Tunable and Diastereoselective Br?nsted Acid Catalyzed Synthesis of β-Enaminones

Article abstract of DOI:10.1021/acs.orglett.5b03445

The Br?nsted acid catalyzed Meyer-Schuster reaction of hemiaminals was studied for the stereoselective synthesis of β-enaminones. Hemiaminals were formed from propargyl aldehydes (or the oxidation of propargyl alcohols) and amines in the presence of Br?ns

Full text of DOI:10.1021/acs.orglett.5b03445

Letter
pubs.acs.org/OrgLett
Tunable and Diastereoselective Brønsted Acid Catalyzed Synthesis of
β‑Enaminones
Ye-Won Kang,† Yu Jin Cho,† Seung Jin Han,† and Hye-Young Jang*,†,‡
†Department of Energy Systems Research, Ajou University, Suwon 443-749, Korea
‡Korea Carbon Capture & Sequestration R&D Center, Deajeon 305-343, Korea
S
* Supporting Information
ABSTRACT: The Brønsted acid catalyzed Meyer−Schuster
reaction of hemiaminals was studied for the stereoselective
synthesis of β-enaminones. Hemiaminals were formed from
propargyl aldehydes (or the oxidation of propargyl alcohols)
and amines in the presence of Brønsted acids. A critical step to
control the stereochemistry of the products is the protonation
of the corresponding allenol intermediate, which is dictated by the Brønsted acid used, the steric effect of the amine, and the
electronic effect of the propargyl aldehyde.
alcohols, α-functionalized unsaturated carbonyl compounds
he classical Meyer−Schuster rearrangement has previously
Tbeen employed to convert propargyl alcohols to α,β- have been obtained via Meyer−Schuster reaction followed by
α-addition.5 β-Functionalized unsaturated carbonyl compounds
unsaturated carbonyl compounds under various metal-catalyzed
and metal-free conditions.1−4 Extensive studies on the
are also synthesized by a tandem protocol involving
nucleophilic addition to propargyl carbonyl compounds to
form hemiaminal intermediates, which subsequently undergo
Meyer−Schuster rearrangement. A gold-catalyzed reaction of
propargyl aldehydes with primary amides and a metal-free
reaction of propargyl aldehydes with amines were reported as
recent examples of the synthesis of β-functionalized unsaturated
carbonyl compounds.2l,6
Although classical Meyer−Schuster reactions are known to
occur in the presence of Brønsted acids such as sulfuric acid,
acetic acid, and formic acid, the effect of these acids on the
stereochemistry of the product has not been extensively
studied. In the case of the Meyer−Schuster reactions of
hemiaminals, Z-alkenes have previously been observed as major
products (Scheme 1).2l,6 In the gold-catalyzed rearrangement of
hemiaminals, additional treatment of the reaction mixtures was
required to alter the stereochemistry of the products.2l
However, to the best of our knowledge, there is no catalytic
reaction to direct the selective formation of E or Z isomers
during the Meyer−Schuster rearrangement of hemiaminals. In
this study, we present the stereocontrolled Brønsted acid-
catalyzed rearrangement of hemiaminals to afford synthetically
and biologically useful β-enaminones (Scheme 1).7−10
mechanism and investigation into efficient catalytic systems
have been conducted. In addition to this simple rearrangement
of propargyl alcohols to α,β-unsaturated carbonyl compounds,
tandem approaches have been demonstrated (Scheme 1)
involving the in situ formation of propargyl alcohols, which is
followed by Meyer−Schuster rearrangement; this avoids the
need for a separate synthesis of propargyl alcohols. By adding
external electrophiles or organometallic species to propargyl
Scheme 1. Meyer−Schuster Rearrangement
The reaction between phenylpropargyl aldehyde 1a and
morpholine 1b was run in the presence of several Brønsted acid
catalysts (0.25 equiv) at 80 °C in air (see Table 1).
Optimization began with isopropyl alcohol (IPA) and
hexafluoroisopropyl alcohol (HFIP) (entries 1 and 2,
respectively). While sterically similar, the pKa values of these
two alcohols are very different. Upon addition of HFIP, the
Received: December 2, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b03445
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Optimization of the Synthesis of 1c
Scheme 2. Tandem Oxidation and Meyer−Schuster
Rearrangement of 1a′
entry
acid catalysts
pKa*
yield (%)
ratio (E/Z)
1
IPA
16.5
9.3
31
55
48
56
60
79
88
82
47
60
74
23
1:3.7
2
HFIP
2.6:1
3
4-OMePhOH
PhOH
10.2
9.95
7.1
1:2.8
benzoic acid was replaced with TsOH, Z-1c was exclusively
obtained in 51% yield. Compared to the reaction using
aldehydes, this tandem approach using both copper and
Brønsted acid catalysts still suffers from copper-catalyzed
oxidation-dealkynylation alongside the desired copper-catalyzed
oxidation−Meyer−Schuster rearrangement, resulting in de-
creased yields. Nevertheless, the stereoselectivity was controlled
by Brønsted acids in a similar manner to the analogous reaction
of aldehydes.
4
1:2.7
5
4-NO2PhOH
phenylacetic acid
PhCO2H
3.1:1
6
4.76
4.2
E only
E only
E only
1:3.2
7
8
2-NO2PhCO2H
TFA
2.2
9
−0.25
2.1
10
11
12
TsOH
1:12.5
1:6.3
camphorsulfonic acid
1.5
1:2.7
To probe the mechanism of the Brønsted acid catalyzed
Meyer−Schuster reaction, an 18O-labeling experiment was
conducted using aldehyde 1a (Scheme 3). The reaction of 1a
*
Evans’ pKa values in H2O.
yield of 1c was increased compared to that upon addition of
IPA. Furthermore, while the IPA-catalyzed reaction was found
to favor the Z-isomer, the HFIP-catalyzed reaction predom-
inately formed the E-isomer. Phenol (PhOH), which has similar
acidity to HFIP, catalyzed the reaction to afford 1c in 56%
yield, which is comparable to the HFIP-catalyzed reaction (55%
yield); however, the Z-isomer was the major product (entries 2
and 4). Phenol derivatives possessing an electron-donating
group (OMe) and an electron-withdrawing group (NO2)
produced 1c in 48% (E/Z = 1:2.8) and 60% (E/Z = 3.1:1)
yield, respectively (entries 3 and 5). Following the use of these
alcohols as acid catalysts, several carboxylic acid derivatives
were also tested; phenylacetic acid, benzoic acid, 2-nitrobenzoic
acid, and trifluoroacetic acid (TFA) (entries 6−9). Except for
TFA, these additives were found to improve the yield of 1c,
favoring complete E-stereoselectivity. In the case of sulfonic
acids, p-toluenesulfonic acid (TsOH), and camphorsulfonic
acid, Z-1c was isolated as the major product (entries 10 and
11). In the absence of an acid catalyst, the reaction still
proceeded to afford 1c in 23% yield with an E/Z ratio of 1:2.7
(entry 12). On the basis of the Brønsted acid screening, it is
apparent that benzoic acid derivatives preferentially form E-1c,
while sulfonic acids form Z-1c with synthetically useful
selectivity.
Scheme 3. 18O-Labeling Experiment
and 1b in the presence of H218O provided 1c with the Z-isomer
as the major product (E/Z = 1:3). In both Z and E isomers,
more amounts of 16O-labeled 1c than 18O-labeled 1c were
observed (see the Supporting Information).
In light of these 18O-labeling experiments, the reaction
mechanism is proposed in Scheme 4. Propargyl aldehyde 1a
Scheme 4. Proposed Reaction Mechanism
In our previous reports on oxidative coupling reactions using
propargyl alcohols, we demonstrated that the combination of
copper salts and TEMPO induces the oxidation of propargyl
alcohols, which leads to good yield in the subsequent Cu-
catalyzed reaction.11 Among copper−TEMPO-catalyzed oxida-
tive reactions, the dealkynylation of propargyl alcohols occurs
via hemiacetal intermediates, which are the common
intermediates of the Meyer−Schuster rearrangement.11b
Various copper salts were tested in order to suppress undesired
dealkynylation and promote the desired Meyer−Schuster
rearrangement of hemiaminals. The best yield of the desired
product was achieved in the presence of CuOTf·benzene (see
the Supporting Information). Phenylpropargyl alcohol 1a′ was
subjected to a tandem reaction involving CuOTf·benzene-
catalyzed oxidation followed by Brønsted acid catalyzed
Meyer−Schuster reaction (Scheme 2). The reaction of 1a′
and 1b in the presence of CuOTf·benzene and benzoic acid
afforded exclusively E-1c in 41% yield. Conversely, when
undergoes an addition with an amine to afford hemiaminal I.
This intermediate would be converted to allenol III, either
through the complete dissociation of water or a 1,3-shift of the
hydroxyl group across the triple bond. On the basis of 18O-
labeling experiments, while both routes occur, the 1,3-shift is
slightly more favored. To elucidate E/Z isomer formation,
independently synthesized E and Z isomers were re-exposed to
Brønsted acidic conditions, as shown in Scheme 5. The ability
of TsOH to promote the formation of Z-isomers was applied to
the reaction of E-1c, resulting in no isomerization. The reaction
of benzoic acid with Z-1c also showed no isomerization.
B
DOI: 10.1021/acs.orglett.5b03445
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
mixture of E and Z isomers in the presence of benzoic acid (E:Z
= 1.5:1). Applying bulky carboxylic acids, such as pivalic acid
and adamantanecarboxylic acid (AdmCO2H) increased the
proprtion of E-12c. Presumably, the reaction of diethylamine
favors the reaction via intermediate V to afford Z-12c (Scheme
4). However, the coordination of a bulky counteranion to the
protonated carbonyl group switches the preferred stereo-
chemistry to the E-isomer. According to these results for
different substrates, the E/Z stereoselectivity of this reaction is
mainly controlled by the Brønsted acids used, but the size of
the amine and the electronic properties of the propargyl
aldehyde also have an impact on electrostatic interaction and
intramolecular hydrogen bonding.
In conclusion, we have presented the stereocontrolled
Meyer−Schuster rearrangement of hemiaminals derived from
propargyl aldehydes and amines, in which Brønsted acids
increase the yield of the product and direct the stereochemistry
of the resulting β-enaminones. A key factor controlling this
stereochemistry is the intramolecular hydrogen bonding
present in the protonated β-enaminone. Weak electrostatic
interaction of the tosylate anion with the protonated β-
enaminone promotes intramolecular hydrogen bonding to
afford Z-isomers, while strong electrostatic interactions favors
formation of the E-isomer. In addition to the effect caused by
various Brønsted acids, the steric effect of the amine and the
electronic properties of the propargyl aldehyde affected the
intramolecular hydrogen bonding of the intermediates to
produce a different distribution of E/Z products.
Scheme 5. Reactions of E and Z Isomers with Brønsted
Acids
Accordingly, the stereochemistry of the β-enaminone products
may be determined during the protonation of allenol III. The
intramolecular hydrogen bonding of intermediate V results in
Z-stereoselectivity, while E-isomers are formed via intermediate
IV. The cationic intermediates IV and V are presumed to exist
alongside a counteranion. Depending on the electrostatic
interaction of the counter-anions with the corresponding
cationic intermediates, the ratio between IV and V can be
varied, resulting in a different ratio of E/Z products. Benzoates
may bind tightly to the cation, which builds up the steric
hindrance on the protonated carbonyl group to prevent
intramolecular hydrogen bonding. Sulfonates may act as weakly
bound anions to promote the intramolecular hydrogen bonding
required for the formation of Z-products.12 Because this
reaction is conducted in a nonpolar solvent, toluene, electro-
static interactions play an important role in controlling the
stereochemistry of the product.
Next, the scope of the reaction was examined (Figure 1).
Substituted aromatic propargyl aldehydes were subjected to the
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b03445.
Experimental procedures and spectra of 1c−12c, copper
salts screening results for Scheme 2, and the mass spectra
of 18O-/16O-labeled 1c (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: hyjang2@ajou.ac.kr.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This study was supported by the Korea CCS R&D Center
(KCRC) grant by the Korea government Ministry of
E d u c a t i o n , S c i e n c e a n d T e c h n o l o g y ( N o .
2015M1A8A1048886), C1 gas refinery program by the Korea
government Ministry of Science, ICT & Future Planning (No.
2015M3D3A1A01065436), and the Human Resources Devel-
opment of the Korea Institute of Energy Technology
Evaluation and Planning (KETEP) grant by the Korea
government Ministry of Trade, Industry & Energy
(No.20154010200820).
Figure 1. Substrate scope.
established Brønsted acid catalyzed Meyer−Schuster rearrange-
ment conditions to afford β-enaminones 1c−6c in good yields
with high stereoselectivities. The benzoic acid catalyzed
reaction favored the formation of E isomers in good yields,
while the TsOH-catalyzed reaction provided the desired
products in slightly lower yields with good Z-selectivity. In
contrast, aliphatic propargyl aldehydes afforded 7c and 8c with
E-selectivity, regardless of the Brønsted acid catalyst used.
Following this, different amines were screened; piperidine,
pyrrolidine, and N-benzylmethylamines showed a similar
product distribution upon the addition of benzoic acid and
TsOH (9c−11c). The reactions of diethylamine with propargyl
aldehyde afforded Z-12c in the presence of TsOH and a
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