Synthesis of Novel Heterocycles by Amide Activation and Umpolung Cyclization

Article abstract of DOI:10.1021/acs.orglett.0c00571

Herein, we report a metal-free synthesis of cyclic amidines, oxazines, and an oxazinone under mild conditions by electrophilic amide activation. This strategy features an unusual Umpolung cyclization mode and enables the smooth union of α-aryl amides and diverse alkylazides, effectively rerouting our previously reported α-amination transform.

Full text of DOI:10.1021/acs.orglett.0c00571

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Letter
Synthesis of Novel Heterocycles by Amide Activation and Umpolung
Cyclization
Haoqi Zhang,§ Margaux Riomet,§ Alexander Roller, and Nuno Maulide*
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ABSTRACT: Herein, we report a metal-free synthesis of cyclic amidines, oxazines, and an oxazinone under mild conditions by
electrophilic amide activation. This strategy features an unusual Umpolung cyclization mode and enables the smooth union of α-aryl
amides and diverse alkylazides, effectively rerouting our previously reported α-amination transform.
ince its original report by Ghosez,1 electrophilic amide
Sactivation using trifluoromethanesulfonic anhydride
different pathway became operative, leading to skeletal
rearrangement products (Scheme 1b).6 Intrigued by these
results and other literature precedents,7 we explored these
(Tf2O) has emerged as a particularly versatile synthetic
method.2 The formation of a keteniminium intermediate (in
transformations further and varied the substrate structure and
reaction conditions for the α-amination of amide.
the case of tertiary amides) or a nitrilium species (for
secondary amides) and their reaction with diverse cyclo-
addition partners or nucleophiles have led to a cornucopia of
domino-like transformations over the past three decades.3
Among the large variety of nucleophiles that can
productively interact with a keteniminium intermediate, we
were intrigued by the versatility of organic azides. Our group
previously reported that the combination of activated amides
with azides delivers α-amination products (Scheme 1a).4 In
another study, we opted to generate the reactive keteniminium
by protonation of an ynamide.5 In this case, an entirely
Surprisingly, when 2-phenylacetamide 1a was activated
under electrophilic conditions, followed by the addition of
homobenzylazide 2a (Scheme 2), the reaction product was not
Scheme 2. Unexpected Synthesis of 3a
Scheme 1. Reactivity of Keteniminiums toward Alkyl Azides
the expected α-aminoamide A as reported previously.4 Rather,
a new product was isolated as a triflate salt whose structure
could be confirmed as the seven-membered ring amidinium
triflate 3a by single-crystal X-ray analysis (Scheme 2). This
unexpected product appeared to result from reaction of a
stabilized intermediate by the pendant arene. We could
previously observe such Umpolung reactivity of the α-carbon
Received: February 13, 2020
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after addition of pyridine N-oxide derivatives on activated
amides.7a,8
In this work, we present the synthesis of cyclic amidinium
triflates, oxazines, and an oxazinone by rerouting of our
previously reported α-amination transformation, including
mechanistic studies of these processes.
At this juncture, we sought to optimize the reaction
parameters to enhance the reaction efficiency toward product
3a. To this end, we screened the stoichiometry of the different
reaction partners as well as temperature and several bases
(Table 1). An initial study showed that a quinoline base was
transformation. Further investigation revealed a beneficial
impact of the decrease in the number of equivalents of
quinoline base (compare entries 1 and 2).
A first study of the quinoline base motif showed that the 2-
chloro substituent was essential in the reaction (see the
Supporting Information for details). Electron-deficient quino-
lines showed better efficiency in the reaction (entries 2, 3, and
5), and 2,4-dichloroquinoline proved to be the best base. We
also observed that an increase in temperature (entry 4) as well
as a larger excess of azide (compare entries 5 and 6) led to
byproducts and decreased the yield of desired product 3a.
Finally, 2 equivalents of triflic anhydride was needed to obtain
the desired product in highest yields (compare entries 6 and
7).
Table 1. Optimization of Conditions for the Formation of
a
Amidinium Triflates
With the optimized reaction conditions in hand, we
investigated the scope of this cyclization reaction (Scheme
3). First, the tolerance toward the amide partner was
investigated (1a−1g). Different N-alkyl substituents were
tolerated on the amide partner and did not display a strong
impact on the reaction (cf. 3a−3c). On the other hand,
substitution on the aromatic moiety was more influential.
Strong electron-donating (3e) and electron-withdrawing para-
substitution (3f and 3g) of the phenyl group decreased the
yield of the desired product. In the case of a p-nitro group (3f),
the α-aminated amide could be isolated as the major
compound (36%). This result supports the necessity of
stabilizing a benzylic carbocation to favor the cyclization
process. The steric hindrance provided by an o-bromo
substitution (3d) did not affect the reactivity.
entry Tf2O (equiv) 2a (equiv) quinoline (equiv) T (°C) yield (%)
1
2
3
4
5
6
7
2
2
2
2
2
2
1.1
2
2
2
2
2
1.1
1.1
A (5)
A (2)
B (2)
B (2)
C (2)
B (2)
B (2)
rt
rt
rt
40
rt
rt
rt
48
63
75
63
66
78
53
a
Reactions were carried out on a 0.2 mmol scale. Yields refer to the
isolated product.
We then diversified the azide partner. Changes in its
pendant arene moiety particularly affected the reactivity.
Electron-donating groups generally gave the desired cyclic
amidinium triflates in high yield. On the other hand, electron-
essential for promoting both amide activation and subsequent
elimination as well as interruption by the aromatic ring in this
a
Scheme 3. Scope of Amidinium Triflates with Arylic Azides
a
b
Reactions were carried out on a 0.2 mmol scale. Yields refer to the isolated product. Product synthesized with 1-(azidomethyl)-4-
methoxybenzene and obtained as a mixture of 6-methoxy and 7-methoxy isomers (0.3:0.7).
B
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withdrawing substituents showed reduced reactivity. Com-
pound 3j, bearing a p-fluorine substituent, was obtained in 39%
yield. A nitro group in the meta position completely inhibited
the reaction, and only traces of 3k could be detected.
Interestingly, the formation of six-membered ring amidinium
salts (3l and 3m) did not proceed as readily as their seven-
membered counterparts. Furthermore, unlike the previous
reactions, the usage of an azide bearing substituents on the
aromatic part led to an unseparable mixture of two
regioisomeric six-membered ring amidinium triflates (3m).
On a 4 mmol scale, 3a was obtained in 83% yield, i.e., >1 g of
material, showing the excellent scalability of the reaction.
Unfortunately, this reaction did not permit access to larger
cycles (eight- or nine-membered rings).
Scheme 5. Mechanistic Proposal for the Formation of
Amidines
a
With a general synthetic route to these structures in hand,
we investigated further derivatization (Scheme 4). After a short
Scheme 4. Further Functionalization of Amidinium Triflates
a
Part I shows the isolation of regioisomers, and part II the proposed
mechanism for the formation of seven- and six-membered rings.
part II, step b), followed by a rearomatizing bond migration
event that can take place in two different modes.
Inspired by this novel transformation, we attempted to use
different mild nucleophiles for the intramolecular nucleophilic
attack by replacing the aromatic portion of the azide partner.
Interestingly, carbonyl groups were highly suitable for this
role and led to the formation of pyrrolidinyl-oxazines in great
yields (Scheme 6). We could obtain a wide range of new
optimization (see the Supporting Information for details),
amidinium 3a could be hydrolyzed using a biphasic system to
obtain a phenyl-3-benzazepinone (4a) in 63% yield.
Benzazepinone derivatives are known for their pharmacological
properties, but access to such compounds often requires long
synthetic sequences.9 Additionally, triflate salt 3a could be
easily converted to its deprotonated form (5a) by a simple
basic extraction. Alkylation then afforded amidinium salt 6a in
56% yield.
a
Scheme 6. Scope of Oxazines with α-Carbonyl-azides
While the formation of seven-membered rings was
completely regioselective, the lack of regioselectivity for their
six-membered ring counterparts was puzzling at first. To
investigate the mechanism, it was essential to determine which
regioisomers were formed. For this purpose, 3m was
hydrolyzed and the resulting 4ba and 4bb could be separated
and identified giving some insight into their formation
(Scheme 5, part I). We propose that, following keteniminium
formation, attack by the azide sets the stage for N2 release,
generating stabilized carbocation I or a stabilized form thereof.
Indeed, nonbenzylic substrates lead to α-amination products
under the reaction conditions (see the Supporting Information
for more details). For the formation of seven-membered rings,
we propose a Friedel−Crafts-like mechanism capturing the
carbocation (Scheme 5, part II, step a), which is supported by
the observed reactivity difference between electron-with-
drawing and -donating substitutions on the azide partner
(Scheme 3, 3i−3k). In the case of six-membered rings, the
formation of isomers 4ba and 4bb suggests that amidine
formation proceeds via spiro-cyclic intermediate II (Scheme 5,
a
Reactions carried out on a 0.2 mmol scale. Yields refer to the isolated
b
product. Oxazinone was obtained using tert-butyl 2-azidoacetate.
C
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Authors
Haoqi Zhang − Institute of Organic Chemistry, Faculty of
oxazines using this process. The transformation took place with
both aromatic and aliphatic azidoketones with good to
excellent yields (8a−8h). The use of a para-electron-donating
group resulted in a noticeable lower yield (8c), unlike its
electron-withdrawing counterpart (8d). This suggests that the
nucleophilic attack of the carbonyl group might not be the
kinetically determinant event in this reaction. While bulky
substituents at the β-position (8b−8e) were tolerated, α-
substitution decreased the yields (8f and 8g) probably due to
increased steric hindrance. In the event, using an azide with a
quaternary carbon at the α-position led to a messy reaction
mixture, suggesting that either proton elimination is decisive in
this oxazine synthesis or tertiary azides are too bulky to be
suitable substrates. The formed tetrasubstituted oxazines were
also less stable than their trisubstituted counterparts and
needed to be handled carefully. The formation of a seven-
membered ring oxazine (8h) was also possible. It was also
possible to generate an oxazinone 8i, starting from an azido
ester instead of a ketone. While both methyl and ethyl esters
failed in this transformation, a tert-butyl ester was ultimately
successful.
In conclusion, we serendipitously discovered and developed
a novel approach for the preparation of cyclic amidinium salts
and oxazines using domino electrophilic activation of phenyl-
acetamides. We propose that the synthesis of seven-membered
ring amidines takes place by Friedel−Crafts-like intramolecular
cyclization, whereas their six-membered ring counterparts
likely result from an intriguing spirocyclic intermediate,
followed by C−C bond migration. Shifting to azidoketone or
azidoester substrates led to the formation of oxazines and one
oxazinone. The transformations shown here interestingly
reroute our previously reported synthesis of α-aminoamides
and showcase the wealth of chemical space that can be
accessed through electrophilic amide activation.
Chemistry, University of Vienna, 1090 Vienna, Austria
Margaux Riomet − Institute of Organic Chemistry, Faculty of
Chemistry, University of Vienna, 1090 Vienna, Austria
Alexander Roller − Institute of Inorganic Chemistry, Faculty of
Chemistry, University of Vienna, 1090 Vienna, Austria
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c00571
Author Contributions
§H.Z. and M.R. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Funding of this work by the Austrian Science Fund (FWF,
P30226) and the European Research Council (ERC, CoG
682002 VINCAT) is acknowledged. The authors thank the
University of Vienna for its continued and generous support of
our research programs.
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ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c00571.
Expended optimization for the formation of amidinium
salts and their hydrolysis, synthetic procedure, and
analytical data of all compounds (PDF)
FAIR data including the primary NMR FID files for
compounds 1c−d; 3a−m; 4a; 4ba; 4bb; 6a; 8a−i; S4−6
(ZIP)
(4) Tona, V.; De La Torre, A.; Padmanaban, M.; Ruider, S.;
́
Gonzalez, L.; Maulide, N. Chemo- and Stereoselective Transition-
Metal-Free Amination of Amides with Azides. J. Am. Chem. Soc. 2016,
138, 8348−8351.
Accession Codes
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Jouvin, K. Ynamides: Versatile Tools in Organic Synthesis. Angew.
Chem., Int. Ed. 2010, 49, 2840−2859. (b) DeKorver, K. A.; Li, H.;
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560−578.
CCDC 1983045−1983046 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
(6) Tona, V.; Ruider, S. A.; Berger, M.; Shaaban, S.; Padmanaban,
AUTHOR INFORMATION
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M.; Xie, L.-G.; Gonzalez, L.; Maulide, N. Divergent ynamide reactivity
■
in the presence of azides an experimental and computational study.
Chem. Sci. 2016, 7, 6032−6040.
Corresponding Author
Nuno Maulide − Institute of Organic Chemistry, Faculty of
Chemistry, University of Vienna, 1090 Vienna, Austria;
Email: nuno.maulide@univie.ac.at
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