A Novel Class of 7-Membered Heterocyclic Compounds

Article abstract of DOI:10.1002/ejoc.202000363

The work presented herein describes the synthesis of a formerly inaccessible class of heterocyclic compounds. The reaction relies on α-phthalimido-amides, which are readily prepared from amino acids in 2 simple reactions steps. Under amide activation conditions in which classical keteniminium ions are not formed, the nitrile solvent is incorporated into the new fused 7-membered ring system. Due to the absence of a keteniminium intermediate, the stereogenic information in the α-position is fully retained.

Full text of DOI:10.1002/ejoc.202000363

Communication
doi.org/10.1002/ejoc.202000363
EurJOC
European Journal of Organic Chemistry
Electrophilic Amide Activation
A Novel Class of 7-Membered Heterocyclic Compounds
Adriano Bauer,[a] Eszter Borsos,[a] and Nuno Maulide*[a]
Abstract: The work presented herein describes the synthesis ions are not formed, the nitrile solvent is incorporated into the
of a formerly inaccessible class of heterocyclic compounds. The new fused 7-membered ring system. Due to the absence of a
reaction relies on α-phthalimido-amides, which are readily pre- keteniminium intermediate, the stereogenic information in the
pared from amino acids in 2 simple reactions steps. Under α-position is fully retained.
amide activation conditions in which classical keteniminium
Introduction
The enhanced nucleophilicity of amides in comparison to other
carbonyl functionalities has been noted already in the 19th cen-
tury.[1] This peculiar reactivity was later leveraged into so-called
electrophilic amide activation, a reactivity principle that relies
on the treatment of the amide with a strong electrophile such
as trifluoromethanesulfonic anhydride (triflic anhydride) and a
base in modern approaches (Scheme 1a).[2] In doing so, the
amide is transformed into an α-trifloxyenamine 2, which resides
in a biased equilibrium with the keteniminium salt 3. The latter,
a highly electrophilic species, can be intercepted by several
nucleophiles, including nucleophilic oxidants,[3–7] and enables
a range of unconventional reactivity profiles for the atoms sur-
rounding the original amide functionality.[8–12] The capture of
the central electrophilic atom of the keteniminium by modestly
nucleophilic entities such as alkenes (in formal [2+2] cyclo-
addition reactions[13,14] or other ring-forming events)[15] or
ethers[16,17] is a well-documented phenomenon. Although the
chemistry of amide activation is dominated by keteniminium
formation from tertiary amides, the use of secondary amide
starting materials or the outright avoidance of keteniminium
formation can be similarly rewarding.[18–22] It is noteworthy that
amide activation is generally a versatile tool for the construc-
tion of heterocyclic compounds.[19,21,23–28]
We recently reported that capture of an activated amide, at
the iminium triflate stage, by a proximal ester affords previously
inaccessible oxazolium salts (Scheme 1b).[25] Omission of the
base was crucial because it precluded keteniminium formation
(and consequently prevented unproductive reaction pathways).
Herein we would like to report a synthesis of structurally novel
7-membered heterocyclic rings, which similarly relies on the ac-
tivation of tertiary amides in the absence of keteniminium spe-
Scheme 1. a) Modern approach to classical amide activation. b) Synthesis of
alkyl-substituted oxazolium salts by amide activation in absence of a base.
c) Formation of a novel class of 7-membered rings via amide activation in
absence of keteniminium ions.
cies (Scheme 1c). This class of compounds has, to the best of
our knowledge, not been accessible so far and represents an
entirely novel scaffold.
Results and Discussion
In the course of our studies on α,ꢀ-dehydrogenation of
α-branched amides we investigated the amino-acid derivative
8a under the typical conditions of amide activation
(Scheme 2).[4,29] The expected desaturation (to product 10) was
observed when the activated amide was treated with pyridine
N-oxide in 1,2-DCE upon heating. However, we noticed that
when acetonitrile was used as the solvent, the main product of
the transformation was the 7-membered ring 9a. Inspection of
the structure reveals that the nitrile solvent was incorporated
into the final product, and indeed nitriles are known to attack
[a] A. Bauer, E. Borsos, Prof. Dr. N. Maulide
Institute of Organic Chemistry, University of Vienna
Währinger Straße 38, 1090 Vienna, Austria
E-mail: nuno.maulide@univie.ac.at
http://maulide.univie.ac.at
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.202000363.
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activated amides.[24] However, in this case, the nitrile-derived
With suitable conditions in hand, we investigated if other
fragment is not attached to the former amide functionality. We substrates undergo this unusual reactivity (Scheme 3). First, a
further noticed that product 9a was not particularly stable and range of substituents in the α-position of the amide was investi-
decomposed slowly under air at room temperature upon stand- gated. As shown, variations on the structure of 8a/8b were tol-
ing.
erated. It seems that a number of α-benzyl or -allyl-substituted
amides were generally privileged substrates for this transforma-
tion (cf. 9d–g). In many cases, the yields determined by 1H NMR
analysis of the crude mixture with mesitylene as the internal
standard resulted much higher than the isolated. This is most
likely due to the decomposition of the unusual heterocycle dur-
ing purification via column chromatography. Neither the unsub-
stituted 9h nor its α-phenyl-substituted cognate 9i could be
generated by this approach, leading instead to complex mix-
tures. α-Succinimide amides gave exclusively the starting mate-
rial back.
Scheme 2. Serendipitous discovery of 7-membered heterocycle 9a. Yields re-
a
fer to pure, isolated material unless otherwise stated. NMR Yield. See SI for
details.
During optimization, which was undertaken on substrate 8b,
we first noticed that the yield was considerably lower on this
very similar substrate under the previously described conditions
(Table 1 – Entry 1). Interestingly, the reaction proceeded in the
absence of a base (Entry 2/3). Moreover, no desired product
was observed when pyridine was used as the base (Entry 4).
These results indicated that, similar to our previous study,
(Scheme 1b) the avoided formation of a keteniminium interme-
diate might be crucial to allowing the formation of 9b. Indeed,
when the sterically hindered proton scavenger 2,6-ditert-butyl-
pyridine (DTBP) was applied, a base that is most likely unable
to deprotonate the α-methine of the activated amide under
these conditions, the yield increased considerably (Entry 5). This
is consistent with the fact that DTBP was only observed to pro-
mote keteniminium formation when less sterically hindered α-
methylene protons were abstracted,[30] although the tempera-
ture might also play a decisive role.[31] Concluding on the exper-
iments of Table 1, the reaction might not need a base that
directly participates in the formation of the product. It is more
likely that DTPB acts as a proton scavenger to improve the yield.
Proton scavengers have been indeed observed to improve the
general efficiency of amide activation reactions.[32]
Table 1. Optimization of the 7-membered ring formation.
Scheme 3. Product scope of the 7-membered ring formation. The yields refer
a
Entry
Tf2O equiv.
Base
Base eq.
Time
Yield[a] Yield
to pure, isolated material unless otherwise stated. Yields determined by
1H NMR analysis of the crude reaction mixture with mesitylene as the internal
standard.
1
2
3
4
5
1.1
3.0
1.1
1.1
1.1
2-Cl Py
/
/
Py
2.2
/
/
2.2
2.2
0.5 h
0.5 h
2 h
0.5 h
0.5 h
15 %
41 %
15 %
0 %
/
/
/
/
Next, we decided to screen other nitrile solvents and elected
to assay butyronitrile as the reaction partner for this transfor-
mation (cf. 9j). The resulting product 9j was formed in a good
70 % yield.
DTBP
55 %
48 %
[a] Yield determined by 1H NMR analysis of the crude product with mesit-
ylene as the internal standard.
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Scheme 4. a) 18O-labeling study. b) Evidence for the absence of keteniminium/vinyltrilfate formation c) Proposed mechanism.
Last, we studied the influence of substituents on the phthal- (carbon 2 in Scheme 4b), strongly suggesting that this reaction
imide moiety. While an electron-donating group on the distal does not proceed via a keteniminium ion. Moreover, we were
position (carbon 11/12) gave a 1:1 mixture of two regioisomers, able to obtain a single crystal of the enantioenriched sample
an electron-withdrawing bromide showed a moderate selecti- (S)-9d in order to confirm the structure by X-ray analysis.
vity for the isomer 9l′. A methyl group in the proximal position
(carbon 10/13) showed a rather distinct regioselectivity of 9:1.
2D-NMR analysis of the mixture suggests that the major isomer
is surprisingly 9m′, i.e. with the methyl group in direct proximity
to the amidine moiety.
Concluding from our experiments in Scheme 4a/b we pro-
pose the following mechanism for this transformation. Follow-
ing the formation of O-triflyl oxyiminium ion 10, one of the
neighboring phthalimido carbonyl oxygens attacks the highly
electrophilic iminium carbon atom. The so generated oxazol-
The stability of these intriguing structures is, not surprisingly, inium ion 10 is then attacked by acetonitrile (the solvent) and,
limited. The remarkable concatenation of an enolester, a 2-aza- upon deprotonation, the ketenimine 12 is generated. This spe-
diene, and a phthalimide-derived amidine is, to the best of our cies then undergoes a 5→7 ring enlargement to yield the
knowledge, unprecedented. Most of the products tended to charged precursor of the final product (14), which is finally
decompose on silica during column chromatography, systemat- converted into the product by aqueous hydrolysis during the
ically resulting in diminished isolated yields when compared to workup. The mechanism is somewhat reminiscent of the revers-
crude NMR assays with an internal standard. When the silica ible ring-opening of 4-oxazolines to azomethine ylides which
was basified with 1 % of trimethylamine or neutral Al2O3 was can act as 1,5-dipoles,[33] although 1,3-dipolar cycloadditions
used as the stationary phase, products decomposed com- are more commonly observed.[34]
pletely. The use of Florisil® on the other hand, resulted in similar
yields (compared to silica gel).
Thereafter mechanistic investigations were undertaken. The
reaction mixture becomes strongly colored after triflic an-
hydride is added and usually turns black after the reaction time
Conclusions
In this work, we showed that certain α-phthalimido-amides can
be converted into unusual 7-membered heterocyclic systems
of 30 minutes. However, during the aqueous quench, the black
under electrophilic amide activation in acetonitrile. Noteworthy,
turbid color fades quickly to a clear red/orange/yellow solution
our results strongly suggest that the reaction does not proceed
(depending on the substrate). This observation led us to the
via a keteniminium intermediate or analogous vinylic species.
The formed products, with a concatenation of sensitive func-
tional groups, can be isolated in yields up to 72 %.
assumption that an iminium ion might be transiently formed,
which is quickly hydrolyzed to the observed lactone moiety.
To support this hypothesis, we quenched the reaction with
18O-labelled water and could indeed observe the full incorpora-
tion of the isotope by mass spectrometry (Scheme 4a).
Experimental Section
In an additional experiment, the enantioenriched (e.r.
> 99 %) phenylalanine derivative (8d) was subjected to the
reaction conditions. Interestingly, no racemization of the
Reaction Procedure (Scheme 3): The α-phthalimido amide
(1.0 equiv., 0.20 mmol) was dissolved in the nitrile (1 mL) and cooled
α-position took place under the optimal reaction conditions to 0 °C. DTBP was added (2.2 equiv., 0.44 mmol, 99 μL), followed by
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Acknowledgments
Funding of this work by the Austrian Science Fund (FWF,
P30226) is acknowledged. We thank the University of Vienna for
its continued and generous support of our research programs.
Keywords: Amide activation · Cyclization · Heterocycles ·
7-Membered rings · Synthetic methods
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Received: March 18, 2020
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Electrophilic Amide Activation
A. Bauer, E. Borsos, N. Maulide* .... 1–5
A Novel Class of 7-Membered Het-
erocyclic Compounds
We report that α-phthalimido-amides tion, where the nitrile solvent is incor-
can be converted into unusual 7-mem- porated into the final product, a keten-
bered heterocycles by electrophilic iminium intermediate appears not to
amide activation. In this transforma- be involved.
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