Chemoselective α,β-Dehydrogenation of Saturated Amides

Article abstract of DOI:10.1002/anie.201808794

We report a method for the selective α,β-dehydrogenation of amides in the presence of other carbonyl moieties under mild conditions. Our strategy relies on electrophilic activation coupled to in situ selective selenium-mediated dehydrogenation. The α,β-unsaturated products were obtained in moderate to excellent yields, and their synthetic versatility was demonstrated by a range of transformations. Mechanistic experiments suggest formation of an electrophilic Se^IV species.

Full text of DOI:10.1002/anie.201808794

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Accepted Article
Title: Chemoselective α,β-Dehydrogenation of Saturated Amides
Authors: Christopher Teskey, Pauline Adler, Carlos Goncalves, and
Nuno Maulide
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201808794
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10.1002/anie.201808794
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Chemoselective α,β-Dehydrogenation of Saturated Amides
Christopher J. Teskey,[a,+] Pauline Adler,[a,+] Carlos R. Gonçalves[a] and Nuno Maulide*[a]
Abstract: We report a method for the selective -dehydrogenation
of amides in the presence of other carbonyl moieties under mild
conditions. Our strategy relies on electrophilic activation coupled to in
situ selective selenium-mediated dehydrogenation. The -
unsaturated products are obtained in moderate to excellent yields and
other areas of research such as bioconjugation or dynamic
combinatorial chemistry.[4]
As a result, methods to synthesize -unsaturated systems are
highly prized. Convenient and efficient pathways include carbonyl
olefination[5] and olefin cross-metathesis,[6] although the ability to
directly generate -unsaturated carbonyl compounds from their
corresponding saturated counterparts by dehydrogenation adds
considerable flexibility to synthetic planning. Pioneering work by
Kingsbury and Cram on the concerted, thermal elimination of alkyl
sulfoxides[7] later inspired similar work on selenoxide
elimination.[8] The Saegusa-Ito oxidation[9] is another well-known
and often employed route to dehydrogenated carbonyl systems
but is a two-step procedure. Despite the original use of
stoichiometric palladium, notable efforts have been made to
develop efficient catalytic reactions based on much greener
oxidants by the groups of Stahl[10] and others.[11] Although reliable,
these methods often involve two steps or are limited to (cyclic)
ketones. Other important contributions include the work of
Nicolaou et. al who reported the use of IBX to oxidise ketones to
the corresponding α,β-enones.[12]
their synthetic versatility is demonstrated by
a
range of
transformations. Mechanistic experiments suggest formation of an
electrophilic Se(IV) species.
More than 130 years have passed since Arthur Michael reported
his groundbreaking studies on the conjugate addition of malonate
nucleophiles.[1] In the intervening time, much work has been
devoted to the development of asymmetric variants of this
reaction, which has become a staple transformation of the organic
chemist’s repertoire.[2] Given the versatility of the carbonyl
functional group, the Michael addition of an enolate to an
unsaturated carbonyl is one of the definitive methods for
generating a 1,5-dicarbonyl relationship and, as a consequence,
such transformations can be frequently found in total syntheses.[3]
When considering the direct dehydrogenation of carbonyl
compounds beyond ketones and aldehydes, a major obstacle is
the significantly reduced -acidity of esters, nitriles or particularly
carboxamides. The Newhouse group has published a number of
impressive reports showcasing how zinc enolates (generated by
transmetallation from the corresponding lithium counterparts) can
be dehydrogenated under palladium catalysis,[13] including those
derived from amides (Scheme 1a).[14] Furthermore, those authors
have demonstrated this methodology to be applicable in total
synthesis.[15]
Dong has used a related strategy to desaturate N-acyllactams,[16]
relying on a two-point binding activation (Scheme 1b) and, most
recently, the group of Huang showed that iridium catalysis could
be used for desaturation in the specific case of -unsaturated
amides (Scheme 1c).[17]
We believed there remains space for complementary methods
that proceed under conditions tolerant of other carbonyl
functionality and that are applicable to structurally diverse amides.
We envisaged the use of electrophilic amide activation[18] for the
possibilities it might afford in developing
a strategy for
chemoselective desaturation of amides in the presence of other
carbonyl functional groups.[19] Herein we report a mild, room-
Scheme 1. Approaches to amide dehydrogenation and work presented herein.
temperature -dehydrogenation of amides with
a broad
applicability and which is selective for amides, thus reaching
beyond the scope of most current protocols as it does not rely on
enolate formation. Our reaction design was based on the simple
assumption that seleninic acid (PhSe(O)OH) might possess
enough nucleophilicity to attack a keteniminium intermediate as
shown in Scheme 1. This might lead to an enamine-type species
such as 2 which could undergo an unusual [1,3]-sigmatropic
rearrangement.[20] The resulting -selenated species 3 should
already lie at the oxidation state required for concerted elimination,
ultimately affording the -dehydrogenated product in a single
step.
The mild conditions of conjugate addition, as the Michael reaction
has come to be colloquially known, also lend this reaction well to
[a]
Dr. C. J. Teskey,[+] Dr. P. Adler,[+] C. R. Gonçalves, Prof. Dr. N.
Maulide
University of Vienna
Institute of Organic Chemistry
Währinger Strasse 38, 1090 Vienna, Austria
Homepage: http://maulide.univie.ac.at
E-mail: nuno.maulide@univie.ac.at
In initial efforts using amide 1a, the desired dehydrogenated
product 4a was observed from the very first experiments, albeit in
yields never surpassing 50% (Table 1, entry 1; see the SI for
additional attempts). Indeed, the crude reaction mixture
[+]
These authors contributed equally.
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201808794
Angewandte Chemie International Edition
COMMUNICATION
commonly contained variable amounts of both -hydroxylated
amide 5 and -selenated amide 6.
yield. This procedure avoided the formation of several other
products, thus simplifying the purification process although
isolated yields were, in most cases, lower than those measured
by NMR due to difficulties in separating the residual starting
materials of nearly identical polarity.
Table 1. Optimization of the reaction.
With the optimized conditions in hand, our attention next turned to
exploring the scope of the reaction (Scheme 2). Pleasingly, a
broad range of tertiary amides were tolerated by this desaturation
protocol. -Substitution with a cyclopentyl chain allowed the
formation of 4b. Different cinnamyl amides could be prepared by
this method (4c-d-e). Notably, -substituted amides could also be
dehydrogenated with the indene 4f and cyclobutene amide 4g
isolated in good yield. The 1,3-diene 4h was also prepared in
moderate yield. The conditions of the reaction tolerated the use of
alkynes (4i) and trifluoromethyl groups (4j). Tertiary amides with
other N-substituents led efficiently to the corresponding
desaturated amides, including removable dibenzyl groups 4k,
morpholine 4l, piperidine 4m or azepine 4n. Aniline-derived
amides also were well tolerated, delivering the products in good
yields (4o-4p).
A unique feature of this -dehydrogenation reaction is its high
chemoselectivity. Amides can be selectively desaturated even in
the presence of commonly more reactive carbonyl functional
groups such as esters and ketones in moderate to good yields.
To the best of our knowledge, no method exists that allows this
type of selectivity. Methyl esters were effectively spectators in the
-dehydrogenation of different tertiary amides 4r-4s-4t-4u.
Furthermore, the presence of a ketone 4v or a nitrile 4w functional
group did not divert the reaction away from the amide moiety.
Amides derived from natural product feedstocks such as oleic
acid (4x) or dehydrocholic acid (4y) could also be selectively
desaturated in good isolated yield. An amide analogue of the
Entry
1
[Se]
Base
Oxidant
-
4a[a]
5[a]
6[a]
1a[a]
PhSeO2H
(1 eq.)
Ag2CO3
(1.1 eq.)
48
20
-
41
2
3
4
5
6
PhSeO2H
(1 eq.)
Et3N
(1.1 eq.)
-
-
24
12
45
-
50
-
14
25
21
10
50
PhSeO2H
(1 eq.)
Et3N
(2.2 eq.)
PIDA
(2.2 eq.)
22
29
73
8
PhSeO2H
(1 eq.)
Et3N
(2.2 eq.)
IBX
(2.2 eq.)
-
PhSeO2H
(1 eq.)
Et3N
(2.2 eq.)
DMP
(2.2 eq.)
-
-
Et3N
(2.2 eq.)
DMP
(2.2 eq.)
2
-
[a] NMR yields (in %) determined with the use of bromoform as an
internal reference
In subsequent experiments, we noted that the use of triethylamine
as a base (Table 1, entry 2) yielded none of the desaturated
product (4a) and 50% of the -selenated amide (6) instead. This
prompted us to try the same reaction with the addition of oxidants
[see SI for more details], with hypervalent iodine species affording
the most promising results (Table 1, entries 3-6). With 2.2
equivalents of Dess-Martin periodinane (DMP), the -
dehydrogenated product was reproducibly formed in 73% NMR
blockbuster
drug
Citalopram
was
also
successfully
dehydrogenated to afford product 4z. Finally, we subjected a 13-
membered lactam to our procedure and pleasingly obtained the
desaturated product 4aa in moderate yield.
Scheme 2. Scope of amide dehydrogenation. a1 mmol scale. bReaction carried out at -20 °C. cReaction carried out at -10 °C. d4.2 mmol scale.
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10.1002/anie.201808794
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COMMUNICATION
pervasiveness of amides in nature,[23] we were keen to apply our
methodology to synthesis of a natural product. We selected
piperine 13 (Scheme 3d), a polyunsaturated amide responsible
for the pungency of pepper. Piperine possesses antioxidant, anti-
inflammatory and antidepressant properties and has been
synthesized previously using a variety of strategies.[24] Here, we
propose an alternative 3-step synthesis starting from the
commercially available aldehyde 9 (Scheme 3c). After
quantitative transformation of 9 into the allylic alcohol 10, this
compound is treated with the in situ prepared 1,1-diamino
alkene 11 in refluxing xylene to yield the ,-unsaturated amide 12
in a very good 73% yield by a modified Claisen-Eschenmoser
rearrangement.[25] Further dehydrogenation of 12 delivered
piperine 13 in moderate 42% yield.
We then turned our attention to the mechanism of the reaction.
Preliminary work had demonstrated the formation of the -
selenated amide 6 in 64% yield by addition of selenenic acid,
PhSeOH, onto
hypothesized that this occurred via
a
keteniminium ion (Scheme 4a). We
[1,3] sigmatropic
a
rearrangement from intermediate 2’. During this reaction, 25% of
-hydroxylated product 5 was also formed, possibly by
nucleophilic attack of the PhSeOH on the  position of the
intermediate 2’ followed by hydrolysis. These results led us to
postulate pathway (i) (Scheme 4) for the dehydrogenation
mechanism by simple analogy, the only difference being the
oxidation state of the selenium atom. However, during the
reaction discovery process it was observed that, in the absence
of an oxidant, the -selenated amide 6 remains the major product
(Table 1, entry 2). Given that pathway (i) generates PhSeOH 18
we believe it possible that DMP could play two distinct roles: (1)
trapping of 18, which is likely more nucleophilic than seleninic acid,
and (2) oxidation of any 6 that is produced. In support of this
hypothesis, we observed that DMP was able to oxidise -
selenated amide 6 to desaturated amide 4a in moderate yield
(Scheme 4c).
Scheme 3. Derivatisation of products and application of the method. aNMR yield.
In order to further probe the selectivity of the reaction, we
subjected a substrate containing both secondary and tertiary
amides to the reaction conditions. Pleasingly, product 4ab
resulting from desaturation adjacent to the tertiary amide, was
exclusively obtained (Scheme 3a). We next sought to showcase
the utility of these Michael acceptor products. Dihydroxylation
proceeded smoothly to give product 7 in 69% (Scheme 3b).[21]
Asymmetric conjugate addition to unsaturated amides, as
recently described by Harutyunyan and co-workers,[22] was
realized on unsaturated amide 4n with EtMgBr, resulting in
product 8 in 91% yield and 96% ee (Scheme 3c). Cognizant of the
Alternatively, because it has been demonstrated that iodyl
benzoic acid can be used as an oxidant to generate benzene
seleninic anhydride (BSA) in situ from diphenyl diselenide
(PhSeSePh)[26], we believe that we may also be generating BSA
(17) under our reaction conditions.[27]
Scheme 4. Mechanistic experiments.
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10.1002/anie.201808794
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From the labelling studies we undertook with H218O (Scheme 4d),
we established that keteniminium species 15 is likely attacked by
either water or acetate released by the DMP, to give the
enamine/enol (acetate) hybrid 16.[28] Conceivably, reaction of 16
with 17 would generate an intermediate that leads to the product
4a (Scheme 4, pathway (i)). Upon replacing DMP with acetic
anhydride (Scheme 4b) we generated a mixture of 6 and 4a. This
further suggests that an electrophilic, oxidized selenium species
(likely the mixed anhydride) plays some role in the reaction but
also emphasizes that DMP is important, either to oxidise 6 to 4a,
or trap and re-oxidise species 18 and lower oxidation state
selenium species.[29] We speculate that the modest efficiency of
reaction 4(c) indicates the major role of the DMP to be as a
secondary oxidant of species 18 which avoids side reactions of
the keteniminium intermediate 15 with lower oxidation state
selenium species.
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In conclusion, we report a novel procedure for the synthesis of
-unsaturated amides from the corresponding saturated amide
starting materials. The reaction proceeds by electrophilic
activation
followed
by
a
unique
selenium-mediated
dehydrogenation. This process conveys good functional group
tolerance and, significantly, enables the desaturation of amides in
the presence of esters, ketones and nitriles. We have applied this
method to the synthesis of natural product piperine. Current
experiments allude to a mechanism which involves attack onto an
electrophilic Se(IV) species however further investigations on this
are underway in our laboratory and will be reported in due course.
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Acknowledgements
[22] M. Rodríguez-Fernández, X. Yan, J. F. Collados, P. B. White, S. R.
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Spiegeleer, J. Ethnopharmacol. 2012, 142, 563–590
We are thankful to the ERC (CoG VINCAT) and FWF (P 30226 to
N.M.; M 2274 to C.J.T.) for financial support of this project. The
University of Vienna is gratefully acknowledged for continued
generous support of our research programs.
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Keywords: dehydrogenation • amide activation • hypervalent
iodine • seleninic acid • triflic anhydride
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[27] Formation of PhSeSePh was observed by NMR upon addition of NEt3
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the solution. In addition, we observed a peak in 77Se NMR (CD2Cl2) at
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COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
Christopher J. Teskey, Pauline Adler,
Carlos R. Gonçalves and Nuno Maulide*
Page No. – Page No.
Chemoselective α,β-Dehydrogenation
of Saturated Amides
Make it a double: We report a method for the selective -dehydrogenation of
amides in the presence of other carbonyl moieties under mild conditions. Our strategy
relies on electrophilic activation coupled to in situ selective selenium-mediated
dehydrogenation. Mechanistic experiments suggest formation of an electrophilic
Se(IV) species.
This article is protected by copyright. All rights reserved.