DBU-Catalyzed Ring-Opening and Retro-Claisen Fragmentation of Dihydropyranones

Article abstract of DOI:10.1002/ejoc.202000858

We present a general protocol for the formal Michael addition of acetone to α,β-unsaturated esters and amides, a transformation difficult to perform using current methods. The protocol comprises of an amidine catalyzed relay ring-opening and fragmentation

Full text of DOI:10.1002/ejoc.202000858

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: DBU Catalyzed Ring-Opening and Retro-Claisen Fragmentation
of Dihydropyranones
Authors: anton Axelsson, Emmelie Hammarvid, Martin Rahm, and
Henrik Sundén
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202000858
Link to VoR: https://doi.org/10.1002/ejoc.202000858
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1/2020

European Journal of Organic Chemistry
10.1002/ejoc.202000858
FULL PAPER
DBU Catalyzed Ring-Opening and Retro-Claisen Fragmentation of
Dihydropyranones
[
a,b]
[a]
[a]
[a,c]
Dr. Anton Axelsson , Ms. Emmelie Hammarvid , Dr. Martin Rahm * and Dr. Henrik Sundén
*
[a]
[b]
[c]
Chemistry and Chemical Engineering, Chalmers University of Technology, Kemivägen 10, 412 96 Göteborg, Sweden
Current affiliation Department of Chemistry, KTH Royal Institute of Technology, Teknikringen 30, 100 44 Stockholm, Sweden
Current affiliation Department of Chemistry and Molecular Biology, University of Gothenburg, Kemivägen 10, 412 96 Göteborg, Sweden
E-mail: *henrik.sunden@chem.gu.se *martin.rahm@chalmers.se
Supporting information for this article is given via a link at the end of the document.
Abstract: We present a general protocol for the formal Michael
A Prevalence of dihydropyranones
O
O
addition of acetone to α,β-unsaturated esters and amides,
a
O
O
transformation difficult to perform using current methods. The protocol
comprises of an amidine catalyzed relay ring-opening and
fragmentation of 3,4-dihydropyranones. The reaction proceeds under
mild conditions, has a broad substrate scope and the products can be
isolated in good to excellent yields. The method can be applied to
homochiral substrates with total preservation of chiral information,
generating products in high optical purity. Kinetic experiments
supported by quantum chemical modeling indicate a mechanism in
which the catalyst takes a bifunctional role, acting both as a Brønsted
base and as a hydrogen bond donor.
3
,4 Dihydropyranone
5,6 Dihydropyranone
AcO
O
O
O
O
H
O
O
O
O
O
H
OH
O
H
O
H
HO
HO
OH
OH
H
Nepetalactone
Cat attractant
Neocucurbitacin A
Inhibits osteogenesis
Aspyrone
Antibiotic
Goniodiol
Cytotoxic
B Synthesis of 3,4-dihydropyranones
O
O
O
NHC-catalyst
[O]
Studer
010
+
R1
H
R2
R3
O
2
O
O
O
O
R1
R3
O
O
Isothiourea
catalyst
Schmidt
011, 2013
O
O
2
+
R2
R3
R2
1R
R1
O
R1
R2
Introduction
O
1. Prolinol catalyst
2. PCC
O
Ma
008
R1
R3
2
R4
+
R4
H
O
R2
R3
The Michael reaction is one of the most well-known and important
reactions in synthetic organic chemistry.[1] During the last three
decades a variety of catalytic methods for asymmetric Michael
additions have been developed.[2] Despite the progress, some
issues remain unsolved. For example, in reactions with
O
Scheme 1. Structure, biological activity and synthesis of dihydropyranones.
unactivated Michael acceptors, such as a,b-unsaturated esters or
amides, poor reactivity is observed due to low electrophilicity.[3] In
Unfortunately, the corresponding valorization of 3,4-
dihydropyranones remains scarce, despite several potential sites
for further manipulation. Which is surprising considering the
addition to problematic electrophiles, some nucleophiles have
also proven challenging in asymmetric Michael reactions.
Acetone is a notorious example of a difficult nucleophile. Direct
Michael addition of acetone is possible only with highly activated
recent surge in organocatalytic methods yielding 3,4-
[10]
dihydropyranones.
For example, in a pioneering report from
Studer et al. enals were shown to react with 1,3-carbonyls via
oxidative N-heterocyclic carbene (NHC) catalysis yielding 3,4-
dihydropyranones (Scheme 1 B).[ Since then, a plethora of
NHC-catalyzed reactions yielding homochiral dihydropyranones
11]
electrophiles such as nitroolefins and a thiourea-based catalyst or
by indirect methods using RAMP/SAMP auxiliaries.[4] Here, we
[12]
have been reported based on both oxidative and redox neutral
describe the DBU catalyzed ring opening/retro-Claisen
fragmentation of dihydropyranones for the formal addition of
acetone to unactivated Michael acceptors. The protocol is highly
modular and allows for asymmetric synthesis of both
oxohexanoates and oxohexanamides.
[
13]
pathways.
oxidant has been reported.[
toward the dihydropyranones involve activation of anhydrides with
Lately, several strategies that uses oxygen as
13e, 14]
Other organocatalytic methods
[15]
isothioureas, as reported by Smith and coworkers,
and
enamine catalysis-oxidation sequences as reported by Ma et
al.[16]
The dihydropyranone is an intriguing structural moiety that is
found in several natural products and biologically active
molecules (Scheme 1 A). For instance, the cat attractant
Nepetalactone and osteogenenesis inhibitor Neocucurbitacin A,
Clearly, the discovery of new general methods for
derivatization of 3,4-dihydropyranones would be beneficial. While
some reactions already have been reported, these are often
single substrate examples. For instance, both Smith et al. and our
[5]
isolated from catnip and Luffa operculta respectively, both contain
group have observed facile ring-opening with methanol when
6]
a
3,4-dihydropyranone moeity.[
The 5,6-dihydropyranone
[14a, 15b]
using Brønsted bases (Scheme 2 A).
Huang et al. have
scaffold is also prevalent in natural products, as seen in the
shown that it is possible to extend this type of reaction by treating
antibiotic Aspyrone and the cytotoxic Goniodiol.[7] Furthermore,
the acyclic ester with either hydrazine or hydroxylamine, yielding
the 5,6-dihydropyranone moiety has proven a useful synthon for
[14c]
pyrazoles or isoxazoles respectively.
A diastereoselective
further manipulation[ and
8]
a
valuable intermediate for the
epoxidation of the enol double bond using m-CPBA with only
slight erosion of enantiopurity was developed by
synthesis of natural products.[9]
1
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European Journal of Organic Chemistry
10.1002/ejoc.202000858
FULL PAPER
A
formation of 2, and yields 3 as the sole product in >90% yield
(Table 1, entries 4–6). Dihydropyranone 1 is stable in methanol in
the absence of base, and no ring-opening is observed after 1h.
Ring-opening
O
O
O
Brønsted
bases
O
O
O
N2H4 or NH2OH
78 °C
Our attempts to replace methanol as solvent was
accompanied with drastically reduced yields (Table 1). When
acetonitrile or toluene was used together with 5 eq. of MeOH this
resulted in selective formation of 3 over 2. Protic nucleophilic
solvents also proved challenging. With water or isopropanol as
the reaction solvent the retro-Claisen reaction was impeded,
yielding the diketone-carboxylic acid or isopropyl ester in >90%
yield respectively (Table 1, entries 9–10). When ethanol was used
as a solvent the corresponding 5-oxoester could be obtained,
albeit in approximately 10% yield after 24h, leaving the dioxoester
as the main product (ca 90% yield, Table 1, entry 11).
O
O
MeOH, rt
N
X
O
Smith,
Sundén
Huang
X= NH or O
B
O
O
Epoxidation
O
O
m-CPBA
0 °C
O
4
O
O
C
Alkylation
O
O
O
BnBr
LiHMDS
O
O
Having identified mild conditions for the synthesis of 5-
oxo-hexanoates, we proceeded to evaluate the scope of the
reaction with respect to the dihydropyranones (Scheme 3). The
reaction works well with electron donating substituents on the
phenyl ring (5, 6, 11) and 4-tolyl substituted 5-oxo-hexanoate 6
could be isolated in 80% yield. The reaction also proceeds
smoothly with dihydropyranones with electron withdrawing
substituents (7–9). For example, fluorinated 5-oxo-hexanoate 8
was obtained in 81% yield. Bulky substituents at the 2-position is
tolerated, and 9-anthracenyl (10) and 2-methoxyphenyl (11)
substituted 5-oxo-hexanoates could be isolated in 64% and 77%
yield respectively. Alkyl substitution at the 5-position is possible,
and methyl substituted 12 could be isolated in 84% yield.
-
78 °C
t-BuO
O
t-BuO
D
O
This work
O
O
O
R
1
O
O
DBU
+
3R
R3
+
R1
R2
XH
2R
X
O
MeOH, rt
X= NR or O
O
O
R1
O
O
R3
+
R3
X
R1
X
modular positions
Difficult
nucleophile
Difficult
electrophile
X= NR or O
Valuable products
High yields
Mild conditions
Mechanistic insight
Table 1. Screening of reaction conditions.
Scheme 2. Reactivity of dihydropyranones.
O
O
O
DBU (15 mol%)
MeOH, rt
O
O
Chi and coworkers (Scheme
2
B).[12c] Diastereoselective
O
O
2, 89%
alkylation of the corresponding lithium enolate with benzyl
bromide has been reported by Evans et al. (Scheme 2 C).[17]
Recently, an oxidative ring contraction of dihydropyranones was
reported.[
DBU (10 mol%)
4 (10 mol%)
O
O
1
18]
MeOH, rt
3
, 95%
O
Intrigued by the potential of the 3,4-dihydropyranones
as starting points for further synthesis, we set out to expand on
the synthetic utility of this neglected synthon. Here, we describe
our efforts towards developing a formal addition of acetone to
I
N
N
N
N
N
N
N
H
N
N
N
N
4
DBU
TBD
DABCO
Et3N
unactivated Michael acceptors by ring-opening and fragmentation
Yield (2, %)a
of 3,4-dihydropyranones (Scheme 2, D).[19]
Entry
Deviation from standard conditions
None
1
2
3
4
5
.
.
.
.
.
89b
83
84
0
TBD instead of DBU
KOH instead of DBU
DABCO instead of DBU
Results and Discussion
Reaction optimization and scope
While examining the ring-opening of dihydropyranone 1,
a striking difference in reactivity was observed upon slight
variation of reaction conditions (Table 1). Treatment with
Et
3
N instead of DBU
0
6
.
K
2
CO
3
instead of DBU
0
equimolar amounts of NHC precatalyst
4
and 1,8-
7.c
MeCN instead of MeOH
PhMe instead of MeOH
Water instead of MeOH
IPA instead of MeOH
EtOH instead of MeOH
0
diazabicyclo[5.4.0]undec-7-ene (DBU) in methanol yielded the
ring-opened dioxoester 3 in 95 % yield, as previously reported.[14a]
However, usage of slightly higher loadings of DBU (15 mol%) in
absence of 4 yielded compound 2 in 89% isolated yield. A
stoichiometric amount of methyl acetate was also detected in the
8
9
.c
0
.d
0
0
1
10.
d
crude reaction mixture by H NMR, suggesting that 2 is formed
via a retro-Claisen fragmentation of the 1,3-diketone of compound
1
1.d
~10%
[20]
3
.
Fascinated by the difference in reactivity, we optimized the
reaction further with respect to oxoester 2. As it turns out, both the
structurally related guanidine base 1,5,7- triazabicyclo[4.4.0]dec-
a1 (0.12 mmol), base (0.15 eq.) solvent (0.4 mL), stirred at ambient temperature
for 24h. Yield determined by 1H NMR using 1,2,4,5-tetramethylbenzene as
b
c
d
5
-ene (TBD) and potassium hydroxide are capable of mediating
internal standard. Isolated yield. 5 equivalents of MeOH added. Based on the
corresponding carboxylic acid, isopropyl ester or ethyl ester as the product
respectively.
the reaction, yielding 2 in slightly lower yields than DBU (Table 1,
entries 2–3). Weaker bases such as nucleophilic 1,4-
diazabicyclo[2.2.2]octane
(DABCO),
non-nucleophilic
triethylamine and potassium carbonate does not allow for the
2
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European Journal of Organic Chemistry
10.1002/ejoc.202000858
FULL PAPER
O
Dihydropyranones with larger alkyl groups in the 5-
O
O
1. Nucleophile
O
O
O
position reacts considerably slower. For example, a propyl
substituted dihydropyranone yielded a mixture of 13 and the
corresponding dioxyester, which proved difficult to separate.
Dimethylated dihydropyranones are tolerated by the reaction but
required slightly higher loadings of DBU (25 mol%). With the latter
modification product 14, which represents the formal total
synthesis of the plant hormone abscisic acid,[21] could be obtained
in 76% yield. Introducing longer alkyl substituents in the 3- and 4-
positions results in sluggish reactions. However, by increasing the
reaction temperature to 70 °C, 5-oxo-heptanoate 15 could be
isolated in 81% yield. In contrast, dihydropyranones with aromatic
substituents in the 3- and 4-position readily react at room
temperature and 16 could be isolated in 77% yield. Lastly, the
reaction of dihydropyranone 17, which may yield two different
products, was investigated. Product 16 and 2 was formed in a
2. DBU, MeOH
+
+
3R
R3
X
XH
O
rt
1
O
O
O
O
O
O
O
O
N
N
N
N
N
21, 96%a
8, 96%a
19, 97%a
O
20, 89%a
1
O
O
O
O
O
O
O
O
O
N
H
N
N
H
N
25, 93%a
22, 91%a
23, 89%a,b
24, 91%a
O
O
O
O
O
O
O
O
1
.7:1 under the developed reaction conditions.
N
H
O
O
OH
Next, we investigated if the ring-opening of
2
6, 96%a
27, 86%c
28, 90%d
29, 53%e
dihydropyranones could be performed with nucleophiles other
than methanol. As it turns out, it is possible to obtain a wide range
of amides in excellent yields (Scheme 4) by reacting
dihydropyranone 1 with an amine, followed by addition of
methanol and DBU. Cyclic amines are well suited for the
transformation as shown in Scheme 4. For example, piperidine,
morpholine, 1-methylpiperazine and pyrrolidine could be used to
synthesize compounds 18–21 in 96%, 97%, 89% and 96% yield,
respectively.
Scheme 4. Scope with respect to the nucleophile. a1 (1.0 eq), amine (1.1–2.0
eq.) 2–12h. Then MeOH and DBU (0.15 eq.), stirred at ambient temperature.
Isolated yield. bThe corresponding hydrochloride salt was used as nucleophile
c
and were neutralized with an equimolar amount of DBU in DCM. Performed in
d
e
EtOH at 70 °C. 1 (1.eq.), KOH(aq) as nucleophile (2.1 eq). Salicylaldehyde (1.5
eq.) as nucleophile using 1.5 eq. of DBU.
reaction to 70 °C, yielding 27 in 86% yield. Attempts to access
Acyclic secondary amines proved viable nucleophiles
and the use of diethylamine yielded amide 22 in 91% yield. The
developed procedure also proved suitable for the construction of
synthetically useful Weinreb amides exemplified with the
synthesis of compound 23, obtained in 89% yield. Several primary
amines can also be used as reagents (24–26). For example,
cyclohexylamine and aniline derived amides 25 and 26, which
could be isolated in 93% and 96% yield, respectively. It was also
discovered, contrary to the optimization results (Table 1, entry 11)
that the corresponding ethyl ester can be obtained by using
ethanol as the solvent and heating the
iso-propyl or tert-butyl esters in
a similar manner were
unsuccessful. It is also possible to obtain the carboxylic acid
product by using aqueous KOH as nucleophile, and 28 was
obtained in 90% yield. Using salicylaldehyde as the nucleophile
together with stochiometric amount of DBU yielded substituted
coumarin 29 in 53% yield. Presumably via acylation, aldol
condensation and retro-Claisen fragmentation. It is worth noting
that compound 29 is only one 4-hydroxyl substituent on the
[22]
coumarin
motif
from
the
anticoagulant
warfarin.
We also investigated the possibility of obtaining these
valuable products in optically pure form (Scheme 5). By relying on
our aerobic oxidative protocol for synthesis of dihydropyranones,
O
O
O
O
R
1
O
O
(S)-1 could be obtained in good yield and 94% ee on gram
DBU
R1
R2
R2
+
2R
O
[14a]
O
scale.
Treatment of (S)-1 with DBU under standard conditions
MeOH, rt
R2
gave (S)-2 in 85% yield with almost complete preservation of
enantiomeric excess (92% ee, Scheme 5). Chiral aminoalcohols
are also viable reaction partners and (S)-prolinol, (S)-valinol, (S)-
tryptophanol and (S)-isoleucinol could be used to synthesize the
corresponding 5-oxo-hexanamides in 87–96% yield. An indanol
OMe
Cl
F
O
O
O
O
O
O
O
O
O
O
O
O
5, 75%
6, 80%
7, 76%
8, 81%
NO2
O
O
O
O
O
O
1. Amine, DCM
+
3R XH
2. DBU, MeOH
rt
R3
X
+
O
O
O
O
O
O
O
O
O
O
O
O
O
9, 68%
1
0, 64%
OMe
11, 77%
12, 84%
(S)-1, 94% ee
O
O
O
O
O
O
O
O
OH
O
O
O
O
O
O
O
O
N
OH
O
O
1
3, Complex mixture
14, 76%a
1
5, 81%b
16, 77%
OMe
N
H
(
S)-2, 85%, 92% eea
30, 96%, > 20:1 drb
31, 93%, > 20:1 drb
O
O
DBU
MeOH, rt
O
O
O
O
+
O
O
OH NH
OH
O
HO
O
O
O
O
O
O
16, 62%a
2, 36%a
1
7
N
H
N
H
N
H
3
2, 95%, > 20:1 drb
33, 87%, > 20:1 drb
34, 92%, > 20:1 drb
Scheme 3. Scope with respect to the dihydropyranone. Dihydropyranone (1.0
Scheme 5. Synthesis of homochiral products. (S)-1 (1.0 eq), MeOH and DBU
a
(0.15 eq.), stirred at ambient temperature. Isolated yield. b(S)-1 (1.0 eq),
aminoalcohol (1.0–1.4 eq.), dichloromethane, stirred overnight. Then MeOH
and DBU (0.15 eq.), stirred at ambient temperature. Isolated yield.
eq.), DBU (0.15 eq.), MeOH stirred at ambient temperature, isolated yield.
a
b
Using DBU (0.25 eq.) for 48h. Performed at 70 °C
1
Diastereomeric ratio (dr) determined by H NMR of crude reaction mixture.
3
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European Journal of Organic Chemistry
10.1002/ejoc.202000858
FULL PAPER
O
based aminoalcohol also proved a competent nucleophile yielding
product 34 in 92% yield. All reactions proceeded with excellent
chemo- and diastereoselectivity without noticeable racemization.
O
O
DBU (15 mol%)
MeOH-d4
O
O
DBU (15 mol%)
MeOH
O
O
O
O
2
2
Investigation of the reaction mechanism
1
To gain further insight into the reaction mechanism, the
reaction was monitored using a gas chromatograph equipped with
a flame ionization detector (GC-FID). The concentration profile of
a reaction shown in Figure 1. The reaction used 0.3 eq. of DBU
to achieve greater conversion during the experiment. In the shown
experiment, the ring-opening of 1 to 3 was complete within
minutes at 297 K,[ while the transformation of 3 to 2 was
considerably slower. Plotting of ln[3] vs. time showed that the
H D
k /k =2.3
Scheme 6. Determination of kinetic isotope effect.
The commonly accepted view is that C–C bond breakage is rate
determining for retro-Claisen fragmentations under alkaline
Combined, knowledge of a primary KIE and a
reaction order above 1 with respect to DBU made us wonder if
23]
[28]
conditions.
2
+
reaction is of the first order with respect to 3 (R =0.99, see Figure
both DBU and the corresponding acid (DBUH ) could be involved
S2 in ESI). Overall, the reaction follows first order kinetics since
the reaction order in 3 is one and the reaction is performed under
pseudo-first order conditions, with [MeOH]≫[3], the concentration
of DBU is constant and that the reaction of 1à3 is essentially
irreversible and considerably faster than 3à2.[24]
in the retro-Claisen reaction.
Two different mechanisms that allow for our
combination of experimental observations are proposed. In both
+
situations DBUH acts as a hydrogen bond donor (HBD) (path A
and B, c.f. Figure 2). Protonated amines are known to be strong
HBDs.[
29]
With HBD parameter values of a~5 they are, for
To study the retro-Claisen fragmentation in greater
detail the reaction of pre-formed 3 into 2 was studied at three
different loadings of DBU (0.15, 0.30 and 0.45 eq.). Plotting ln[3]
vs. time once again produced straight lines (Figure S3 in ESI),
which enabled us to determine the apparent rate (slope=kobs) for
the different reactions. We then used log-log plots to elucidate the
example, considerably stronger than alcohols (for aliphatic
alcohols, a~2.7.
[30]
In our proposed mechanisms, the DBU-catalyzed ring-
opening of dihydropyranone 1 with methanol to yield 3 occurs first,
which completes within minutes at room temperature (Figure 2).
The mechanism for the retro-Claisen fragmentation begins with
the deprotonation of methanol by DBU. The formed methoxide
then adds in a nucleophilic 1,2-addition to one of the ketones in
[25]
reaction order in DBU.
straight line (R =0.99) with a slope of 1.6 (Figure S4 in ESI),
indicating that the reaction is of the 1.6th order in DBU.
Plotting ln(rate) vs. ln[DBU] gave a
2
3
. And here is where the two mechanisms diverge, yielding either
A normal kinetic isotope effect (KIE, ꢀ ⁄ꢀ ) of 2.3 was
+
ꢀ
ꢁ
an anionic hemiacetal in which DBUH is coordinated to the
ketone (in path A) or to the anionic hemiacetal via hydrogen
bonding (in path B). We distinguish between these two complexes
by naming them 35 (in path A) and 37 (in path B). It is possible
that 35 and 37 are in equilibrium, but for clarity they are drawn as
separate catalytic cycles.
measured by running the reaction in MeOH and MeOH-d
4
(
Scheme 6). As a rule of thumb, deuterated hydrogen bonds are
[26]
weaker than their protonated counterpart.
A KIE of this size
suggests a primary effect, i.e. that a bond to hydrogen is directly
involved in the rate determining step. The measured value is too
large to be caused by several secondary KIEs.[27] The observed
kinetics (Figure 1) indicates that the rate determining step should
be part of the retro-Claisen fragmentation.
In path A, 35 collapses into the hydrogen bonded
enolate 36 and methyl acetate. Proton transfer between DBUH+
and the enolate subsequently yields product 2 and regenerates
DBU, completing the catalytic cycle. A similar mechanism has
O
O
previously been suggested in ring-opening polymerization
O
O
[31]
O
O
reactions.
In path B, 37, instead collapses to 38, a complex
O
O
different from 36 in that it lacks an explicit hydrogen bond to
O
O
+
1
2
DBUH . In path B it is instead the formed methyl acetate 39, which
3
is hydrogen bonded. Dissociation of complex 39 and subsequent
protonation of enolate 38 yields product 2 and regenerates DBU.
The type of mechanisms we are considering (A and B,
c.f. Figure 2) are both able to explain the observed first order
dependence in 3 and the 1.6th order dependence in DBU, the
primary KIE and the sensitivity towards sterical encumbrance
close to the 1,3-diketone moiety (c.f. products 13–15 and 27). So,
how can we determine which mechanism that is governing?
We used Density Functional Theory (DFT) calculations
to evaluate the effect of the catalyst and which of the two
considered pathways is more likely. The calculations were
performed using the Gaussian 16 package, revision B.01.[
Geometry optimizations and frequency analyses were performed
at the ωB97X-D/6-311+G(2d,p) level of theory. Final single point
energies were computed using the larger 6-311++G(2df,2pd)
basis set. Implicit consideration of solvent effects in methanol was
included through the Solvation Model based on Density (SMD)
method in all calculations.[ The dispersion-corrected and range-
separated hybrid functional ωB97X-D has previously been
successfully used together with Pople-style basis sets to model
organocatalytic reactions were hydrogen bonding is important,
including hydrogen bonding involving amine superbases such as
DBU.[
32]
33]
Figure 1. Example concentration profile for the reaction of 1 yielding 2. The ring-
opening of 1 to yield 3 is very rapid, while the retro-Claisen fragmentation of 3
to give 2 is considerably slower. The experiment was run with 0.3 eq. of DBU
34]
as catalyst.
4
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European Journal of Organic Chemistry
10.1002/ejoc.202000858
FULL PAPER
Path A
Hydrogen bond
O
O
N
MeOH
O
2
N
DBU
N
N
N
H
+
MeO
O
O
O
N
H
O
3
6
O
O
3
O
MeO
O
O
O
MeOAc
RDS
O
O
3
5
O
DBU
O
H
N
1
O
O
+
MeOH
N
Path B
Ion pair
O
O
O
N
MeOH
2
Figure 3. Computed free energy (298.15 K, 1M) diagram for path A-C. A
superscript C (X ) denotes the corresponding structures without coordination of
N
C
DBU
N
NH
DBUH+. Energies relative to the 1,3-diketone 3 and free MeOH are shown in
kcal/mol.
N
+
MeO
O
average error of the ωB97X-D functional for predicting general
O
O
N
H
[69,35,33c]
reaction barriers is ~1.5 kcal/mol)
However, error
N
O
N
cancellation is expected to play an important role when comparing
the relative energies of such similar transition states. To verify our
predictions the transitions state energies were re-calculated using
the M06-2X-D3 DFT functional with similar results (see Table S20
3
8
H
O
O
3
O
O
O
O
RDS
O
O
3
9
3
7
O
OMe
DBU
[36]
O
in the ESI). We note that the identified lowest reaction barrier
H
N
1
O
O
of ~18 kcal/mol is in good qualitative agreement with experiment,
as it infers a reasonable reaction rate near room temperature
(reaction time ∼24h).
+
MeOH
N
Figure 2. Two proposed mechanism for the ring-opening and fragmentation of
dihydropyranones. Both options are in agreement with experimental data. RDS
Conformational sampling is one possible source of
error. In addition to the rate determining steps outlined in Figure
=
rate determining step.
3
, we have carefully evaluated a large number of other competing
The transformation of 1 into 2 was chosen as a model
possibilities, including several that have been suggested for
related processes (for a discussion see ESI S18-S21). These
include considering synchronous protonation of the enolate/C–C
bond breakage, synchronous deprotonation of the neutral
hemiacetal/C–C bond breakage, intramolecular proton transfer,
formation of acyl ammonium species by a Lewis base mechanism
as suggested by Wolf et al. for a related process, and a cyclic
TS as suggested in Lewis acid catalyzed retro-Claisen
reactions.
higher in free energy (typically ∆ꢁ >30 kcal/mol, see figure S10).
The proposed dual role of DBU, as both a strong base and a
potent HBD, represent a new mode of activation for retro-Claisen
processes.
reaction in our calculation. We considered three different
+
mechanisms – path A in which DBUH coordinates to the ketone
Figure 3, green line), path B where DBUH+ coordinates to the
(
anionic hemiacetal (Figure 3, blue line) and path C, in which
DBUH takes no part (Figure 3, red line).
+
0
The calculated difference in Gibbs energy (∆G ) for the
[37]
first step, the exergonic ring-opening of 1 to yield 3, is −10.3
kcal/mol. The value agrees with observations showing that the
[38]
The alternatives mentioned calculate as distinctly
concentration of 1 is close to zero throughout the reaction (Figure
‡
C
1
). Formation of the anionic hemiacetals (35, 35 or 37) is
significantly endergonic relative to 3. The ion-paired structure 37
calculates as 0.7 kcal/mol lower in energy compared to the
C
uncoordinated 35 and 1.4 kcal/mol below hydrogen bonded 35.
The C-C bond breakage step, e.g. 35 ➝ 36, is exergonic
relative the anionic hemiacetal in all three cases, but to what
extent varies considerably (Figure 3). Our calculations for this
step might be less exact due to the separate implicit solvation
The former energy difference is an estimate of the hydrogen bond
+
strength between the hemiacetal and DBUH . Because we are
relying on implicit models to account for solvation effects, we must
stress that the estimate is approximative. Our calculations are
+
+
treatment of the formed DBUH –ester complex. Fortunately, the
sensitive to the solvation energy of DBUH . More accurately
step is inconsequential for determining the governing reaction
mechanism. In the final step, all three competing mechanisms
proceed via protonation of the formed enolate to yield the product
estimates to solvation effects in general would require explicit
consideration of solvent molecules. Such calculations would
ideally rely on molecular dynamics simulations, which we
consider outside the scope of the current work.
(
2) and regenerate DBU. Relative to 3, the overall process is
thermodynamically downhill by ~15 kcal/mol. We should also add
that our results do not demand that the coordination of DBUH is
constant during the reaction, i.e. 35 might form, rearrange to 37
and react via TS . The situation is analogous with a reaction
The third step is where the rate determining C–C bond
+
A
cleavage takes place. Transition state TS calculates as lowest in
‡
free energy at ∆ꢁ =18.4 kcal/mol. Which is arguably in part due
A
+
B
to the hydrogen bonding interaction with DBUH (Figure 3). TS
[39]
under Curtin-Hammet control. Although both path A, B and C
‡
calculates as second to lowest, at ∆ꢁ =20.1 kcal/mol. Finally,
TS , which correspond to no DBUH -coordination, is predicted to
lie highest at ∆ꢁ =20.6 kcal/mol. The competing transition states
is deemed energetically possible our computational study
supports pathway A (Figure 3) as the main reaction path. How
can the conclusion be explained?
C
+
‡
are predicted to lie close in energy, and near, in fact, to the
accuracy of the used DFT method (the estimated
One way to rationalize the outcome is by analyzing the
intermediates directly before and after the transition states. In
+
path A, coordination of DBUH destabilizes the anionic hemiacetal
5
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European Journal of Organic Chemistry
10.1002/ejoc.202000858
FULL PAPER
TSA
TSB
TSC
1
.77
2
.13
2
.10
2
.06
1
.78
‡
‡
‡
∆
" =18.4
∆" =20.1
∆" =20.6
Figure 5. Optimized structures and selected distances of TS , TS and TSC (in Å) together with Gibbs energy reaction barriers (298K, 1M, in kcal/mol).
A
B
but stabilizes the enolate as compared to path C, while the
opposite is true for path B. We note that the stabilization of 36
in path A (~4.5 kcal/mol compared to path C) is considerably
larger than the stabilization of 37 in path B (~0.7 kcal/mol
compared to path C). Hence, the only clearly favorable
and secondary, tertiary and Weinreb amides. The synthetic
approach enables access to chiral 5-oxo-hexanoates and
stereoselective functionalization of chiral aminoalcohols under
mild conditions.
Kinetic studies have revealed that the initial ring-
opening is rapid and completes within minutes at ambient
conditions, while the cleavage of the C–C bond in the
corresponding 1,3-diketone is slower. The breakage of the C–
C bond proceed in first order with respect to the 1,3-diketone
and with a reaction order above 1 with respect to the DBU
+
interaction between DBUH and the substrate is found in path
A. Moreover, it is worth noting that the length of the C–C bond
being broken in the rate determining transition state varies as
path A (2.06 Å) < path C (2.10 Å) < path B (2.13 Å), in
[40]
agreement with the Hammond postulate (Figure 5).
catalyst. These observations, together with
a measured
Another possible reason for the energetic ordering of
primary kinetic isotope effect, have led us to propose a
mechanism in which DBU acts both as a Brønsted base and a
hydrogen bond donor. A quantum chemical investigation
the transition states can be gleamed from their optimized
A
geometries. A closer look at the hydrogen bonds in TS and
B
TS shows that the O–H–N bond angle is close to the
+
supports the mechanism and suggests that DBUH lowers the
A
calculated optimal linear rearrangement (∠
= 177ꢂ°) in TS ,
ꢂꢀꢃ
activation barrier for the C–C bond scission by coordinating to
the ketone (Figure 3, path A). Our method provides access to
valuable compounds from readily available and previously
overlooked starting materials.ƒ
while in TSB the hydrogen bond is more skewed (∠
=
ꢂꢀꢃ
B
1
63ꢂ°). At the same time, the O–H distances in TSA and TS
are very similar (1.78 Å vs. 1.77 Å). The O–N distance is
B
A
slightly shorter in TS compared to in TS (2.81 Å vs. 2.77 Å).
An additional aspect that favors path A is interactions between
+
A
+
DBUH and the phenyl ring. In the favored TS , DBUH and the
phenyl ring adopts a slipped stacked conformation that lowers
the energy by ~1.3 kcal/mol (see comparison with unstacked
Experimental Section
D
TS in Figure S10 the ESI). However, path A remains the
Representative procedure for the synthesis of 5-
oxo-hexanoates. A pear-shaped flask, equipped with a
magnetic stirrer, was charged with 5-acetyl-6-methyl-4-phenyl-
3,4-dihydro-2H-pyran-2-one 1 (30.4 mg, 0.13 mmol) and
methanol (0.45 mL). The heterogenous mixture was gently
stirred and DBU (3.0 mg, 0.020 mmol) was added and the
mixture turned homogenous within one minute. The mixture
favored mechanisms even without the interactions associated
with the slipped stacked conformation shown in Figure 5.
Which is because the lost interaction (mainly dispersion) is
D
partly compensated by stronger hydrogen bonding in TS (DO-
= 1.73 Å in TSD vs. DO-H = 1.78 Å in TS , Figure S10 in the
A
H
ESI).
1
was stirred at ambient temperature and monitored via H NMR.
SUMMARY
When the reaction had reached completion (typically within 24
h), the crude reaction mixture was purified using the biotage
with a 100 % heptane followed by dichloromethane/methanol
solvent mixture (20 mL/min, 100% heptane, 100% DCM à 2%
methanol à 4 % methanol à 5 % methanol à 10% methanol
in dichloromethane). The product 2 was obtained as a clear oil
that slowly solidified into a white solid (25.7 mg, 0.12 mmol, 89
We have presented a method for the formal addition
of acetone to unactivated Michael acceptors. Until now, the use
of acetone and unactivated Michael acceptors have been
plagued by low selectivity and low reactivity, respectively. Our
method consists of DBU-catalyzed ring-opening and retro-
Claisen fragmentation of 3,4-dihydropyranones and produces
%
).
5
-oxo-hexanoates and 5-oxo-hexanamides in good to
excellent yields. The reaction is compatible with a wide range
of nucleophiles, providing access to esters, carboxylic acids,
Note: The reaction is sensitive to any traces of
Brønsted acids. 1 is prone toward hydrolysis, especially if
6
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.202000858
FULL PAPER
exposed to “wet” solvents or ambient atmosphere for a
prolonged period of time. The product of the hydrolysis is the
corresponding carboxylic acid, which seriously impedes the
reaction. To avoid hydrolysis, 1 should be stored at -18 °C and
time spent at temperatures above -18 °C should be kept to a
minimum.
Technol. 2012, 2, 42-53; e) P. Chauhan, S. Mahajan, U. Kaya,
D. Hack, D. Enders, Adv. Synth. Catal. 2015, 357, 253-281.
a) A. J. M. Farley, C. Sandford, D. J. Dixon, J. Am. Chem. Soc.
[
3]
2
015, 137, 15992-15995; b) J. Yang, A. J. M. Farley, D. J. Dixon,
Chem. Sci. 2017, 8, 606-610; c) S. Matsunaga, T. Kinoshita, S.
Okada, S. Harada, M. Shibasaki, J. Am. Chem. Soc. 2004, 126,
7
559-7570; d) D. S. Allgäuer, H. Jangra, H. Asahara, Z. Li, Q.
Chen, H. Zipse, A. R. Ofial, H. Mayr, J. Am. Chem. Soc. 2017,
139, 13318-13329.
a) S. B. Tsogoeva, D. A. Yalalov, M. J. Hateley, C. Weckbecker,
K. Huthmacher, Eur. J. Org. Chem. 2005, 2005, 4995-5000; b)
S. B. Tsogoeva, S. Wei, Chem. Commun. 2006, 1451-1453; c)
H. Huang, E. N. Jacobsen, J. Am. Chem. Soc. 2006, 128, 7170-
Representative procedure for the synthesis of 5-
oxo-hexanamides. A pear-shaped flask, equipped with a
magnetic stirrer, was charged with 5-acetyl-6-methyl-4-phenyl-
[4]
3
,4-dihydro-2H-pyran-2-one 1 (36.2 mg, 0.16 mmol) and
cyclohexylamine (17.2 mg, 0.17 mmol, 1.1 eq.) (1.0-2.0 eq. of
amine used for the reported examples). The mixture was gently
stirred overnight. Methanol (0.52 mL) and DBU (3.6 mg, 0.023
mmol) were added and the mixture is stirred at ambient
7
171; d) T. Mandal, C. G. Zhao, Angew. Chem. Int. Ed. 2008,
47, 7714-7717; e) A. Lu, T. Liu, R. Wu, Y. Wang, G. Wu, Z. Zhou,
J. Fang, C. Tang, J. Org. Chem. 2011, 76, 3872-3879; f) T. Liu,
M. Zhou, T. Yuan, B. Fu, X. Wang, F. Peng, Z. Shao, Adv. Synth.
Catal. 2017, 359, 89-95; g) D. Enders, K. Papadopoulos,
Tetrahedron Lett. 1983, 24, 4967-4970.
1
temperature and monitored via H NMR. When the reaction
had reached completion (typically within 24 h), the crude
reaction mixture was purified using the biotage with a 100 %
heptane followed by dichloromethane/methanol solvent
mixture (20 mL/min, 100% heptane, 100% DCM à 2%
methanol à 4 % methanol à 5% methanol à 10% methanol
in dichloromethane). The product 24 was obtained as a white
solid (42.1 mg, 0.15 mmol, 93%). For solid or less nucleophilic
amines dichloromethane (0.6 M) was used as a solvent in the
first step, followed by removal of volatiles under reduced
pressure before addition of methanol and DBU. More
information about the variations can be found in the
characterization section of each compound.
[
5]
a) N. B. Pigni, S. Berkov, A. Elamrani, M.Benaissa, F. Viladomat,
C. Codina, J. Bastida, Molecules 2010, 15, 7083-7089; b) L.-X.
Chen, H. He, F. Qiu, Nat. Prod. Rep. 2011, 28, 705-740; c) F.
Shi, A.-X. Dai, S. Zhang, X.-H. Zhang, S.-J. Tu, Eur. J. Med.
Chem. 2011, 46, 953-960; d) J. A. Marco, M. Carda, in Natural
Lactones and Lactams: Synthesis, Occurrence and Biological
Activity, 1st ed. (Ed.: T. Janecki), Wiley-VCH, Germany, 2013.
a) S. M. McElvain, R. D. Bright, P. R. Johnson, J. Am. Chem.
Soc. 1941, 63, 1558-1563; b) N. Kawahara, A. Kurata, T.
Hakamatsuka, S. Sekita, M. Satake, Chem. Pharm. Bull. 2001,
[6]
4
9, 1377-1379.
[
[
[
[
7]
a) X.-P. Fang, J. E. Anderson, C.-J. Chang, J. L. McLaughlin, P.
E. Fanwick, J. Nat. Prod. 1991, 54, 1034-1043; b) T. Sugiyama,
T. Murayama, K. Yamashita, T. Oritani, Biosci. Biotechnol.
Biochem. 1995, 59, 1921-1924.
a) J. Tummatorn, G. B. Dudley, J. Am. Chem. Soc. 2008, 130,
5050-5051; b) A. Ortiz, T. Benkovics, G. L. Beutner, Z. Shi, M.
Bultman, J. Nye, C. Sfouggatakis, D. R. Kronenthal, Angew.
Chem. Int. Ed. 2015, 54, 7185-7188.
Note: Excess of amine impedes the C-C bond
scission of the 1,3-diketone, possibly via formation of the
corresponding enaminone. If a reaction does not react reach
full conversion repeating the reaction with lower loadings of the
amine might prove fruitful.
8]
9]
a) K. C. Nicolaou, Q. Kang, S. Y. Ng, D. Y. K. Chen, J. Am.
Chem. Soc. 2010, 132, 8219-8222; b) J. Shimokawa, T. Harada,
S. Yokoshima, T. Fukuyama, J. Am. Chem. Soc. 2011, 133,
1
7634-17637.
Gram scale synthesis 1. To a 200 mL round bottom flask was
added 1,4-dimethyl-4-H-1,2,4-trizole iodide 4 (174.2 mg, 0.77
mmol), tetrahydrofuran (70 mL), DBU (115.2 mg, 0.76 mmol),
and 3,3',5,5'-tetra-tert-butyl-[1,1'-bi(cyclohexylidene)]-2,2',5,5'-
tetraene-4,4'-dione (S1,310.1 mg, 0.76 mmol). The dark brown
mixture is stirred at ambient temperature for 5 minutes.
Pentane-2,4-dione (1136.1 mg, 11.35 mmol) and
cinnamaldehyde (1.00 gram, 7.57 mmol) were added and the
mixture was stirred for 5 minutes. To the stirring mixture was
added iron (II)phthalocyanine (431.8 mg, 0.76 mmol) and the
mixture was stirred overnight (18 h). The volatiles were
removed under reduced pressure and the crude mixture was
purified using manual flash-chromatography using ethyl
acetate/petroleum ether (40 °C–60 °C) 1:3 as the eluent. The
product 5-acetyl-6-methyl-4-phenyl-3,4-dihydro-2H-pyran-2-
one 1 was obtained as a white powder (1.390 g, 6.04 mmol,
10]
D. C. M. Albanese, N. Gaggero, Eur. J. Org. Chem. 2014, 2014,
5631-5640.
S. De Sarkar, A. Studer, Angew. Chem. Int. Ed. 2010, 49, 9266-
[11]
9
269.
[
12]
a) Z.-Q. Zhu, X.-L. Zheng, N.-F. Jiang, X. Wan, J.-C. Xiao, Chem.
Commun. 2011, 47, 8670-8672; b) Z.-Q. Rong, M.-Q. Jia, S.-L.
You, Org. Lett. 2011, 13, 4080-4083; c) J. Mo, L. Shen, Y. R.
Chi, Angew. Chem. Int. Ed. 2013, 52, 8588-8591.
[
13]
a) Z.-Q. Zhu, J.-C. Xiao, Adv. Synth. Catal. 2010, 352, 2455-
2
3
458; b) F. G. Sun, L. H. Sun, S. Ye, Adv. Synth. Catal. 2011,
53, 3134-3138; c) G. Wang, X. Chen, G. Miao, W. Yao, C. Ma,
J. Org. Chem. 2013, 78, 6223-6232; d) Q. Ni, J. Xiong, X. Song,
G. Raabe, D. Enders, Chem. Commun. 2015, 51, 14628-14631;
e) Y. Que, Y. Lu, W. Wang, Y. Wang, H. Wang, C. Yu, T. Li, X.-
S. Wang, S. Shen, C. Yao, Chem. Asian J. 2016, 11, 678-681.
a) A. Axelsson, E. Hammarvid, L. Ta, H. Sundén, Chem.
Commun. 2016, 52, 11571-11574; b) L. Ta, A. Axelsson, H.
Sundén, Green Chem. 2016, 18, 686-690; c) Q. Wang, J. Chen,
Y. Huang, Chem. Eur. J. 2018, 24, 12806-12810.
[
14]
8
0%).
[15]
a) D. Belmessieri, L. C. Morrill, C. Simal, A. M. Z. Slawin, A. D.
Smith, J. Am. Chem. Soc. 2011, 133, 2714-2720; b) E. R. T.
Robinson, C. Fallan, C. Simal, A. M. Z. Slawin, A. D. Smith,
Chem. Sci. 2013, 4, 2193-2200.
ACKNOWLEDGMENT
[16]
J. Wang, F. Yu, X. Zhang, D. Ma, Org. Lett. 2008, 10, 2561-2564.
D. A. Evans, R. J. Thomson, F. Franco, J. Am. Chem. Soc.
1
7]
Funding from the Swedish Research Council (VR 2014-04664
and Formas 2016-00484) is gratefully acknowledged. The
research relied on computational resources provided by the
Swedish National Infrastructure for Computing (SNIC) at
C3SE.
2
005, 127, 10816-1081.
[18]
R. Dagenais, T. Lussier, C. Y. Legault, Org. Lett. 2019 21,
5290-5294
A. Axelsson, E. Hammarvid, M. Rahm, H. Sundén, Formal
Addition of Acetone to Unactivated Michael Acceptors via Ring-
[
[
19]
20]
Opening
and
Retro-Claisen
Fragmentation
of
Dihydropyranones, 2019. ChemRxiv. Preprint.
https://doi.org/10.26434/chemrxiv.9822575.v1
a) W. C. Han, K. Takahashi, J. M. Cook, U. Weiss, J. V. Silverton,
J. Am. Chem. Soc. 1982, 104, 318-321; b) R. Visbal, A. Laguna,
M. C. Gimeno, Chem. Eur. J. 2016 , 22 , 4189; c) Y. Zhu, L.
Zhang, S. Luo, J. Am. Chem. Soc., 2016 138, 3978-3981; d) M.
[
[
1]
2]
T. Tokoroyama, Eur. J. Org. Chem. 2010, 2010, 2009-2016.
a) B. E. Rossiter, N. M. Swingle, Chem. Rev. 1992, 92, 771-806;
b) S. B. Tsogoeva, Eur. J. Org. Chem. 2007, 2007, 1701-1716;
c) S. Mukherjee, J. W. Yang, S. Hoffmann, B. List, Chem. Rev.
2
007, 107, 5471-5569; d) Y. Zhang, W. Wang, Catal. Sci.
7
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.202000858
FULL PAPER
A. Hussein, V. T. Huynh, R. Hommelsheim, R. M. Koenigs T.
V. Nguyen Chem. Commun., 2018, 54, 12970-12973.
[
21]
a) A. I. Meyers, M. A. Sturgess, Tetrahedron Lett. 1989, 30,
1
741-1744; b) D. L. Roberts, R. A. Heckman, B. P. Hege, S. A.
Bellin, J. Org. Chem. 1968, 33, 3566-3569.
[
[
22]
23]
S. Shapiro, Angiology 1953, 4, 380-390.
For DBU loadings between 0.1–0.3 eq., >95% conversion of 1 to
3
is observed within 3 minutes.
[
[
24]
25]
E. V. Anslyn, D. E. Dougherty, in Modern Physical Organic
Chemistry, University Science Books, U.S., 2006.
J. P. Birk, J. Chem. Ed. 1976, 53, 704.
[
[
[
[
26]
27]
28]
29]
L. Sobczyk, M. Obrzud, A. Filarowski, Molecules 2013, 18, 4467-
4
476.
a) F. H. Westheimer, Chem. Rev. 1961, 61, 265-273; b) S. E.
Scheppele, Chem. Rev. 1972, 72, 511-532.
R. G. Pearson, E. A. Mayerle, J. Am. Chem. Soc. 1951, 73, 926-
9
30.
S. J. Pike, E. Lavagnini, L. M. Varley, J. L. Cook, C. A. Hunter,
Chem. Sci. 2019, 10, 5943-5951.
[
[
30]
31]
C. A. Hunter, Angew. Chem. Int. Ed. 2004, 43, 5310-5324.
X. Wang, J. Liu, S. Xu, J. Xu, X. Pan, J. Liu, S. Cui, Z. Li, K. Guo,
Polym. Chem. 2016, 7, 6297-6308.
[
32]
M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M. A.
Robb, J. R. Cheeseman, G. Scalmani, V. Barone, G. A.
Petersson, H. Nakatsuji, X. Li, M. Caricato, A. V. Marenich, J.
Bloino, B. G. Janesko, R. Gomperts, B. Mennucci, H. P.
Hratchian, J. V. Ortiz, A. F. Izmaylov, J. L. Sonnenberg, Williams,
F. Ding, F. Lipparini, F. Egidi, J. Goings, B. Peng, A. Petrone, T.
Henderson, D. Ranasinghe, V. G. Zakrzewski, J. Gao, N. Rega,
G. Zheng, W. Liang, M. Hada, M. Ehara, K. Toyota, R. Fukuda,
J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H.
Nakai, T. Vreven, K. Throssell, J. A. Montgomery Jr., J. E.
Peralta, F. Ogliaro, M. J. Bearpark, J. J. Heyd, E. N. Brothers, K.
N. Kudin, V. N. Staroverov, T. A. Keith, R. Kobayashi, J.
Normand, K. Raghavachari, A. P. Rendell, J. C. Burant, S. S.
Iyengar, J. Tomasi, M. Cossi, J. M. Millam, M. Klene, C. Adamo,
R. Cammi, J. W. Ochterski, R. L. Martin, K. Morokuma, O.
Farkas, J. B. Foresman, D. J. Fox, Wallingford, CT, 2016.
a) R. Krishnan, J. S. Binkley, R. Seeger, J. A. Pople, J. Chem.
Phys. 1980, 72, 650-654; b) A. D. McLean, G. S. Chandler, J.
Chem. Phys. 1980, 72, 5639-5648; c) J.-D. Chai, M. Head-
Gordon, Phys. Chem. Chem. Phys. 2008, 10, 6615-6620; d) A.
V. Marenich, C. J. Cramer, D. G. Truhlar, J. Phys. Chem. B.
[
[
33]
34]
2
009, 113, 6378-6396.
a) S. M. Bachrach, J. Org. Chem. 2013, 78, 10909-10916; b) Á.
Madarász, Z. Dósa, S. Varga, T. Soós, A. Csámpai, I. Pápai,
ACS Catal. 2016, 6, 4379-4387; c) J. V. Alegre‐Requena, E.
Marqués‐López, R. P. Herrera, Chem. Eur. J. 2017, 23, 15336-
1
5347; d) J. V. Alegre-Requena, E. Marqués-López, R. P.
Herrera, ACS Catal. 2017, 7, 6430-6439; e) I. G. Sonsona, J. V.
Alegre-Requena, E. Marqués-López, M. C. Gimeno, R. P.
Herrera, Chem. Eur. J. 2020, 26, 5469-5473.
[
[
35]
36]
D. H. Ess, K. N. Houk, J. Phys. Chem. A 2005, 109, 9542-9553.
a) Y. Zhao, D. G. Truhlar, Theor. Chem. Acc. 2008, 120, 215-
2
41; b) S. Grimme, J. Antony, S. Ehrlich, H. Krieg, J. Chem.
Phys. 2010, 132, 154104.
[
[
37]
38]
a) R. Ding, P. R. Bakhshi, C. Wolf, J. Org. Chem. 2017, 82, 2,
1
3
273-1278; b) R. Ding, C. Wolf, Chem. Commun. 2016, 52,
576-3579, X. Li, D. Wei, Z. Li, ACS Omega 2017 2, 7029-7038.
a) A. Kawata, K. Takata, Y. Kuninobu, K. Takai, Angew. Chem.
Int. Ed. 2007, 46, 7793-7795; b) S. Biswas, S. Maiti,U. Jana, Eur.
J. Org. Chem., 2010, 2010, 2861-2866.
[
[
39]
40]
J. I. Seeman, Chemical Reviews 1983, 83, 83-134.
G. S. Hammond, J. Am. Chem. Soc. 1955, 77, 334-338.
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European Journal of Organic Chemistry
10.1002/ejoc.202000858
FULL PAPER
Entry for the Table of Contents
O
O
No method
available
R1
O
O
O
O
DBU
3R XH
R3
R3
+
+
1R
R2
R1
X
X
MeOH, rt
O
X= NR or O
Easily accessible
starting materials
Difficult
nucleophile
Difficult
electrophile
The selective addition of acetone to unactivated Michael acceptors is still troublesome. We present an alternative method for the
synthesis of these products by ring-opening and fragmentation of dihydropyranones. The developed protocol has a broad reaction
scope and delivers the products in good two excellent yields (32 examples, up to 97% yield). A mechanism is proposed based on
both kinetic and quantum chemical results.
9
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.202000858
FULL PAPER
1
0
This article is protected by copyright. All rights reserved.