25 mm i.d.). Response factors of
authentic Baylis-Hillman products versus methyl benzoate
(internal standard) were calculated for determining reaction
conversion.
General Kinetic Procedure. All reactions were carried
out with methyl acrylate, aldehyde, DABCO, and methyl
benzoate at concentrations of 0.84, 0.83, 0.27, and 0.066 M,
respectively. Reactions were started with the addition of
methyl acrylate to a solution of aldehyde, DABCO, and methyl
benzoate in a given solvent. The reactions were monitored by
diluting 5-7 µL of the reaction mixture into 1.5 mL of CH2Cl2
at appropriate time intervals for GC analysis. For the acrylate,
DABCO, and aldehyde order plots, the amount of DMSO and
the reaction volume were held constant to eliminate solvent
effects. THF was used as the nonreactive substitute for absent
reagents. No substitutions were necessary when THF was the
solvent for the order plot, as THF has no impact on rate. All
reactions were monitored before 10% conversion. No byprod-
ucts were detected at high conversions. Relative rates were
determined in Sigma Plot 8.0. Aberrant rates were eliminated
by using the Student’s t-test at the 95% confidence interval.
Preparation of r-Deuterio Methyl Acrylate (2d). The
preparation was modified from that of Baldwin and Cianciosi.36
DABCO (25 g, 0.22 mol) was dissolved in methanol-d (108 mL,
2.65mol) with stirring. Methyl acrylate (20 mL, 0.22 mol) was
added, and the solution was stirred at room temperature for
approximately 12 h. The solution was then diluted in o-
dichlorobenzene (ODCB) and washed with water and brine.
The organic phase was dried over Na2SO4 and fractionally
distilled to remove 2d from the ODCB. 2d was isolated as a
colorless liquid (7 g, 36%) and contained <2% ODCB, as
provide one method to enhance the stereoselectivity. In
Leahy’s case, the cyclization may be rate limiting and as
such, the transition state leading to the cyclic product
will be sensitive to stereochemistry by virtue of potential
1,3-diaxial interactions (see Scheme 3).
Auge, Aggarwal, Hu, and Tang report large rate
enhancements caused by water and other polar protic
additives. To extend the mechanism, we measured the
order in aldehyde in the protic solvent/THF mixtures and
the R-position KIE for one water/THF mixture. The
reaction was found to be second-order in aldehyde under
all protic conditions tested (Table 2). Also the KIE was
>2, indicating a rate-limiting R-proton cleavage that is
consistent with the proposed mechanism. In addition, the
order in the additive was one for each protic additive
testedsformamide, water, and methanolsusing THF as
the cosolvent. Each additive also showed saturation
behavior, indicating that the protic additive may form a
hemiacetal ground state at high protic concentrations.
A first-order solvent dependence is also observed for polar
aprotic solvents such as DMSO.30
The solvent-induced acceleration, under either protic
or aprotic conditions, roughly follows the dielectric con-
stant of the solvent or mixture. For instance, the ac-
celeration caused by DMSO is very similar to the mixture
of formamide and THF (Table 2). The first-order depen-
dence on solvent could be interpreted as a medium effect
or as a molecular interaction. Because the rate correlates
with solvent polarity, we suggest that the rate increase
is a medium effect in which the ionic transition states
are stabilized in the presence of polar solvents.
1
determined by H NMR spectroscopy. This volume difference
was accounted for when running methyl-d acrylate kinetics.
2d was approximately 87% deuterated and was stored cold
over Na2SO4. The batch used for the H2O/THF KIE was ∼80%
1
d. H NMR (300 MHz, CDCl3) δ 6.40 (m, 1H), 6.12 (m, 0.15
H), 5.83 (m, 1H), 3.75 (s, 3H).
Preparation of C,C-Dideuterio-C-(4-nitrophenyl)meth-
anol (9). 4-Nitrobenzoyl chloride (8.0 g, 43.1 mmol) was
dissolved in dry THF (200 mL) and added dropwise to a
suspension of lithium aluminum deuteride (2.2 g, 51.8 mmol)
in THF (100 mL) at -78 °C over 2 h. The reaction mixture
was allowed to stir for an additional hour at -78 °C and then
In conclusion, we have used rate and isotope data to
demonstrate that the mechanism featured in Scheme 5
is general for aryl aldehydes with different electronic
properties. The mechanism is also valid when polar
aprotic, nonpolar, and nonpolar/protic additive mixtures
are used. This general mechanism is a useful model that
(36) Baldwin, J. E.; Cianciosi, S. J. J. Am. Chem. Soc. 1992, 114,
9401-9408.
3986 J. Org. Chem., Vol. 70, No. 10, 2005

A New Interpretation of the Baylis-Hillman Mechanism
allowed to warm to room temperature for 30 min. The reaction
mixture was quenched with 1 N HCl, diluted with EtOAc, and
filtered. The filtrate was washed with brine and water, dried
over Na2SO4, and concentrated to produce a yellow solid (70%,
NMR (500 MHz, CDCl3) δ 166.3, 152.5, 149.0, 140.7, 127.4,
121.6, 72.2, 52.2.42
Preparation of 2-[Hydroxyphenylmethyl]acrylic Acid
Methyl Ester (13). This compound was synthesized by using
the general kinetic procedure with DMSO as the solvent.
Spectroscopic data are consistent with those in the literature.43
H NMR (400 MHz, CDCl3) δ 7.26-7.35 (m, 5H), 6.33 (s, 1H),
5.82 (s, 1H), 5.56 (s, 1H), 3.72 (s, 3H). 13C NMR (400 MHz,
CDCl3) δ 166.8, 141.8, 141.2, 128.4, 127.8, 126.5, 126.2, 109.8,
73.7, 52.0.
1
4.7 g). H NMR (400 MHz, acetone-d6) δ 8.20 (d, J ) 8.8 Hz,
2H), 7.58 (d, J ) 8.8 Hz, 2H), 4.62 (s, 1H).37 Complete
characterization was carried out after 9 was converted to 10.
Preparation of r-Deuterio-4-nitrobenzaldehyde (10).
The material was prepared following the general procedure
of More and Finney.38 Product 9 (4.3 g, 27.7 mmol), o-
iodoxybenzoic acid (IBX) (23.3 g, 83.2 mmol), and EtOAc (200
mL) were combined in a 500-mL round-bottom flask equipped
with a condenser. Caution: IBX can explode on impact or
heating.39 The reaction mixture was stirred vigorously at 80
°C overnight, open to atmosphere. The reaction mixture was
then cooled, filtered, and concentrated to produce a yellow
solid. The solid was purified by flash chromatography on silica
(preloaded with CH2Cl2, eluted with 4:1 hexanes:EtOAc) to
produce a yellow crystalline solid (93%, 3.9 g). The spectro-
scopic data correspond to those in Wubbels et al. 1H NMR (400
MHz, CDCl3) δ 8.38 (d, J ) 8.8 Hz, 2H), 8.08 (d, J ) 8.8 Hz,
2H).40 2H NMR (500 MHz, CHCl3 spiked with CDCl3) δ 10.02
(s, 1D). 13C NMR (500 MHz, DMSO-d6) δ 191.9 (t, JCD ) 28.2
Hz), 150.6, 140.0 (t, JCD ) 3.2 Hz), 130.6, 124.2.
Preparation of 2-[Hydroxy(4-nitrophenyl)methyl]acryl-
ic Acid Methyl Ester (11). This compound was synthesized
by using the general kinetic procedure with DMSO as the
solvent. The spectroscopic characterization is consistent with
the published characterization.41 1H NMR (500 MHz, CDCl3)
δ 8.19 (d, J ) 8.8 Hz, 2H), 7.56 (d, J ) 9.3 Hz, 2H), 6.38 (s,
1H), 5.86 (s, 1H), 5.62 (s, 1H), 3.73 (s, 3H). 13C NMR (500 MHz,
CDCl3) δ 166.4, 148.5, 147.4, 140.8, 127.3, 127.3, 123.6, 72.7,
52.2.
Determination of the Final Location of 2H. The reaction
was run with pNBA and 2d, using the general kinetic
procedure with acetonitrile as the solvent. An aliquot of the
reaction mixture was removed. Two resonances were observed
in the 2H NMR spectrum (400 MHz), 5.92 and 4.12 ppm,
corresponding to the deuterated methyl acrylate and the
deuterated alcohol in the product (benzene-d6 as the internal
standard).
Reversibility of the Baylis-Hillman Reaction. The
product of the Baylis-Hillman reaction, 11 (0.21 mmol), was
added to a solution of DABCO (0.0633 mmol) in 1 mL of
DMSO. The reaction mixture was heated at 60 °C and sampled
repetitively. At times ranging from 45 min to 100 h, no
aldehyde was detected by GC.
Rate Law Determination. The rate law was simplified
by using Mathematica (v. 5.0).
Acknowledgment. We thank Cornell University,
Dreyfus Foundation, 3M, NSF (CCMR-MRSEC and
SENSORS), NYSTAR, and NIH (CBI Training Grant)
for support and David Collum and Barry Carpenter for
general discussion.
Preparation of 2-[Hydroxypyridin-4-ylmethyl]acrylic
Acid Methyl Ester (12). PYR (1.07 g, 10 mmol) was added
to a solution of DABCO (1.12 g, 10 mmol) in acetonitrile.
Methyl acrylate (1.29 g, 15 mmol) was then added and the
reaction was stirred at room temperature for 24 h. The product
was isolated as a white powder (0.283 g, 14.7%). 1H NMR (500
MHz, CDCl3) δ 8.53 (d, J ) 6.4 Hz, 2H), 7.35 (d, J ) 6.4 Hz,
2H), 6.38 (s, 1H), 5.89 (s, 1H), 5.53 (s, 1H), 3.73 (s, 3H). 13C
Note Added after ASAP Publication. Two [D] terms
were missing on p 154 of the Supporting Information
published ASAP April 14, 2005; the corrected version was
published April 15, 2005.
Supporting Information Available: Kinetics data, order
plots, rate law derivation, and selected NMR spectra. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(37) Choi, H. S.; Kuczkowski, R. L. J. Org. Chem. 1985, 50, 901-
902.
JO050202J
(38) More, J. D.; Finney, N. S. Org. Lett. 2002, 4, 3001-3003.
(39) Plumb, J. B.; Harper, D. J. Chem. Eng. News 1990, 68, 3-3.
(40) Wubbels, G. G.; Kalhorn, T. F.; Johnson, D. E.; Campbell, D.
J. Org. Chem. 1982, 47, 4664-4670.
(42) Aggarwal, V. K.; Emme, I.; Fulford, S. Y. J. Org. Chem. 2003,
68, 692-700.
(43) Sammelson, R. E.; Gurusinghe, C. D.; Kurth, J. M.; Olmstead,
M. M.; Kurthy, M. J. J. Org. Chem. 2002, 67, 876-882.
(41) Shi, M.; Li, C. Q.; Jiang, J. K. Tetrahedron 2003, 59, 1181-
1189.
J. Org. Chem, Vol. 70, No. 10, 2005 3987