Oxazolium Salts as Organocatalysts for the Umpolung of Aldehydes

Article abstract of DOI:10.1021/acs.orglett.8b02636

Oxazolium salts were successfully employed for the first time as organocatalysts for benzoin, Stetter, and redox esterification reactions. An N-mesityl oxazolium salt catalyzed homobenzoin reaction of aromatic, heteroaromatic, and aliphatic aldehydes delivered α-hydroxy ketones in high yields. This new type of catalyst proved remarkably effective for the Stetter reaction of challenging substrates such as β-alkyl-α,β-unsaturated ketones and electron-rich aromatic aldehydes in comparison to common thiazolium and triazolium salts.

Full text of DOI:10.1021/acs.orglett.8b02636

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Oxazolium Salts as Organocatalysts for the Umpolung of Aldehydes
Venkata Krishna Rao Garapati and Michel Gravel*
Department of Chemistry, University of Saskatchewan, Saskatoon, SK Canada, S7N 5C9
S
* Supporting Information
ABSTRACT: Oxazolium salts were successfully employed for
the first time as organocatalysts for benzoin, Stetter, and redox
esterification reactions. An N-mesityl oxazolium salt catalyzed
homobenzoin reaction of aromatic, heteroaromatic, and
aliphatic aldehydes delivered α-hydroxy ketones in high
yields. This new type of catalyst proved remarkably effective
for the Stetter reaction of challenging substrates such as β-
alkyl-α,β-unsaturated ketones and electron-rich aromatic
aldehydes in comparison to common thiazolium and triazolium salts.
Scheme 1. Synthesis of Oxazolium Salts Used in This Study
he catalytic activation of aldehydes through the formation
Tof an acyl anion equivalent has a long history that is best
exemplified by the benzoin and Stetter reactions.1 In the
decades following a seminal paper by Ukai et al. on the
benzoin reaction,2 the preferred catalysts were based on the
thiazolium framework. Other carbene precursors have since
been utilized, such as triazolium, imidazolium, and bis(dialkyl-
amino)cyclopropenium salts.3 Each family of catalysts has its
own advantages and drawbacks. Perhaps due to their
unhindered nature, thiazolium salts can catalyze many Stetter
reactions with great efficiency, whereas chiral triazolium salts
have shown to be particularly effective at catalyzing a variety of
reactions enantioselectively. Many challenges remain, however,
such as the limited scope of cross-benzoin reactions and of
enantioselective intermolecular Stetter reactions. Owing to the
numerous ongoing challenges, we became interested in
exploring other azolium salts with the aim of uncovering new
or unexpected reactivity.
We turned our attention to oxazolium salts, which have been
left largely unexplored since early work by Ukai.4 In that work,
3-methyl benzoxazolium iodide and 2,3-dimethyl benzoxazo-
lium iodide were used in an attempt to catalyze the
homobenzoin reaction of benzaldehyde. The reported
conditions employed NaOH in methanol, and no benzoin
product was detected when the benzoxazolium salts were used
as catalysts. We surmised that the salts’ heterocyclic framework
underwent methanolysis under these conditions,5 thus
thwarting their ability to act as catalysts. Based on this
assumption, we decided to take another look at oxazolium salts
using aprotic solvents.
before undergoing a dehydrative cyclization to provide the N-
aryl oxazolium salt.7,8 The oxazolium salts could be more
conveniently purified and handled as borate salts following
anion exchange (see Supporting Information).9
With these candidate catalysts (1−4) in hand, we first
examined their catalytic activity in a benchmark homobenzoin
reaction of benzaldehyde (Table 1). Using dichloromethane as
solvent and DBU as base, a color change was immediately
observed for all catalysts. However, only the reaction using the
N-Mes oxazolium salt 3 provided the product in appreciable
yield (entries 1−4). Changing the solvent to toluene again
showed catalyst 3 to be far superior, with the reaction being
clean and complete within an hour under those conditions
(entries 5−8). The more polar solvents THF and Et2O were
also screened with catalyst 3, but the transformation proved
less efficient (entries 9−10). The conversion and yield proved
very sensitive to the catalytic loading, as shown in entries 11−
12.
Having established the optimized conditions, a sampling of
representative aldehydes were subjected to the homobenzoin
reaction (Scheme 2). The namesake benzoin (5) was obtained
from the dimerization of benzaldehyde in 97% isolated yield.
Excellent yields were also obtained in reactions using electron-
Four oxazolium salts were synthesized, each bearing a
different N-substituent (Scheme 1). An N-alkyl oxazolium salt
was prepared by simply refluxing oxazole and benzyl bromide
in toluene for 16 h, affording N-benzyl oxazolium bromide
(1).6 Oxazolium salts 2−4 bearing various N-aryl substituents
were synthesized from the corresponding anilines and acetoin
in three high-yielding steps. Acid-catalyzed condensation
delivered the α-amino ketone, which was then N-formylated
Received: August 17, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02636
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Optimization of the Homo-benzoin Reaction
Scheme 3. Cross-benzoin Reaction between Furfural and N-
Boc Valinal
b
entry
catalyst
solvent
time (h)
yield (%)
1
2
3
4
5
6
7
8
9
10
1
2
3
4
1
2
3
4
3
3
3
3
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
PhCH3
PhCH3
PhCH3
PhCH3
Et2O
3
3
3
3
1
1
1
1
1
1
1
1
<5
<5
64
13
<5
<5
98
33
22
56
90
<5
catalyst at 70 °C in toluene for 4 h did result in the
chemoselective formation of product 12 in 56% yield.
However, the observed 3:1 diastereomer ratio is lower than
that reported under our previous conditions, possibly due to
the stronger base used in conjunction with the oxazolium
catalyst.11 Nevertheless, the prospect of using oxazolium salts
in cross-benzoin reactions, in particular those involving
aliphatic aldehydes, opens the door to interesting synthetic
opportunities.
THF
PhCH3
PhCH3
c
11
12
The potential of oxazolium salts as catalysts was next
explored in the Stetter reaction between trans-chalcone and
methyl 4-formylbenzoate (Table 2). Catalyst 3 bearing an N-
d
a
Benzaldehyde (0.25 mmol), catalyst (10 mol %), DBU (10 mol %).
Entries 1 to 4: concn 0.25 M. Entries 5 to 10: concn 0.5 M. Yield was
determined by H NMR using trichloroethylene as internal standard.
Catalyst (5 mol %), DBU (5 mol %), concn 1 M. Catalyst (1 mol
b
1
a
c
d
Table 2. Optimization of the Stetter Reaction
%), DBU (1 mol %), concn 1 M.
a
Scheme 2. Scope of the Homo-benzoin Reaction
b
entry
catalyst
solvent
time (h)
yield (%)
1
2
3
4
5
6
7
8
1
2
3
4
3
3
3
3
PhCH3
PhCH3
PhCH3
PhCH3
CH2Cl2
Et2O
2
2
2
2
2
2
2
3
<5
<5
79
66
63
5
THF
PhCH3
35
99
a
Aldehyde (0.33 mmol), trans-chalcone (0.25 mmol), catalyst 10 mol
b
%, DBU 10 mol %, concn 0.5 M. % yield was calculated by 1H NMR
using trichloroethylene as the internal standard.
Mes substituent once again proved to be the most active
(entries 1−4), although catalyst 4 bearing an electron-rich aryl
substituent also catalyzed the reaction effectively. A brief
survey of solvents confirmed toluene to be optimal (entries 3,
5−7). Finally, the reaction could be brought to completion by
increasing the reaction time (entry 8). It is important to note
that the use of a prolonged reaction time does not always result
in increased conversions in NHC-catalyzed reactions due to
the gradual decomposition of the catalyst.
A variety of different reaction partners were then used in the
Stetter reaction (Scheme 4). Electron-poor aromatic aldehydes
and benzaldehyde all delivered the Stetter product in high yield
(13−15). Remarkably, the much less reactive p-methoxyben-
zaldehyde could also be employed with great efficiency even at
room temperature (16). Heteroaromatic aldehydes can be
used under these conditions, as exemplified by the efficient
formation of the Stetter product derived from furfural (17).
The challenging Stetter reaction with β-alkyl-α,β-unsaturated
ketones was then explored. To our surprise, this transformation
could be performed under the same mild conditions with 4-
formyl methyl benzoate as the aldehyde (18). Furfural and
benzaldehyde could also be coupled in moderate yield with
this type of unsaturated ketone using a higher catalytic loading
a
The yield in parentheses refers to a reaction performed on a 2.0
mmol scale. All other reactions were performed on a 0.5 mmol scale.
b
20 mol % of 3 and DBU were used.
poor benzaldehyde derivatives (6−8).10 Surprisingly, even the
electron-rich p-methoxybenzaldehyde underwent the reaction
at room temperature, although the catalytic loading had to be
increased in that case (9). As expected, the reaction to form
furoin (10) proceeded smoothly. We were pleased to confirm
that the scope also extends to aliphatic aldehydes, as shown by
the formation of 11 derived from hydrocinnamaldehyde.
The successful use of both heteroaromatic and aliphatic
aldehydes prompted us to test the catalytic activity of catalyst 3
in a cross-benzoin reaction (Scheme 3). Interestingly, the
reaction between furfural and N-Boc valinal with 20 mol %
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DOI: 10.1021/acs.orglett.8b02636
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Scheme 4. Scope of the Stetter Reaction
Scheme 6. Catalyst Comparison in the Stetter Reaction
Involving a β-Alkyl-α,β-Unsaturated Ketone
last two cases, formation of the homobenzoin product was
observed in 18% and 41% yields, respectively.
The efficiency of N-Mes oxazolium catalyst 3 in reactions
involving acyl anion equivalents (i.e., benzoin and Stetter
reactions) stands in contrast to the observed preference of N-
Mes triazolium salts to catalyze reactions involving homo-
enolate or azolium enolate intermediates. With this in mind,
we were curious to test the potential of 3 in the redox
esterification of aldehydes.13 Accordingly, cinnamaldehyde was
treated with ethanol in the presence of catalyst 3 and DBU
(Scheme 7). The product of redox esterification 23 was cleanly
a
The yield in parentheses refers to a reaction performed on a 1 mmol
Scheme 7. Redox Esterification
scale of chalcone. All other reactions were performed on a 0.25 mmol
scale. 20 mol % catalyst and base used at 125 °C for 1 h.
b
and temperature (19−20). Prolonged heating of the reaction
mixture in these cases did not lead to an increase in yield, but
rather to product decomposition. Aliphatic aldehydes proved
resistant to undergoing the Stetter reaction under the
optimized conditions and provided the corresponding
homobenzoin product instead.
The surprising catalytic activity of oxalium 3 when using
electron-rich aldehydes prompted us to directly compare its
performance with commonly used catalysts (Scheme 5). In the
obtained under these conditions, demonstrating the ability of
oxazolium salts to be used in both acyl anion and homoenolate
equivalent reactions.
In summary, N-benzyl and N-aryl oxazolium salts have been
synthesized successfully. For the first time, an oxazolium salt
was employed as an organocatalyst for benzoin and Stetter
reactions, generally affording the products in high yields. The
same catalyst proved to be competent in the redox
esterification of unsaturated aldehydes and outperformed
commonly employed thiazolium and triazolium salts in the
Stetter reactions of challenging substrates.
Scheme 5. Catalyst Comparison in the Stetter Reaction
between p-Methoxybenzaldehyde and trans-Chalcone
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.8b02636.
Experimental procedures, characterization data, and
spectra of products (PDF)
reaction between p-methoxybenzaldehyde and trans-chalcone,
the reaction is already half complete after 1 h at room
temperature when using oxazolium catalyst 3. In contrast, only
starting materials were observed in the presence of thiazolium
catalyst 21, whereas triazolium catalyst 22 catalyzed the
formation of the homobenzoin product (47% conversion) but
not that of the desired Stetter product.12
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: michel.gravel@usask.ca.
ORCID
The same catalysts were then compared in a Stetter reaction
using a notoriously unreactive β-alkyl-α,β-unsaturated ketone
(Scheme 6). Again, oxazolium 3 showed much higher catalytic
activity compared to thiazolium 21 and triazolium 22. In the
Michel Gravel: 0000-0003-3656-7108
Notes
The authors declare no competing financial interest.
C
DOI: 10.1021/acs.orglett.8b02636
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(10) Despite numerous claims to the contrary, meta-alkoxy
substituents are electron-withdrawing in benzaldehyde derivatives.
This is borne out by our own experience with these aldehydes and by
the Hammett constant of +0.11 for m-OCH3.
(11) (a) Haghshenas, P.; Gravel, M. Chemo- and Diastereoselective
N-Heterocyclic Carbene-Catalyzed Cross-Benzoin Reactions Using
N-Boc-α-amino Aldehydes. Org. Lett. 2016, 18, 4518−4521.
(b) Haghshenas, P.; Gravel, M. Substrate-Controlled Diastereose-
lectivity Reversal in NHC-Catalyzed Cross-Benzoin Reactions Using
N-Boc-N-Bn-Protected α-Amino Aldehydes. J. Org. Chem. 2016, 81,
12075−12083.
ACKNOWLEDGMENTS
■
We thank the Natural Sciences and Engineering Research
Council (NSERC) of Canada (RGPIN-2017-06230), the
Canada Foundation for Innovation (CFI 15875), and the
University of Saskatchewan for financial support.
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