Direct Synthesis of Enamides via Electrophilic Activation of Amides

Article abstract of DOI:10.1021/jacs.1c04363

A novel, one-step N-dehydrogenation of amides to enamides is reported. This reaction employs the unlikely combination of LiHMDS and triflic anhydride, which serves as both the electrophilic activator and the oxidant, and is characterized by its simple setup and broad substrate scope. The synthetic utility of the formed enamides was readily demonstrated in a range of downstream transformations.

Full text of DOI:10.1021/jacs.1c04363

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Direct Synthesis of Enamides via Electrophilic Activation of Amides
Philipp Spieß, Martin Berger, Daniel Kaiser, and Nuno Maulide*
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ABSTRACT: A novel, one-step N-dehydrogenation of amides to enamides is reported. This reaction employs the unlikely
combination of LiHMDS and triflic anhydride, which serves as both the electrophilic activator and the oxidant, and is characterized
by its simple setup and broad substrate scope. The synthetic utility of the formed enamides was readily demonstrated in a range of
downstream transformations.
Scheme 1. Previous Approaches to the Synthesis of
Enamides by N-Dehydrogenation of Amides and Our
Proposal
he chemistry of enamines is a fundamental cornerstone of
Tthe organic synthetic toolbox, driven by this compound
class’s exceptional nucleophilicity. Nevertheless, the unique
reactivity of enamines is accompanied by a high propensity to
undergo hydrolysis, leading to considerable difficulties in the
handling of these compounds.1 Enamides, long regarded as
sluggishly reacting surrogates, have recently experienced a
renaissance, occupying a niche position at the intersection of
desirable resistance to hydrolysis and tunable reactivity. While
tempering the nitrogen center with an electron-withdrawing
group leads to a reactivity profile more akin to that of classical
olefins, enamides are versatile reactants, used in a number of
settings, such as transition-metal catalysis, photochemistry, or
asymmetric catalysis.2 Several approaches for the preparation
of enamides have been reported, typically starting from
prefunctionalized substrates.3 However, the most straightfor-
ward approach to access enamides is arguably the direct N-
dehydrogenation of the corresponding amides. Whereas routes
for the direct desaturation to form enecarbamates have
recently become well established,4 pathways leading from
carboxamides to enamides remain elusive (Scheme 1A).
Gevorgyan reported a photoinduced palladium-catalyzed
dehydrogenation protocol enabled by hydrogen abstraction
and starting from prefunctionalized 2-iodobenzamides,5 while
Morandi et al. recently published a ruthenium-catalyzed variant
of this reaction.6 Additionally, an electrochemical approach for
such an oxidation has been developed. Therein, amides mostly
derived from cyclic amines are transformed into hemiaminal
methyl ethers that collapse in a second step under acidic
conditions.7 A further appealing approach is the light-mediated
one-step, direct oxidation of N-acetyl-pyrrolidine in the
presence of titanium dioxide and a copper(II) salt.8 However,
the single enamide reported was merely detected spectroscopi-
cally. It thus appears that the development of novel
dehydrogenation methods that do not require prefunctional-
ization and can accommodate N-cyclic and -acyclic amide
substrates is in high demand.
methods to functionalize the carbonyl portion, as well as the α-
position (Scheme 1B).11 However, N-functionalization of
amides has remained virtually uncharted territory. Our long-
standing interest in the field of amide activation prompted us
to speculate whether the initially formed iminium triflate I
(Scheme 1B) might offer a pathway for N-dehydrogenation.
We hypothesized this intermediate to exhibit enhanced
acidity of the proton α to nitrogen and became intrigued by
the possibility of activating it in the presence of a strong, non-
nucleophilic base.12 Herein, we report the development of a
Received: April 27, 2021
Published: July 7, 2021
In recent years, electrophilic amide activation has emerged
as a powerful tool to overcome the intrinsic low electrophilicity
of amides.9 In particular, the combination of triflic anhydride
and suitable pyridine bases10 has enabled a plethora of
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a
new protocol that allows access to enamides from amides via
electrophilic amide activation.
Scheme 2. Scope of N-Alkylamides.
Extensive optimization was necessary to unlock N-
dehydrogenation reactivity on model substrate 1a,13 with the
unprecedented combination of LiHMDS, triflic anhydride
(Tf2O) and diethyl ether as the solvent proving optimal and
affording product 2a in 89% isolated yield (Table 1, entry 1). It
a
Table 1. Optimization of the Reaction Conditions
b
entry
deviation from standard conditions
yield (%)
c
1
2
3
4
5
6
7
8
none
NaHMDS
KHMDS
2-I-pyr
LDA
THF
−78 °C
inverse addition
94 (89 )
15
traces
0
11
84
87
52
d
e
a
Reaction conditions: 1a (0.30 mmol), LiHMDS (1.44 mmol, 1 M
solution in THF, 4.8 equiv), Tf2O (0.72 mmol, 2.4 equiv), Et2O (1.5
b
c
d
mL). GC yields using decane as internal standard. Isolated yield. 2-
I-pyr (2.2 equiv) followed by the addition of Tf2O (1.1 equiv), DCM,
e
0 °C to rt, 16 h. First addition of Tf2O, then LiHMDS; average result
based on two runs.
is noteworthy that KHMDS and NaHMDS performed
considerably worse, and other bases showed marginal to no
reactivity altogether (entries 2−5). When diethyl ether was
replaced by tetrahydrofuran or when the temperature was
elevated, a slightly lower conversion was observed (entries 6
and 7). These conditions are all the more surprising as it is well
known (and confirmed by our experience) that ethereal
solvents are generally incompatible with Tf2O, as they undergo
swift polymerization at noncryogenic temperatures. To our
surprise, the counterintuitive preaddition of LiHMDS played a
significant role in the success of this process: a considerable
decrease in yield (from 94% to 52%) was observed when Tf2O
was added first (entry 8).
With reliable reaction conditions in hand, we proceeded to
investigate the scope of this reaction, initially focusing on the
nitrogen substituent of the amide (Scheme 2). Good to
excellent yields were obtained for enamides of different ring
sizes (2a−c, 2a gave 80% yield on gram scale). Additionally,
heteroatom-substituted (2d), bicyclic (2e), and also morpho-
line- and piperazine-derived enamides (2f, 2g), were readily
synthesized in good yields. Importantly, acyclic amides, which
are scarcely reported in other oxidation protocols (vide supra),
were also amenable to this method, and E-enamides were
obtained exclusively (2h−j).
Next, nonsymmetric amides were analyzed, showing a
marked preference for N-dehydrogenation of the least
encumbered nitrogen substituent (2k−o), and even modest
selectivity between ethyl and butyl substituents was found
(2p). On the basis of these auspicious results, we turned our
attention to some more complex systems. An amide derivative
of the drug paroxetine, bearing one β-substituent, was
desaturated regioselectively (albeit in modest yield) to provide
a
Reaction conditions: amide (0.30 mmol), LiHMDS (1.44 mmol,
1 M solution in THF, 4.8 equiv), then Tf2O (0.72 mmol, 2.4 equiv),
b
Et2O (1.5 mL). DCM was used as cosolvent.
a single regioisomeric enamide 2q, and a derivative of
norlaudanosine, a dopamine metabolite, was N-dehydrogen-
ated smoothly (2r).
Following the study of different nitrogen substituents, our
focus shifted to the investigation of the carbon portion of the
carboxamide (Scheme 3). The highly encumbered enamide 4a
and anthracenyl-derived enamide 4b were obtained in good
yields. Importantly, unsubstituted benzamides also delivered
the desired enamides, albeit in lower yields (4c, 4d). Again,
upscaling allowed a gram-scale synthesis of the enamide 4c.
Interestingly, while shuffling methyl (4e, 4f) and methoxy
(4g−i) substituents around the aromatic ring, an enhanced
reactivity was observed for substrates carrying a methyl group
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Communication
a
To showcase the utility of the products, we performed
several further functionalization reactions (Scheme 4). The
Scheme 3. Scope of Benzamide Derivatives
Scheme 4. Application of Enamides
a
4c (1.0 equiv), methyl coumalate (1.1 equiv), toluene, 130 °C, 15 h.
4c (1.0 equiv), ethyl 4-aminobenzoate (1.0 equiv), p-chlorobenzal-
b
dehyde (1.0 equiv), Sc(OTf)3 (0.2 equiv), MeCN, rt, 3 d, then DDQ
c
(2.0 equiv), CHCl3, rt, 16 h. 2a (1.0 equiv), 2-(trimethylsilyl)phenyl
trifluoromethanesulfonate (3.0 equiv), CsF (4.0 equiv), 1,4-dioxane,
d
110 °C, 16 h. 4c (1.0 equiv), (4-methoxyphenyl)hydrazine
e
hydrochloride (1.2 equiv), AcOH/EtOH/H2O, 110 °C, 1 h. 4c
(1.0 equiv), Selectfluor (4.0 equiv), AgBF4 (2.5 equiv), acetone/H2O,
f
rt, 16 h. 4j (1.0 equiv), CF3SO3H/CHCl3 (1:1), rt, 16 h. R = H/
g
OMe (9:1). 2a (1.0 equiv), diphenyliodonium triflate (2.0 equiv),
copper(II) triflate (0.2 equiv), DCM, 80 °C, 24 h.
enamides generated herein could be readily engaged in
cycloaddition reactions featuring inverse electron-demand
Diels−Alder reactions (5a, 5b), or even a [2+2] cycloaddition
with arynes (5c).15−17 Moreover, ring deconstruction was
readily achieved under oxidative fluorinating conditions,
allowing access to a decarbonylated fluorinated acyclic amine
(5e).18 In a Fischer indole synthesis-type reaction, the carbon
core again was easily deconstructed, allowing the synthesis of a
phenyl-melatonin derivative (5d).19 In addition, under acidic
treatment, a Nazarov-type cyclization was observed, forming
tricyclic lactam 5f in good yield.20 Finally, β-arylation of the
enamide was readily achieved under copper catalysis, affording
5g in modest yield.21 The broad spectrum of reactivity
presented by these functionalizationsfrom cycloadditions to
ring deconstructions to cyclizationshighlights the versatility
of enamides as building blocks.
Mechanistic studies shed additional light on this unusual
transformation (Scheme 5). Use of an 18O-enriched amide
(6a) revealed conservation of the isotopic label in the obtained
product (6b). This is a very unusual trait in electrophilic amide
activation, where the carboxamide oxygen is otherwise almost
always lost.22 Additional labeling experiments employing
deuterated substrates (6c, 6f) revealed kinetic isotope effects
(KIE) of 4.8 for a cyclic (6d:6e) and 34.2 for an acyclic
(6g:6h) substrate. Both results strongly suggest that
a
Reaction conditions: amide (0.30 mmol), LiHMDS (1.44 mmol,
1 M solution in THF, 4.8 equiv), then Tf2O (0.72 mmol, 2.4 equiv),
Et2O (1.5 mL). LiHMDS (3.6 equiv) and Tf2O (1.8 equiv) were
used. DCM was used as cosolvent.
b
c
in the ortho position, whereas a methoxy group was shown to
be advantageous in the meta and para position.14
Other electron-rich aromatics (4j−l) were also amenable to
the reaction, as were various aryl halides (4m−o). In addition,
the process proved to be tolerant of several functional groups,
including vinyl (4p), thiol (4q), and nitrile (4r) substituents.
Unfortunately, thienoyl- and furoylamides (3s, 3t) failed to
react, and no conversion was observed. To our delight, a
ferrocene-derived enamide (4u) was obtained in good yield,
and we were pleased to find a functional-group-heavy
conjugate of vanillic acid and febuxostat to provide the desired
N-dehydrogenated product 4v. With the exception of 3u, all
reactions with nonbenzamide substrates were unsuccessful,
presumably due to a slower activation with triflic anhydride for
α-tertiary amides or the generation of a keteniminium ion in
the case of enolizable amides.13
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a
Scheme 5. Mechanistic Studies and Our Proposal
a
b
For exact reaction conditions see Table 1, entry 1. Conditions: −78 °C, THF.
abstraction of the proton α to nitrogen is involved in the rate-
determining step of the reaction. Moreover, the latter result,
which shows an unusually high primary isotope effect, leads to
the conclusion that quantum tunneling might come into play.
As tunneling effects are well known to gain influence at lower
temperatures, and in particular when using highly sterically
hindered bases,23 we tested the same substrate (6f) at a higher
temperature (−41 °C), which revealed a diminished KIE of
13.2. Additionally, in the 19F NMR analysis of the crude
reaction mixture, the presence of triflinate (7) was observed
and analysis of the crude reaction mixture by HRMS even
revealed the presence of a mixed S(IV)/S(VI) species (8) (see
the Supporting Information for a proposed mechanism for the
formation of 8). Importantly, a deuteration experiment
indicated no direct abstraction of the N-α-hydrogen by the
base, precluding an alternative deprotonation/triflation mech-
anism.13 On the basis of these findings, we postulate a
mechanism in which amide activation to an iminium triflate by
Tf2O decisively acidifies the N-α-hydrogen, after which a
deprotonation/elimination step takes place, leading to
extrusion of a triflinate anion (7), thus accounting for the
18O label retention. A subsequent elimination leads to the
observed enamide products.
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
Nuno Maulide − Institute of Organic Chemistry, University of
Vienna, 1090 Vienna, Austria; orcid.org/0000-0003-
3643-0718; Email: nuno.maulide@univie.ac.at
Authors
Philipp Spieß − Institute of Organic Chemistry, University of
Vienna, 1090 Vienna, Austria; orcid.org/0000-0003-
2674-0165
Martin Berger − Institute of Organic Chemistry, University of
Vienna, 1090 Vienna, Austria
Daniel Kaiser − Institute of Organic Chemistry, University of
Vienna, 1090 Vienna, Austria; orcid.org/0000-0001-
8895-9969
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.1c04363
In conclusion, we have described a new method to access
enamides via an oxidation event mediated by electrophilic
amide activation under unusual conditions. To the best of our
knowledge, this is the first general one-step approach for the
synthesis of N-cyclic and -acyclic enamides that does not
require prefunctionalization of the substrates. Applications
include modification of drug derivatives, cycloadditions, as well
as ring deconstructions and emphasize the privileged position
of enamides as unique building blocks. Most importantly, the
unlocking of N-functionalization through electrophilic amide
activation promises to open yet further perspectives in this
chemistry.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work has been supported by the Austrian Science Fund
(FWF, P32206) and the European Research Council (CoG
VINCAT 682002). We are grateful to the University of Vienna
for continued, generous support of our research programs.
M.B. was a fellow of the FWF-funded doctoral program
́
MolTag (W1232). We acknowledge Dr. J. Matyasovsky, Dr. P.
Grant, Mr. S. Heindl, and Mr. M. Vavrik (all from U. Vienna)
for auxiliary experiments and proofreading, as well as Ing. A.
Roller (U. Vienna) for X-ray crystallography measurements.
Lastly, we would like to thank the MS department (U. Vienna)
and Prof. H. Kählig (U. Vienna) for NMR assistance.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.1c04363.
■
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REFERENCES
■
Experimental procedures; spectroscopic and X-ray data
(PDF)
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Accession Codes
CCDC 2075992 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
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