Theory-guided design of Br?nsted acid-assisted phosphine catalysis: synthesis of dihydropyrones from aldehydes and allenoates

Article abstract of DOI:10.1016/j.tet.2008.04.075

The phosphine-catalyzed addition of 2,3-butadienoates to aldehydes has been extended to the formation of disubstituted dihydro-2-pyrones. The requisite shift in equilibrium of the intermediate zwitterionic β-phosphonium dienolates toward the s-cis intermediate was accomplished through the use of a Br?nsted acid additive, which disrupts the favorable Coulombic interaction present in the s-trans intermediate. The detailed nature of the synergistic interactions involving the Br?nsted acid additives and phosphine involved in the formation of s-cis β-phosphonium dienolates was analyzed through a series of DFT calculations. Unlike previously reported annulations of aldehydes with allenoates, where trialkylphosphines are optimal catalysts, in this study triphenylphosphine was also found for the first time to be a suitable catalyst for the synthesis of dihydropyrones. This method provides a one-step route toward functionalized dihydropyrones from simple, stable starting materials. In addition, new reaction pathways of phosphine-catalyzed allene annulations are unveiled, with the formation of dihydropyrones being the first example of dual activation in this sphere.

Full text of DOI:10.1016/j.tet.2008.04.075

Tetrahedron 64 (2008) 6935–6942
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Theory-guided design of Brønsted acid-assisted phosphine catalysis:
synthesis of dihydropyrones from aldehydes and allenoates
,
Gardner S. Creech a, Xue-Feng Zhu a, Branden Fonovic b, Travis Dudding b, Ohyun Kwon a
*
a Department of Chemistry and Biochemistry, University of California, Los Angeles 607 Charles E. Young Drive East, Los Angeles, CA 90095-1569, United States
b Department of Chemistry, Brock University, St. Catharines, Ontario, Canada LS2 3A1
a r t i c l e i n f o
a b s t r a c t
Article history:
The phosphine-catalyzed addition of 2,3-butadienoates to aldehydes has been extended to the formation
Received 2 February 2008
Received in revised form 17 April 2008
Accepted 18 April 2008
of disubstituted dihydro-2-pyrones. The requisite shift in equilibrium of the intermediate zwitterionic b-
phosphonium dienolates toward the s-cis intermediate was accomplished through the use of a Brønsted
acid additive, which disrupts the favorable Coulombic interaction present in the s-trans intermediate. The
detailed nature of the synergistic interactions involving the Brønsted acid additives and phosphine
Available online 24 April 2008
involved in the formation of s-cis
b-phosphonium dienolates was analyzed through a series of DFT
Keywords:
Phosphine
Catalysis
Lewis base
Brønsted acid
Dihydropyrone
Aldehyde
calculations. Unlike previously reported annulations of aldehydes with allenoates, where tri-
alkylphosphines are optimal catalysts, in this study triphenylphosphine was also found for the first time
to be a suitable catalyst for the synthesis of dihydropyrones. This method provides a one-step route
toward functionalized dihydropyrones from simple, stable starting materials. In addition, new reaction
pathways of phosphine-catalyzed allene annulations are unveiled, with the formation of dihydropyrones
being the first example of dual activation in this sphere.
Allenoate
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
part to the increase in concentration of the zwitterionic in-
termediate.6 The addition of an alcohol or water has also been
Dual activation is a powerful technology in the development of
novel reaction pathways.1 In particular, the combined use of com-
patible acidic and basic reagents to activate multiple reactive cen-
ters in reactants can have a powerful synergistic effect on rate and
reaction modality; additionally, enantioselective processes are
possible with a single chiral activator.2 We became interested in
applying this concept of dual activation to the phosphine-catalyzed
annulations of 2,3-butadienoates. Although numerous catalytic
asymmetric Morita–Baylis–Hillman (MBH) processes have been
reported employing chiral Brønsted acids that are compatible with
nucleophilic Lewis bases,3,4 the literature examples of dual activa-
tion for the mechanistically similar nucleophilic phosphine-cata-
lyzed allene annulations are rare.5 Indeed, the use of an additive to
manipulate the reactivity in phosphine-catalyzed annulations of
allenes has as of yet been explored only for the synthesis of dihy-
dropyrones, as we describe in further detail below.
demonstrated in several cases to substantially increase the reaction
rate,7 which is often attributed to added assistance during the
proton transfer steps.8 Chiral Lewis and Brønsted-acidic compo-
nents possessing free hydrogen bond donors have been applied to
activate the electrophilic partner, thereby increasing the reaction
rate and inducing facial selectivity.9 Bifunctional catalysis,10 a par-
ticularly promising type of dual activation, has also led to many
extremely rewarding discoveries in the MBH reaction. Such cata-
lysts, which commonly comprise a nucleophilic reactive site and
a hydrogen bond donor to activate the electrophilic partner,11 in-
crease the rate of the reaction and its scope, frequently inducing
high levels of enantiomeric excess in the products. The power of
dual activation by means of nucleophilic catalysis in conjunction
with an additional component is well documented.1,2
The scope of phosphine-catalyzed annulations of 2,3-butadie-
noates with unsaturated electrophiles has been greatly expanded
over the last decade or so.12 In addition to the reported reactions of
electron-poor alkenes and imines, we have previously demon-
strated that aldehydes are viable electrophiles for the selective
formation of dioxane and pyrone oxacycles (Scheme 1).13 The use of
small phosphines, such as trimethylphosphine, leads to the for-
mation of dioxane products (2) whereas bulky phosphines form
pyrone products (3) exclusively. It is believed that the key mecha-
nistic difference lies in the equilibrium between the two isomeric
There is much evidence supporting dual activation in the nu-
cleophile-catalyzed MBH reaction.3 In addition to using a Lewis
basic nucleophile as a catalyst, the presence of certain hydrogen
bond donors4 can dramatically increase the rate of reaction, due in
* Corresponding author.
E-mail address: ohyun@chem.ucla.edu (O. Kwon).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.04.075

6936
G.S. Creech et al. / Tetrahedron 64 (2008) 6935–6942
formation of 7. The concomitantly generated alkoxide R1Oꢀ facili-
tates deprotonation of the -phosphonium lactone 7; the resulting
zwitterion proceeds to form the pyrone 3 and regenerate the
R2
b
R2CHO
CO2R1
O
O
cat. PMe3
phosphine catalyst. We suspect that conjugate addition of the
R2
1
CO2R1
O
alkoxide followed by facile
b-elimination of the phosphine,
2
resulting in dihydropyrone 4, is blocked by the bulky phosphine
required for the formation of 5. An alternative method for stabi-
lizing the s-cis b-phosphonium dienolate 5 would potentially allow
a smaller phosphine to act as a catalyst, with subsequent formation
of disubstituted dihydropyrones 4. Given that the electrostatic at-
traction between the phosphonium cation and the alkoxide anion
facilitates the formation of the s-trans b
-phosphonium dienolate 50,
we envisioned the possibility of using hydrogen bond donors to
stabilize the alkoxide moiety and induce the desired s-cis dienolate
5. It occurred to us that addition of an alcohol R1OH would be
especially attractive because the competing reaction pathway to
the pyrone 3 would be discouraged.
R2
O
R2CHO
CO2R1
cat. PCyp3
3
O
R2CHO
O
CO2R1
cat. PR3
additive
OR1
R2
4
Scheme 1. Phosphine-catalyzed annulations of 2,3-butadienoates with aldehydes as
electrophiles.
To evaluate the viability of this mechanistic proposal, we per-
formed a series of quantum chemical calculations rooted within the
formalism of the generalized gradient approximation (GGA)-hybrid
Kohn–Sham density functional theory (KS-DFT) using Becke’s
three-parameter exchange functional (B3)14 with inclusion of Lee,
Yang, and Parr’s electron correlation method (LYP)15 and Pople’s 6-
3lG(d) basis set.16 The reported energies represent computed
values from single-point implicit conductor-like polarizable con-
b
-phosphonium dienolates formed upon addition of the tertiary
phosphine catalyst to the butadienoate; we suspected that an
alternative means of influencing this equilibrium, other than
changing the phosphine’s size, would enable the formation of
dihydropyrone oxacycles (4).
tinuum model (CPCM) solvation calculations (benzene
3
¼2.25)
2. Results and discussion
performed on B3LYP/6-31G(d)-(CPCM)//B3LYP/6-31G(d)-opti-
mized geometries.17 All quantum chemical calculations were
undertaken using the Gaussian suite of programs G0318 and
Gaussview 3.0.19 To accomplish this goal, we conducted a system-
atic survey of the potential energy surface (PES) within the vicinity
corresponding to the transition state for Pþ–C bond formation
during the phosphine-to-allenoate addition in the presence of
MeOH (Scheme 3). From this survey, we located two nearly ener-
getically equivalent lowest-energy first-order saddle points TSa
In the first step of the nucleophilic phosphine catalysis of
allenes, the addition of the phosphine catalyst to the 2,3-butadie-
noate 1 results in an equilibrium mixture of dienolates 5 and 50
(Scheme 2).13c If the phosphine is small, such as trimethylphos-
phine, then the intermediate dienolate 50 having s-trans geometry
is dominant because of Coulombic attraction between the phos-
phonium unit and the delocalized negative charge of the enolate
alkoxide moiety. The addition of an aldehyde to the s-trans in-
(
DDGz ¼0 kcal/mol) and TSb
(
DDGz ¼0.7 kcal/mol). The de-
termediate results in the formation of the b-phosphonium enoate
solv
solv
fining metrics of these transition state structures included Pþ–C
bond forming distances of 2.24 Å and 2.20 Å, respectively. In
addition, present within each structure was a hydrogen bond (H-
60 having Z geometry, which incorporates a second equivalent of
aldehyde and undergoes 6-exo-trig cyclization onto the enoate to
release the catalyst and form the dioxane 2.13a In an alternative
reaction pathway, if the phosphine catalyst is bulky, for instance
triisopropyl-, tricyclohexyl-, or tricyclopentylphosphine, steric
hindrance around the phosphine unit appears to disrupt the fa-
vorable Coulombic interaction and shift the equilibrium toward the
dienolate 5 having s-cis geometry. Upon addition of the aldehyde to
bond) contact between the MeOH hydroxyl group and the Odꢀ
-
carbonyl oxygen atom of the reacting allenoate, measuring 1.82 Å
for TSa and 1.85 Å for TSb, which functionally impart degrees of
stability to these transition states. Upon subsequent optimization of
TSa and TSb to their respective local minima 5 and 5a, corre-
sponding to the immediate products of Pþ–C bond formation,
a most revealing mechanistic feature was unveiled: in the presence
of Brønsted-acidic methanol, the intermediate products formed
the g b-phosphonium enoate 6 having E ge-
-carbon atom,13b the
ometry is formed. The spatial proximity between the alkoxide and
enoate units in intermediate 6 allows lactonization, resulting in the
CO2R1
s-trans-isomer
R2
PR3
OR1
R2
CO2R1
O
O
2
PR3
O
O
PR3
R2
R2CHO
5'
6'
PR3
CO2R1
R1OH + PR3
R2CHO
R2
O
O
O
1
R2
O
O
R2
O
CO2R1
OR1
3
O
R3P
R1O
PR3
R2
O
5
PR3
s-cis-isomer
7
6
OR1
PR3
Scheme 2. Formation of dioxanes 2, 2-pyrones 3, and dihydro-2-pyrones 4.
4

G.S. Creech et al. / Tetrahedron 64 (2008) 6935–6942
6937
O
relative to that obtained using benzyl alcohol. Further decreases
in pKa were detrimental: we observed no apparent consumption of
the starting butadienoate when the additive was 2-bromoethanol,
2,2-dichloroethanol, 2,2,2-trichloroethanol, or 2,2,2-trifluoroethanol
(Table 1, entries 7–10). The use of mismatched alkyl ester and
additive alkoxides resulted in mixtures of products through
transesterification and the potential addition of two Michael
donors; subsequently, we found that the application of matched 2-
chloroethyl- and 2-fluoroethyl-2,3-butadienoates resulted in single
dihydropyrone products with similar efficiencies (Table 1, entries
11 and 12). In addition to alcohols, we screened an assortment of
other Brønsted-acidic additives having values of pKa within
the desirable range (Table 1, entries 13–22); disappointingly,
only N,N0-dimethylurea and water produced the dihydropyrone
product, but with diminished yields and mass recoveries. Due
to their promising mix of pKa and nucleophilicity, we subjected
the 2-chloroethanol and 2-fluoroethanol additives to further eval-
uation. The structural connectivity of dihydropyrone product
was established unequivocally through X-ray crystallography
of 6-(4-bromophenyl)-4-(2-fluoroethyl)-5,6-dihydro-2H-pyran-2-
one (Fig. 1).23
OMe
OMe
O
s-cis
s-trans
PMe3 + MeOH
H3CO
PMe3
2.23
O
2.44
H
Me
+
H3C
δ
H
1.85
Me
H
O
δ
P
Me
O
+
+
Me
1.82
δ
δ
−
O
P
H
O
Me
Me
Me
Me
P
2.24
−
δ
−
δ
O
2.24
Me
TSb
O
2.20
TSa
TSc
Me
0 kcal/mol
0.7 kcal/mol
Me
Me
Me
P
Me
Me
P
Me
Me
Me
Me
O
P
H
MeO
O
H
OMe
H3CO
1.81
O
OMe
5'
1.81
H3CO
5a
5
0 kcal/mol
0.06 kcal/mol
Scheme 3. Structures of the transition states and the resulting phosphonium dienolate
zwitterions in the presence and absence of methanol.
Next, we further optimized the reaction parameters for the 2-
chloroethyl and 2-fluoroethyl butadienoates (Table 2). Diminished
yields of the desired dihydropyrone were observed when using
tributylphosphine and triethylphosphine as catalysts (Table 2,
entries 1 and 2), perhaps due to their increased steric bulk, relative
to that of trimethylphosphine, being detrimental to the requisite
Michael addition of the alcohol. Trimethylphosphine was the
optimal catalyst for the coupling of 3-chlorobenzaldehyde with
2-chloroethyl allenoate (Table 2, entry 3). Unexpectedly, triphe-
nylphosphine also induced dihydropyrone formation, albeit with
diminished yield (Table 2, entry 4). This result is notable because it
is the first example of triphenylphosphine facilitating the coupling
between a butadienoate and an aldehyde. Additionally, in this case
we observed no non-cyclic product, presumably because a de-
crease in rate of the Michael addition/elimination step allowed
lactonization to compete effectively with catalyst regeneration.
From a solvent screening evaluation, the optimal solvent was
dichloromethane, which combined an increase in efficiency with
a higher yield of cyclized product (Table 2, cf. entry 5 with entries
6–11 for other common organic solvents). We believe that the
favorable outcome with non-polar solvents is the result of more-
efficient association of the alcohol additives with the zwitterionic
intermediates. In dichloromethane, the combination of 2-fluo-
roethyl allenoate and 2-fluoroethanol furnished a higher yield of
the dihydropyrone as well as better ratio with respect to the non-
cyclic product (Table 2, entry 12). Interestingly, the yield increased
further when using triphenylphosphine as the catalyst; more
importantly, no non-cyclic product was formed (57%; Table 2,
entry 13).
With the choice of catalyst, solvent, and Brønsted acid additive
optimized, we proceeded to probe the scope of the formation of
dihydropyrones (Table 3). In the hope of reducing the degree of
undesirable allenoate oligomerization as a side reaction limiting
the mass recovery, the 0.25 M butadienoate solution was added
slowly. Benzaldehydes presenting a variety of electron-withdraw-
ing substituents provided their dihydropyrones in good yields
(Table 3, entries 1–5). Interestingly, trimethylphosphine proved to
be a more effective catalyst for some substrates, such as the
trifluoromethyl-substituted benzaldehydes (Table 3, entries 6 and
7). As demonstrated in previous allene/aldehyde annulations,12
electron-rich aromatic aldehydes exhibited low efficiencies (entries
8–11). A heteroaromatic substrate, 3-pyridine carboxaldehyde, was
also compatible with the optimized reaction conditions, providing
the corresponding substituted pyridine in 68% yield (entry 12).
Disubstituted dihydropyrones were obtained rapidly in a single
were the minima 5 and 5a possessing s-cisoid geometries. These
findings represent a dramatic departure from our previous in silico
mechanistic studies addressing nucleophilic phosphine-triggered
zwitterionic enolate formation in the absence of Brønsted-acidic
alcoholic additives (see 50 in Scheme 3).20 In our prior studies we
established that the s-trans enolate 50 was the direct and most
stable product formed from the transition state TSc of the phos-
phine-to-allenoate addition. Accordingly, based upon our new
calculationsdin what certainly reflects a cause-and-effect rela-
tionshipdthe addition of a Brønsted acid, in this case methanol,
leads to a Boltzmann distribution toward the s-cis zwitterions 5 and
5a from favoring the s-trans zwitterion 50 in non-polar media. These
two minima, 5 and 5a, vary structurally solely in terms of the rel-
ative orientation of their hydrogen-bond-coordinated methanol
units.21
Having verified, through DFT calculations, that addition of a
hydrogen bond donor could induce formation of the s-cis isomer 5
by disrupting the putative Coulombic attraction stabilizing 50, we
acted upon this mechanistic insight experimentally. Promisingly,
initial experiments using isopropanol and ethanol (Table 1, entries
1 and 2) revealed a small induction of the desired dihydropyrones,
but the majority of the product was the dioxane, presumably
because the phosphonium dienolate equilibrium favored the un-
desired s-trans isomer 50. The use of methanol provided more en-
couraging results, with an increase in total mass recovery to 78%
and the major product being the dihydropyrone (Table 1, entry 3).
The second major product was the three-component-coupling
adduct 8, formed from the aldehyde, allenoate, and alcohol, which
formed presumably through regeneration of the phosphine catalyst
via Michael addition of the alkoxide prior to lactonization of the
intermediate 6 (see Scheme 2).22 We suspected that a decrease in
the nucleophilicity of the additive would suppress this interruptive
Michael addition. Accordingly, the slightly more-acidic benzyl al-
cohol provided exclusively the dihydropyrone product 4, although
the mass recovery was unexpectedly low (Table 1, entry 4). This
observation led us to explore more-acidic alcohols. We expected
that the commercially available halogenated ethanol derivatives,
which exhibit decreased nucleophilicity and, simultaneously, de-
creased pKa would preferentially induce formation of the desired
dihydropyrone (Table 1, entries 5–12). Indeed, a decrease in the
yield of the non-cyclic product 8 occurred when we used the less-
nucleophilic 2-fluoroethanol and 2-chloroethanol additives (Table
1, entries 5 and 6), with an overall increase in the mass recovery

6938
G.S. Creech et al. / Tetrahedron 64 (2008) 6935–6942
Table 1
Screening of various hydrogen-bond-donating additives
R3
O
2 equiv R2OH
26 mol% PMe3
5 equiv R3CHO
CHCl3, rt
OH OR2
CO2R1
O
O
O
+
+
OR2
R3
1
R3
R3
CO2R1
CO2R1
4
8
2
R3 = 3-chlorophenyl
Entry
R1
R2 or additive
pKa of R2OH in H2O (DMSO)a
Yieldb (%; 4/8c/2)
1
2
3
4
5
6
7
8
i-Pr
Et
Me
Bn
Me
Me
i-Pr
Me
Me
Me
CH2CH2Cl
CH2CH2F
Me
i-Pr
Et
Me
Bn
CH2CH2Cl
CH2CH2F
CH2CH2Br
CH2CHCl2
CH2CCl3
CH2CF3
CH2CH2Cl
CH2CH2F
H2O
16.5 (30.3)
16.0 (29.8)
15.5 (29.0)
15.2, 15.4
14.3
13.9, 14.2
13.8
12.9
11.8, 12.2
11.4, 12.4 (23.5)
14.3
13.9, 14.2
15.7 (31.4)
54 (16:0:84)
70 (23:21:55)
78 (54:39:7)
36 (100:0:0)
55 (90:10:0)d
49 (85:15:0)d
0
Trace
0
0
9
10
11
12
13
41 (81:19:0)
51 (89:11:0)
31 (46:4:50)e
O
Me
Me
14
15
Me
Me
14.6 (26.9)f
11 (100:0:0)e
N
H
N
H
O
14.5 (23.3)
0
NH2
NH2
16
17
18
19
CH2CH2Cl
CH2CH2F
CH2CH2F
CH2CH2F
(26.5)
(28.4)
13.7
0
0
0
0
N
NH2
Br
OH
OH
13.0
F
OH
OH
20
21
CH2CH2F
13.1
0
F
F
OH
CH2CH2F
12.7
0
F
22
i-Pr
Ethylene glycol
14.77
Decomposition
a
Data collected from Ref. 24; if two sources report slightly different pKa values in water, both values are provided.24
Isolated yields.
b
c
d
e
f
The alkene stereochemistry was exclusively E (NOESY NMR spectroscopy).
Both methoxide and the 2-haloethoxide were incorporated as b
-substituents (OR2) in 4 and 8.
Methoxide incorporated as the b-substituent.
Value of pKa for urea in DMSO.
step from simple, bench-stable starting materials in moderate to
good yields.
3. Conclusion
We have uncovered a new mode for the phosphine-catalyzed
reaction of 2,3-butadienoates with aromatic aldehydes, namely the
formation of disubstituted dihydropyrones, through the addition of
Brønsted-acidic additives, which presumably interact with the
zwitterionic b-phosphonium dienolate 5, shifting the equilibrium
toward its s-cis isomer. Previously, such a shift had required the use
of an extremely bulky phosphine catalyst, which inhibited Michael
addition of an alkoxide, resulting instead in the formation of pyrone
products. Using an additive, in addition to a nucleophilic phosphine
Figure 1. X-ray crystallographic representation of 6-(4-bromophenyl)-4-(2-fluo-
roethyl)-5,6-dihydro-2H-pyran-2-one 4i.

G.S. Creech et al. / Tetrahedron 64 (2008) 6935–6942
6939
Table 2
4. Experimental
Screening of solvents and phosphine catalysts
O
4.1. General
2 equiv ROH
OH OR
phosphine, cat.
CO2R
O
+
5 equiv R1CHO
solvent, rt
R1
All reactions were performed under an argon atmosphere with
dry solvents and anhydrous conditions, unless otherwise noted.
Tetrahydrofuran (THF) and diethyl ether were distilled over so-
dium/benzophenone ketyl; dichloromethane, benzene, and tolu-
ene were freshly distilled from CaH2. All other anhydrous solvents
were packaged in Sure/SealÔ bottles and were used as received
from Aldrich; chloroform was further distilled from calcium chlo-
ride immediately prior to use. All the aldehydes were commercially
available and purchased from Aldrich or Acros Organics. The liquid
aldehydes were washed sequentially with saturated sodium bi-
carbonate and saturated sodium chloride and then distilled prior to
use. Solid aldehydes were dissolved in dichloromethane, washed
with saturated sodium bicarbonate, evaporated to dryness, and
then stored under vacuum over phosphorus pentoxide. All the
phosphines were commercially available and purchased from
Aldrich, Strem Chemicals, Inc., Organometallics, Inc., or Maybridge
Chemicals. All other reagents were used as received from com-
mercial sources, with the alcohols stored over 4 Å molecular sieves.
Reactions were monitored through thin layer chromatography
(TLC) on 0.25-mm Silicycle silica gel plates (TLG-R10011B-323),
visualizing with UV light or staining with permanganate or ani-
saldehyde. Flash column chromatography was performed using
1
R1
OR
CO2R
4
8
R1 = 3-chlorophenyl
Entry
R
Solvent
Phosphinea
Yieldb (%; 4/8)c
1
2
3
4
5
6
7
8
CH2CH2Cl
CH2CH2Cl
CHCl3
CHCl3
CHCl3
CHCl3
CH2Cl2
DCE
Benzene
Toluene
Et2O
THF
DMF
CH2Cl2
CH2Cl2
P(n-Bu)3
PEt3
PMe3
PPh3
PMe3
PMe3
PMe3
PMe3
PMe3
PMe3
PMe3
PMe3
PPh3
0
15 (100:0)
41 (81:19)
18 (100:0)
48 (88:13)
31 (86:14)
29 (86:14)
28 (84:16)
12 (100:0)
8 (100:0)
0
CH2CH2Cl
CH2CH2Cl
CH2CH2Cl
CH2CH2Cl
CH2CH2Cl
CH2CH2Cl
CH2CH2Cl
CH2CH2Cl
CH2CH2Cl
CH2CH2F
CH2CH2F
9
10
11
12
13
51 (89:11)
57 (100:0)
a
Trialkylphosphine: 26 mol %; PPh3: 20 mol %.
Isolated yields.
The alkene stereochemistry was exclusively E (NOESY NMR spectroscopy).
b
c
catalyst, to induce an alternate reaction pathway is an example of
dual activation of the starting material substrates. Adjustment of
the pKa and nucleophilicity of the additives was necessary to pre-
vent formation of non-cyclized products, which formed pre-
sumably through premature catalyst regeneration; 2-fluoroethyl
butadienoate and 2-fluoroethanol were the optimal substrate and
additive. Additionally, the use of triphenylphosphine as the catalyst
led to complete inhibition of the non-cyclized product, possibly due
to a reduction in rate of Michael addition of the alkoxide so that
complete lactonization could occur. The dual activation present in
the mechanism of this reaction pathway suggests many avenues for
chiral induction: e.g., bifunctional catalysts featuring both hydro-
gen-bond-donating and nucleophilic reaction sites, asymmetric
phosphine catalysts, or chiral Brønsted-acidic additives. In addition,
Silicycle Silia-P gel (50-mm particle size, R12030B) and compressed
air. IR spectra were recorded on a Perkin–Elmer Paragon1000 FT-IR
spectrometer. NMR spectra were obtained on a Bruker Avance-500
instrument and calibrated using residual non-deuterated chloro-
form as an internal reference (7.26 ppm for 1H NMR; 77.00 ppm for
13C NMR). Data for 1H NMR spectra are reported as follows:
chemical shift (d ppm), multiplicity, coupling constant (Hz), and
integration. Data for 13C NMR spectra are reported in terms of
chemical shift and multiplicities, with coupling constants (Hz) in the
case of JCF coupling. The following abbreviations are used to explain
the multiplicities: s, singlet; d, doublet; t, triplet; q, quartet; sept,
septet; m, multiplet; br, broad; and app, apparent. High-resolution
electrospray ionization/time of flight (ESI-TOF) mass spectrometry
data were collected on a QStar Elite Hybrid LC/MS/MS system, with
caffeine and MRFA peptide (methionine-argenine-phenylalanine-
alanine) peptide used as internal calibration standards.
increasing the allenoate’s complexity through either
substitution would increase the complexity of the resultant
dihydropyrones.
a- or g-
4.2. General procedure for the synthesis of dihydropyrones
Table 3
Syntheses of various 6-aryl-4-(2-fluoroethoxy)-5,6-dihydro-2-pyronesa
Dry solvent (10 mL) was added to a flame-dried, 15-mL round-
bottom flask under an argon atmosphere, followed by the neat
aldehyde (5.0 equiv), the alcohol additive (2.0 equiv), and the
phosphine (20 mol % for PPh3; 26 mol % for PMe3); in the case of
a solid phosphine, additive, or aldehyde, the compound was added
O
phosphine, cat.
2 equiv ROH
O
O
5 equiv ArCHO
CH2Cl2, rt
1.5 h for PMe3
6 h for PPh3
O
F
F
O
Ar
4
prior to the solvent and the argon was replenished. Using a 250-mL
micro syringe, the allenoate (1.0 mmol) was added dropwise over
a period of 30 min. An orange-red solution was obtained; the
mixture was stirred at room temperature until TLC (eluant: 20%
EtOAc/hexanes; permanganate stain) revealed consumption of the
allenoate. The reaction mixture was concentrated and the residue
purified through flash column chromatography (SiO2; 33–50%
EtOAc/hexanes) to give the products.
Entry
Ar
Phosphineb
Product
Yield (%)c
1
2
3
4
5
6
7
8
4-NCC6H4
3-NCC6H4
PPh3
PPh3
PPh3
PPh3
PPh3
PMe3
PMe3
PMe3
PMe3
PMe3
PMe3
PMe3
4a
4b
4c
4d
4e
4f
4g
4h
4i
81
72
77
61
58
58
55
30
40
21
39
68
3-O2NC6H4
3-ClC6H4
4-AcC6H4
4-F3CC6H4
2-F3CC6H4
C6H5
4-BrC6H4
3-MeC6H4
3-MeOC6H4
3-Pyridyl
4.2.1. 4-Benzyloxy-6-(3-chlorophenyl)-5,6-dihydro-2H-pyran-
2-one
9
10
11
12
4j
4k
4l
Yield 36%; thick oil; IR (neat) nmax 1700, 1622, 1558, 1540, 1506,
1472, 1456, 1224 cmꢀ1 1H NMR (500 MHz, CDCl3)
; d 7.44–7.28 (m,
9H), 5.44 (dd, J¼12.2, 3.8 Hz, 1H), 5.36 (d, J¼1.5 Hz, 1H), 4.99 (d,
a
Dilute allenoate addition; see Section 4 for a detailed procedure.
PPh3: 20 mol %; PMe3: 25 mol %.
Isolated yield.
b
c
J¼2.5 Hz, 2H), 2.84 (ddd, J¼17.0, 12.0, 1.5 Hz, 1H), 2.68 (dd, J¼17.0,
4.0 Hz, 1H); 13C NMR (125 MHz, CDCl3)
d 170.9, 166.2, 140.1, 134.6,

6940
G.S. Creech et al. / Tetrahedron 64 (2008) 6935–6942
134.1, 129.9, 128.8, 128.7, 128.7, 127.8, 126.1, 123.9, 91.6, 76.2, 71.1,
35.0; MS (ESI-TOF) calcd for C18H16O3Clþ [MþH]þ 315.0788, found
315.0782.
137.2, 128.7, 125.9, 91.5, 80.5 (JCF¼171 Hz), 76.4, 67.9 (JCF¼20 Hz),
34.8, 26.6; MS (ESI-TOF) calcd for C15H16O4Fþ [MþH]þ 279.1033,
found 279.1027.
4.3. Optimized experimental procedure for the synthesis of
dihydropyrones
4.3.5. 4-(2-Fluoroethoxy)-6-(4-trifluoromethylphenyl)-5,6-
dihydro-2H-pyran-2-one (4f)
Yield 57.8%; white solid; IR (neat) nmax 1713, 1626, 1327, 1228,
Dry solvent (8 mL) was added to a flame-dried, 15-mL round-
bottom flask under an argon atmosphere, followed by the neat
aldehyde (5.0 equiv), the alcohol additive (2.0 equiv), and the
phosphine (20 mol % for PPh3; 26 mol % for PMe3); in the case of
a solid phosphine, additive, or aldehyde, the compound was added
prior to the solvent and then the argon was replenished. A solution
of the allenoate (1 mmol) in dry solvent (4 mL) was added over
1168, 1125, 1068, 1018 cmꢀ1 1H NMR (500 MHz, CDCl3)
; d 7.68 (d,
J¼8.5 Hz, 2H), 7.55 (d, J¼8.0 Hz, 2H), 5.52 (dd, J¼12.0, 4.0 Hz, 1H),
5.27 (d, J¼1.5 Hz, 1H), 4.74 (dt, J¼47.5, 4.0 Hz, 2H), 4.26–4.10 (m,
2H), 2.84 (ddd, J¼17.0, 12.0, 1.5 Hz, 1H), 2.72 (dd, J¼17.0, 4.0 Hz, 1H);
13C NMR (125 MHz, CDCl3)
d
170.8, 165.8, 141.9, 130.8 (q, JCF¼32 Hz),
126.1, 125.7 (q, JCF¼3.8 Hz), 123.8 (q, JCF¼270.4 Hz), 91.5, 80.5
(JCF¼172 Hz), 76.2, 68.0 (JCF¼20 Hz), 34.8; MS (ESI-TOF) calcd for
30 min using
a
syringe pump. An orange-red solution was
C
14H13O3F4 [MþH]þ 305.0801, found 305.0806.
obtained; the mixture was stirred at room temperature until TLC
(eluant: 20% EtOAc/hexanes; permanganate stain) revealed
consumption of the allenoate. The reaction typically took 1.5 h for
PMe3 and 6 h for PPh3. The reaction mixture was concentrated and
the residue purified through flash column chromatography (SiO2;
33–50% EtOAc/hexanes) to give the products. Spectral data for the
new dihydropyrones listed in Table 3 are provided below.
4.3.6. 4-(2-Fluoroethoxy)-6-(2-trifluoromethylphenyl)-5,6-
dihydro-2H-pyran-2-one (4g)
Yield 54.9%; white solid; IR (neat) nmax 1722, 1712, 1626, 1315,
1229, 1165, 1118, 1072 cmꢀ1 1H NMR (500 MHz, CDCl3)
; d 7.85 (d,
J¼7.5 Hz, 1H), 7.69–7.64 (m, 2H), 7.48 (t, J¼7.7 Hz, 1H), 5.82 (dd,
J¼12.5, 4.0 Hz, 1H), 5.27 (d, J¼2.0 Hz, 1H), 4.80–4.68 (dm, J¼47.0 Hz,
2H), 4.26–4.21 (m, 2H), 2.79 (ddd, J¼17.5, 12.5, 1.5 Hz, 1H), 2.65 (dd,
4.3.1. 6-(4-Cyanophenyl)-4-(2-fluoroethoxy)-5,6-dihydro-2H-
pyran-2-one (4a)
J¼17.5, 3.8 Hz, 1H); 13C NMR (125 MHz, CDCl3)
d 171.0, 166.1, 136.9,
132.4,128.7,128.2,126.9 (q, JCF¼30 Hz), 125.6 (q, JCF¼6 Hz),124.0 (q,
JCF¼272 Hz), 91.2, 80.5 (d, JCF¼171 Hz), 73.4, 68.0 (d, JCF¼20 Hz),
35.7; MS (ESI-TOF) calcd for C14H13O3F4 [MþH]þ 305.0801, found
305.0802.
Yield 80.8%; white solid; IR (neat) nmax 1712, 1626, 1391, 1228,
1076, 918, 835, 583 cmꢀ1 1H NMR (500 MHz, CDCl3)
; d 7.71 (dd,
J¼6.8, 1.7 Hz, 2H), 7.55 (d, J¼8.5 Hz, 2H), 5.50 (dd, J¼11.8, 4.2 Hz,
1H), 5.26 (d, J¼1.5 Hz, 1H), 4.73 (dt, J¼47.5, 4.0 Hz, 2H), 4.25–4.10
(m, 2H), 2.81 (ddd, J¼17.0, 12.0, 1.5 Hz, 1H), 2.71 (dd, J¼17.3, 4.3 Hz,
4.3.7. 4-(2-Fluoroethoxy)-6-phenyl-5,6-dihydro-2H-pyran-
2-one (4h)
1H); 13C NMR (125 MHz, CDCl3)
d 170.6, 165.6, 143.1, 132.5, 126.4,
118.2, 112.6, 91.5, 80.4 (JCF¼172 Hz), 75.9, 68.0 (JCF¼20 Hz), 34.7; MS
Yield 30.4%; white solid; IR (neat) nmax 1726, 1711, 1632, 1223,
(ESI-TOF) calcd for C14H13O3NF [MþH]þ 262.0879, found 262.0873.
1068, 917, 702, 577 cmꢀ1; 1H NMR (500 MHz, CDCl3)
d 7.43–7.34 (m,
5H), 5.45 (dd, J¼12.0, 4.0 Hz, 1H), 5.25 (d, J¼1.5 Hz, 1H), 4.73 (dt,
4.3.2. 6-(3-Cyanophenyl)-4-(2-fluoroethoxy)-5,6-dihydro-2H-
pyran-2-one (4b)
J¼47.5, 4.0 Hz, 2H), 4.24–4.12 (m, 2H), 2.88 (ddd, J¼17.3,12.3,1.5 Hz,
1H), 2.67 (dd, J¼17.0, 4.0 Hz,1H); 13C NMR (125 MHz, CDCl3)
d 171.2,
Yield 72.3%; white solid; IR (neat) nmax 1710, 1621, 1392, 1294,
166.4, 138.0, 128.6, 128.6, 125.9, 91.4, 80.57 (JCF¼171 Hz), 77.1, 67.8
(JCF¼20 Hz), 34.8; MS (ESI-TOF) calcd for C13H14O3F [MþH]þ
237.0927, found 237.0927.
1235, 1191, 1072, 1021 cmꢀ1 1H NMR (500 MHz, CDCl3)
; d 7.74 (s,
1H), 7.68 (t, J¼6.5 Hz, 2H), 7.54 (t, J¼8.0 Hz, 1H), 5.48 (dd, J¼12.0,
4.0 Hz, 1H), 5.27 (d, J¼1.5 Hz, 1H), 4.74 (dt, J¼47.5, 4.0 Hz, 2H), 4.26–
4.11 (m, 2H), 2.83 (ddd, J¼17.0, 12.0, 1.5 Hz, 1H), 2.71 (dd, J¼17.5,
4.3.8. 6-(4-Bromophenyl)-4-(2-fluoroethoxy)-5,6-dihydro-2H-
pyran-2-one (4i)
4.0 Hz, 1H); 13C NMR (125 MHz, CDCl3)
d 170.6, 165.5, 139.6, 132.2,
130.1, 129.6, 129.4, 118.1, 113.0, 91.5, 80.43 (JCF¼172 Hz), 75.7, 68.0
(JCF¼20 Hz), 34.7; MS (ESI-TOF) calcd for C14H13O3NF [MþH]þ
262.0879, found 262.0880.
Yield 40.1%; white solid; IR (neat) nmax 1704, 1630, 1389, 1347,
1224,1059, 914, 828, 443 cmꢀ1; 1H NMR (500 MHz, CDCl3)
d 7.53 (d,
J¼8.5 Hz, 2H), 7.30 (d, J¼8.5 Hz, 2H), 5.41 (dd, J¼12.0, 4.0 Hz, 1H),
5.24 (d, J¼1.5 Hz, 1H), 4.73 (dt, J¼47.0, 4.0 Hz, 2H), 4.24–4.09 (m,
2H), 2.82 (ddd, J¼17.5, 12.0, 1.5 Hz, 1H), 2.66 (dd, J¼17.5, 4.0 Hz, 1H);
4.3.3. 4-(2-Fluoroethoxy)-6-(3-nitrophenyl)-5,6-dihydro-2H-
pyran-2-one (4c)
13C NMR (125 MHz, CDCl3)
d 171.0, 166.1, 137.1, 131.9, 127.6, 122.7,
Yield 77.0%; white solid; IR (neat) nmax 1715, 1625, 1532, 1353,
91.5, 80.6 (d, JCF¼171 Hz), 76.4, 68.0 (d, JCF¼20 Hz), 34.5; MS (ESI-
1228, 1074, 816, 740 cmꢀ1 1H NMR (500 MHz, CDCl3)
; d 8.31 (t,
TOF) calcd for C13H13O3FBrþ [MþH]þ 315.0032, found 315.0026.
J¼1.5 Hz, 1H), 8.24 (d, J¼8.0 Hz, 1H), 7.80 (t, J¼8.0 Hz, 1H), 7.62 (t,
J¼8.0 Hz, 1H), 5.56 (dd, J¼12.0, 4.0 Hz, 1H), 5.29 (d, J¼1.5 Hz, 1H),
4.74 (dt, J¼47.0, 4.0 Hz, 2H), 4.27–4.12 (m, 2H), 2.88 (ddd, J¼17.3,
12.3, 1.5 Hz, 1H), 2.76 (dd, J¼17.3, 4.3 Hz, 1H); 13C NMR (125 MHz,
4.3.9. 4-(2-Fluoroethoxy)-6-(3-tolyl)-5,6-dihydro-2H-pyran-
2-one (4j)
Yield 21.3%; white solid; IR (neat) nmax 1711, 1625, 1391, 1291,
CDCl3)
d
170.6, 165.5, 148.3, 140.1, 131.9, 129.9, 123.6, 120.9, 91.5,
1225, 1072, 924, 885 cmꢀ1 1H NMR (500 MHz, CDCl3)
; d 7.30–7.25
80.5 (JCF¼172 Hz), 75.7, 68.1 (JCF¼20 Hz), 34.7; MS (ESI-TOF) calcd
(m, 2H), 7.18 (t, J¼9.0 Hz, 2H), 5.42 (dd, J¼12.0, 4.0 Hz, 1H), 5.24 (d,
J¼2.0 Hz, 1H), 4.74 (dt, J¼47.5, 4.0 Hz, 2H), 4.24–4.09 (m, 2H), 2.87
(ddd, J¼17.0, 12.0, 1.5 Hz, 1H), 2.66 (dd. J¼17.0, 4.0 Hz, 1H); 13C NMR
for C13H13O5NFþ [MþH]þ 282.0778, found 282.0772.
4.3.4. 6-(4-Acetylphenyl)-4-(2-fluoroethoxy)-5,6-dihydro-2H-
pyran-2-one (4e)
(125 MHz, CDCl3) d 171.2, 166.5, 138.4, 137.9, 129.3, 128.5, 126.6,
122.9, 91.4, 80.5 (JCF¼171 Hz), 77.1, 67.8 (JCF¼20 Hz), 34.9, 21.3; MS
Yield 57.6%; yellow oil; IR (neat) nmax 1711, 1681, 1625, 1360,
(ESI-TOF) calcd for C14H16O3F [MþH]þ 251.1083, found 251.1083.
1270, 1227, 1074, 603 cmꢀ1 1H NMR (500 MHz, CDCl3)
; d 7.99 (d,
J¼8.0 Hz, 2H), 7.52 (d, J¼8.0 Hz, 2H), 5.51 (dd, J¼12.0, 4.0 Hz, 1H),
5.26 (d, J¼1.5 Hz, 1H), 4.73 (dt, J¼47.0, 4.0 Hz, 2H), 4.25–4.10 (m,
2H), 2.84 (ddd, J¼17.0, 12.0, 1.5 Hz, 1H), 2.71 (dd, J¼17.0, 4.0 Hz, 1H),
4.3.10. 6-(3-Anisyl)-4-(2-fluoroethoxy)-5,6-dihydro-2H-pyran-2-
one (4k)
Yield 39.1%; white solid; IR (neat) nmax 1710, 1624, 1458, 1392,
2.61 (s, 3H); 13C NMR (125 MHz, CDCl3)
d
197.4, 170.8, 165.9, 143.0,
1226, 1045, 924, 884 cmꢀ1 1H NMR (500 MHz, CDCl3)
; d 7.31 (t,

G.S. Creech et al. / Tetrahedron 64 (2008) 6935–6942
6941
10. For a review on bifunctional catalysis, see: (a) Shibasaki, M.; Sasai, H.; Arai, T.
Angew. Chem., Int. Ed. 1997, 36, 1236; For examples, see: (b) Hiemstra, H.;
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Chem. Soc. 2005, 127, 16762.
J¼8.3 Hz, 1H), 6.98–6.96 (m, 2H), 6.90 (dd, J¼8.5, 2.0 Hz, 1H), 5.43
(dd, J¼12.0, 4.0 Hz, 1H), 5.24 (d, J¼1.5 Hz, 1H), 4.73 (dt, J¼47.0,
4.0 Hz, 2H), 4.24–4.10 (m, 2H), 3.83 (s, 3H), 2.87 (ddd, J¼17.3, 12.3,
1.5 Hz, 1H), 2.67 (dd, J¼17.0, 4.0 Hz, 1H); 13C NMR (125 MHz, CDCl3)
11. (a) Oishi, T.; Oguri, H.; Hirama, M. Tetrahedron: Asymmetry 1995, 6, 1241; (b)
d
171.1, 166.4, 159.8, 139.5, 129.7, 118.0, 114.2, 111.3, 91.4, 80.5
´
Marko, I. E.; Giles, P. R.; Hindley, N. J. Tetrahedron 1997, 53, 1015; (c) Barrett, A.
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G. M.; Cook, A. S.; Kamimura, A. Chem. Commun. 1998, 2533; (d) Iwabuchi, Y.;
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4.3.11. 4-(2-Fluoroethoxy)-6-(3-pyridyl)-5,6-dihydro-2H-pyran-2-
one (4l)
Yield 68.4%; yellow oil; IR (neat) nmax 1710, 1622, 1392, 1228,
1076, 1023, 916, 820 cmꢀ1 1H NMR (500 MHz, CDCl3)
; d 8.66 (d,
J¼2.0 Hz, 1H), 8.63 (dd, J¼4.5, 1.5 Hz, 1H), 7.83 (dt, J¼8.0, 1.8 Hz, 1H),
7.38 (dd, J¼8.0, 4.5 Hz, 1H), 5.55 (dd, 12.5, 4.0 Hz, 1H), 5.31 (d,
J¼1.5 Hz, 1H), 4.74 (dt, J¼47.0, 4.0 Hz, 2H), 4.26–4.11 (m, 2H), 2.89
(ddd, J¼17.0, 12.0, 1.5 Hz, 1H), 2.71 (dd, 17.5, 4.0 Hz, 1H); 13C NMR
(125 MHz, CDCl3) d 170.8,165.8,150.0,147.4,133.8,133.7,123.6, 91.5,
80.4 (JCF¼171.5 Hz), 74.8, 68.0 (JCF¼20 Hz), 34.5; MS (ESI-TOF) calcd
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for C12H13O3NF [MþH]þ 238.0879, found 238.0868.
Acknowledgements
This study was supported by the NIH (R01GM071779 and
P41GM081282). T.D. thanks the Research Corporation (Cottrell
College Science Award), the Natural Sciences and Engineering
Research Council of Canada (NSERC), the Canada Foundation for
Innovation (CFI), and Merck for financial support. We thank Dr.
Saeed Khan for performing the X-ray crystallographic analysis.
References and notes
1. For a review of dual activation, see: Ma, J.-A.; Cahard, D. Angew. Chem., Int. Ed.
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G.S. Creech et al. / Tetrahedron 64 (2008) 6935–6942
20. It is noted that an energetically less favorable twisted-dienolate minimum,
originating from MeOH-mediated hydrogen bond stabilization, possessing
publication no. CCDC 675758. Copies of the data can be obtained, free of charge,
on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax: þ44
(0)1223–336033; e-mail: deposit@ccdc.cam.ac.uk).
a conjugated
p-system perturbed from what is an optimal syn-periplanar ge-
ometry was obtained from this PES-study. The reaction barrier for aldehyde
addition to this intermediate was, however, calculated to be more endergonic
than the aldehyde addition modes computed to date for 5 and 5a; conse-
quently, it does not contribute to a productive pathway.
24. (a) Ripin, D. H.; Evans, D.A. Table of pKa values compiled for Chem 206. http://
daecr1.harvard.edu/pdf/evans_p-Ka_table.pdf (accessed online). (b) Williams,
R.; Jencks, W.P.; Westheimer, F.H. Table of pKa values. www.webqc.org/pka-
constants.php (accessed online). (c) Dalby, K. N.; Kirby, A. J.; Hollfelder, F.
21. We are currently investigating the subsequent aldehyde addition to elucidate
the complete mechanism of dihydropyrone formation.
22. The non-cyclized product, once isolated, did not undergo equilibration or cy-
clization when subjected to the reaction conditions.
23. Crystallographic data (excluding structure factors) for compound 4i have been
deposited with the Cambridge Crystallographic Data Centre as supplementary
J. Chem. Soc., Perkin Trans. 2 1993, 1269; (d) Calculated using Advanced
Chemistry Development (ACD/Labs) Software (v. 8.14) for Solaris (1994–2007
ACD/Labs); error reported as ꢁ0.10. (e) Menger, F. M.; Ladika, M. J. Am. Chem.
Soc. 1987, 109, 3145; (f) Nakagawa, Y.; Uehara, K.; Mizuno, N. Inorg. Chem. 2005,
44, 9068; (g) Textbook of Drug Design and Discovery, 3rd ed.; Krogsgaard-Larsen,
P., Liljefors, T., Madsen, U., Eds.; CRC: New York, NY, 2002; p 432.