TCIMAIL No.

186 l Spring 2021

Research Article

Trifluoromethanesulfonic Anhydride in Amide Activation:

A Powerful Tool to Forge Heterocyclic Cores

Haoqi Zhang, Margaux Riomet, Nuno Maulide

Institute of Organic Chemistry, University of Vienna, Währinger Strasse 38, 1090 Vienna, Austria
E-mail: [email protected]

Abstract
Trifluoromethanesulfonic anhydride is a powerful reagent for the activation of a wide range of functionalities.
Among them, the electrophilic activation of amides is a compelling approach to access heterocycles under mild reaction
conditions. Herein, we outline the most recent achievements in the construction of heterocycles via amide activation
with trifluoromethanesulfonic anhydride.

Keywords: Trifluoromethanesulfonic anhydride, triflic anhydride, amide activation, heterocycle, Umpolung

Introduction well as the presence (or absence) of a base (Scheme 1).

When subjected to triflic anhydride 2, amides are
In recent decades, trifluoromethanesulfonic generally rapidly converted to the corresponding
anhydride, also known as triflic anhydride, has proven iminium triflates 3. Further deprotonation, usually by
to be an extraordinary reagent for a broad range a pyridine derivative can lead to formation of a highly
of transformations. Given its high affinity towards electrophilic intermediate – a nitrilium ion 5 in case of
O-nucleophiles, reaction with alcohols, carbonyls, sulfur- secondary amides, or a keteniminium ion 6 for their
phosphorus- and iodine oxides towards formation of tertiary counterparts. These ionic species participate in
the corresponding triflates is strongly favoured. As one an equilibrium with the pyridine adducts 7 and 8. Amide
of the premier leaving groups in organic chemistry, activation with triflic anhydride has yielded a literal
the generated triflates then open the door to various cornucopia of novel transformations.[5–7] In particular,
downstream transformations, including (but not limited recent years have seen its exploitation by various groups
to) substitution reactions, cross-coupling processes, redox for the generation of heterocyclic cores. Due to their
reactions and rearrangements.[1,2] pervasive presence in biological and pharmaceutically
relevant structures, the preparation of heterocycles
In this ocean of possible applications, our group remains a focal point in organic synthesis. In this short
has been particularly interested in the electrophilic review, we will focus on recent discoveries for the
activation of amides with triflic anhydride. Thanks to the formation of heterocycles via amide activation with triflic
pioneering work of Ghosez and Charette,[3,4] it is known anhydride.
that the reaction can proceed through different reactive
intermediates, depending on the nature of the amide 1 as

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Scheme 1. Amide activation with Tf2O and formation of different reaction intermediates.

Activation of Secondary Amides with Triflic Anhydride

Intramolecular Annulations
The susceptibility of amides for nucleophilic attacks
after activation with triflic anhydride was explored for
a range of cyclisation processes. Movassaghi et. al.
showcased its utility for a Bischler-Napieralski type
process (Scheme 2A). [8] After amide activation, the
intermediate underwent intramolecular SEAr reaction;
rearomatization then resulted in isoquinolines 11
and their 3,4-dihydro derivatives. In comparison to
classical Bischler-Napieralski conditions using POCl3,
elevated reaction temperatures could be avoided, while
acid-sensitive substrates were well tolerated. As an
alternative approach, Hendrickson’s reagent, obtained
from triphenylphosphine oxide and triflic anhydride,
was employed in the same transformation to further
exacerbate oxophilicity in the amide activation event.[9]

As an extension of this mild cyclodehydration

reaction, the activation of N-(2-pyridinylmethyl)-
benzamides 12 with triflic anhydride resulted in formation
of bicyclic imidazo[1,5-a]pyridines 13 (Scheme 2B).
By utilising an electron richer base in form of 2-methoxy-
pyridine in conjunction with mild heating, the conversion
could be further increased. [10] In contrast, amide
activation in presence of a conjugated C-C double bound
(14) led to increased β-electrophilicity as showcased Scheme 2. Intramolecular annulations of activated secondary amides.
in the intramolecular cyclisation of N-aryl cinnamyl A: isoquinolines. B: imidazo[1,5-a]pyridines. C: quinolin-2(1H)-ones
amides 15 (Scheme 2C).[11] 2,3-Dichloro-5,6-dicyano- (DTA = N,N-dimethyl trifluoroacetamide).
1,4-benzoquinone (DDQ) was employed as an additional
oxidant to decrease the reaction time and improve
selectivity towards poly-substituted quinolin-2(1H)-ones
15.

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Intermolecular Annulations
The activation of amides opens the doorway to a
broad range of external nucleophiles. The nucleophilic
addition of a nitrile 18 to the in-situ formed nitrilium
ion 17 led to the formation of a new nitrilium species
19 (Scheme 3A). [12,13] In presence of an N-vinyl or
N-aryl moiety, Movassaghi showed that this reactive
intermediate further underwent an electrocyclisation
event, convergently yielding pyrimidine derivatives 20.
Similarly, the reaction with alkynes 22 or enol-ethers
23 proceeded with formation of corresponding cations
followed by cyclisation and aromatization to pyridine
and quinoline derivatives 24 (Scheme 3B).[14–16]

In complementary fashion, our group investigated

the transformation with alkynes 26 in absence of N-vinyl
or N-aryl functionality on the amide substrate 25 (Scheme
3C). In comparison to the former approaches, the reaction
was conducted at elevated temperature and with an excess
of amide starting material, resulting in poly-substituted
pyrimidine derivatives 27. Comparable to the previous
reaction, a vinylcation intermediate 29 is formed after
addition of the alkyne substrate 26. Fuelled by the high
reaction temperatures, the initial nitrilium species also
partially underwent fragmentation to the corresponding
nitrile 30, which subsequently attacked the vinylcation
intermediate. Ensuing cyclisation and dealkylation
eventually resulted in formation of the heterocyclic core
27.[17]

Scheme 3. Intermolecular annulations of activated secondary amides.

A: pyrimidines via nitriles. B: pyridines and quinolines via alkynes
and enols. C: pyrimidines via formal (2+2+2) with alkynes.

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Furthermore, the use of ethyl diazoacetate 34 as

nucleophile in conjunction with N-aryl amides 33, Wang
and coworkers achieved a concise, single step synthesis
of indoles 35 (Scheme 4A).[18] Of particular note was the
necessity for catalytic amounts of 2,6-dichloropyridine
in addition to the usual 2-chloropyridine. The authors
reasoned this as the consequence of reversible formation
of a highly electrophilic species 36, which could be
further intercepted by ethyl diazoacetate 34. The
resulting intermediate 37 underwent a Friedel-Crafts
type cyclisation releasing nitrogen gas and producing
the indole core 35 after tautomerization. Moreover, the
activation of N-aryl amides with triflic anhydride was
exploited for an one-pot Pictet-Spengler-like cyclisation
(Scheme 4B). [19] This domino process started with
the in-situ condensation of aldehyde 39 and amine 40
to imine 42, followed by nucleophilic attack thereof
on the activated amide, prior to electrophilic aromatic
substitution to obtain 3,4-dihydroquinazolines 41.

In absence of N-aryl or N-vinyl moieties, the

cyclisation event can also be realized by condensation of
the former amide nitrogen. This approach was employed
for the synthesis of highly substituted 1,2,4-triazoles
45 (Scheme 4C).[20] Here, the attack of hydrazide 44 on
activated amide 43 was followed by cyclodehydration
to forge the heterocyclic core. In parallel, our group
has realized the regioselective synthesis of tetrazolium
scaffolds 48 through a formal [3 + 2] cyclisation (Scheme
4D). [21] Computational studies revealed a stepwise
mechanism initiated by the nucleophilic attack of azide
47 on the nitrilium intermediate, followed by annulation
to the final heterocycle.

Scheme 4. Attack of various nucleophiles on nitrilium ion

and subsequent cyclisation. A: indoles via ethyldiazoacetate.
B: 3,4-dihydroquinazolines via Pictet-Spengler-like cyclisation.
C: 1,2,4-triazoles via hydrazines. D: tetrazolium ions via azides.

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Activation of Tertiary Amides with Triflic Anhydride

Intramolecular Annulations

Scheme 5. Intramolecular cyclisations initiated by activation of tertiary amides. A: lactones by rearrangement of ethers. B: lactones by attack of
alcohol derivatives. C: benzazepinones with alkenes. D: base dependent regio-selective formation of pyrimidines. E: oxazolium ions in absence of
base.

Compared to the aforementioned secondary amides, 6-membered lactones 51. Complementary to this work,
the activation of tertiary derivatives with triflic anhydride the direct use of alcohols or ether derivatives 54, non-
in presence of a weak nucleophilic base typically forms amenable to sigmatropic rearrangement, produced the 5-,
keteniminium ions as reactive intermediates. Our group 6- and 7-membered heterocycles 55 (Scheme 5B).[23]
investigated the reactivity of tertiary amides 49 carrying For this approach, the absence of the usual base was
an inbuilt ether moiety (Scheme 5A).[22] After formation crucial to avoid formation of elimination products.
of intermediate 50, the reaction favoured the nucleophilic The competition between the [2+2] cycloaddition
attack of the ether oxygen and formation of oxonium and nucleophilic pathways with alkenes was further
ion 52. The intermediate subsequently underwent a investigated by De Mesmaeker and coworkers with
[3,3]-sigmatropic rearrangement, leading to intermediate 53. α-aminoamides 56 (Scheme 5C).[24] In presence of an
Further hydrolysis resulted in functionalised 5- and electron-withdrawing substituent on the amino nitrogen

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56, the [2+2] cyclisation was favoured. With electron- α-Umpolung of Amides with Triflic Anhydride
neutral or -donating substituents on 56, amide activation
promoted the nucleophilic attack of the styryl group and In all presented cases above, the electrophilic
ultimately yielded benzazepinones 58. activation of amides yields a highly electrophilic amide
carbon. Under suitable conditions, this reactivity can also
Additionally, the susceptibility of keteniminium ions be transferred to the usually nucleophilic α-carbon. This
towards intramolecular capture was showcased in the concept was recently investigated by our group in the
synthesis of 3-amino-thiophene derivatives [25–27] and α-Umpolung of amides (Scheme 6). Following activation
aminoimidazo-pyrimidines 60 and 61 (Scheme 5D).[28] with triflic anhydride, the keteniminium intermediate
In the latter reaction, the nature of the base played a can be intercepted by a pyridine-N-oxide derivative 65,
paramount role in the regioselectivity. The authors forming the adduct 66. It is noteworthy that this species
hypothesised that the 2-fluoropyridine-promoted reaction possesses electrophilic character at what was formerly
kinetically favoured the cyclisation to pyrimidine 60. the α-carbon to the amide functionality in the starting
On the other hand, 2,6-difluoropyridine primary acted amide 64. Postulated fragmentation to the epoxide 67
as a buffer for the in situ generated triflic acid and thus allows attack at the α-carbon by triflate ion. In contrast
supported the formation of the thermodynamic product to the starting amide 64, the resulting reactive key
61. Our group further investigated the role of the pyridine intermediate 68 is now susceptible toward nucleophiles
base during regio- and chemoselective cyclisation of at the α-position, opening up a broad range of new
amide 62 to bicyclic alkoxy oxazolium ions 63 (Scheme transformations.
5E).[29] To our surprise, the addition of a base suppressed
the reaction and only starting material was recovered. In
stark contrast, the absence of base quantitatively yielded
the desired heterocycle.

Scheme 6. Umpolung of amides with triflic anhydride and N-oxides

Our group utilised this electrophilic Umpolung of In absence of the competing N-oxide, the transformation
amides for an intramolecular, metal-free C-C coupling involved migration of the sulfonyl group, consequently
reaction (Scheme 7A). [30] As opposed to previously yielding imidazole derivatives 72 as the final products.
discussed transformations originating from a Friedel- In a similar fashion, using 1,4,2-dioxazol-5-ones (as
Crafts-like cyclisation, the activation of amide 70 and both Umpolung-reagent and nucleophilic substrate), an
subsequent Umpolung by lutidine N-oxide resulted in C-C alternative direct synthesis of amino-oxazole scaffolds 77
coupling at the α-carbon, ultimately affording a broad was achieved (Scheme 7C).[32]
range of pyridinone and isoquinolinone derivatives 71.
By taking this concept further, arylalkylazides 79
Further investigation revealed that the absence of an were investigated as Umpolung reagents and nucleophiles
internal nucleophile in nitrile solvents leads to a different to forge heterocycles. In presence of a bulky, weak
reaction mode (Scheme 7B).[31] Instead of the formation nucleophilic base, such as 2,4-dichloroquinoline, addition
of the triflate intermediate, the in-situ formed epoxide of arylalkylazide 79 resulted in a domino cyclisation
was attacked by the ubiquitous solvent, resulting in the event (Scheme 7D).[33] Depending on the chain length of
annulation product 74. By exchanging acetonitrile to the azides, 6- or 7-membered cyclic amidiniums 80 were
alternative nitriles, a broad palette of amino oxazoles accessible. By interchanging the arene functionality with
could be synthesised. Additionally, the employment of an other nucleophiles such as ketones or esters, an efficient
N-sulfonyl functionality at the amide α-position resulted synthesis of functionalised oxazines/oxazinones 82 was
in a mechanistically intriguing rearrangement sequence. achieved.

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Scheme 8. Synthesis of novel heterocycles by a cascade rearrangement

reaction.

Conclusion
The electrophilic activation of amides with triflic
anhydride provides a mild and sustainable approach to
forge heterocyclic cores. Depending on the nature of the
amides and the presence or absence of base additives,
highly reactive intermediates in form of vinyl- triflates,
nitrilium ions or keteniminium ions are accessible. Each
Scheme 7. Heterocycle formation by Umpolung of amides.
of these species offers new pathways for functionalisation
A: pyridinone and isoquinolinone derivatives by C-C coupling.
B: imidazoles and oxazoles via nitriles. C: oxazoles with and annulation, leading to a wide palette of heterocycles.
1,4,2-dioxazol-5-ones as the Umpolung-reagent. D: cyclic amidiniums By using suitable reacting partners, such as N-oxides or
and oxazine derivatives with azides and cascade cyclisation. azides, the α-Umpolung of amides is enabled. This in turn
opens the door to an array of powerful transformations,
Miscellaneous including C-C bound formation, α-oxidation and
mechanistically intriguing rearrangement reactions. The
In addition to the discussed methodologies, the breadth of recent examples of heterocycle formation
mild activation of amides with triflic anhydride also highlights the utility of triflic anhydride for electrophilic
allows unusual reactivity en route to heterocycles. amide activation and outlines its potential for the future
In an example from our own work, the presence of a discovery of further, hitherto unknown transformations.
phthalimide functionality on the α-branched amide 83 led
to an unexpected rearrangement reaction with acetonitrile
(Scheme 8). [34] In contrast to the usual conditions,
2,6-di-tert-butylpyridine (DTBP) was used as a base. We
hypothesized that this base would not add to the activated
amide, thus favouring cyclisation to 84. A nucleophilic
attack followed by deprotonation of acetonitrile might
then afford intermediate 85. Subsequent ring opening to
86, followed by 7-membered ring closure and hydrolysis
resulted in novel heterocyclic scaffolds 87.

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Haoqi Zhang

B.Sc., M.Sc.

Institute of Organic Chemistry, University of Vienna

Haoqi Zhang is a Ph.D. student in the group of Professor Nuno Maulide at

the University of Vienna, where he received his MSc degree in 2020 working
on electrophilic Umpolung of amides for the construction of cyclic amidines and oxazines. For his
Ph.D. thesis, he remained at the Maulide Group and his current interest lies in natural product
synthesis and drug design.

Margaux Riomet

Dipl.-Ing. Dr., M.Sc.

Institute of Organic Chemistry, University of Vienna

Margaux Riomet currently occupies a postodoctoral position in the research

group of Professor Nuno Maulide at the University of Vienna. She studied
chemistry at Ecole Nationale Supérieure de Chimie de Paris where she completed her
Engineering Degree and Msc degree in 2015 in partnership with Université Pierre et Marie
Curie. In 2018, she obtained her PhD degree under the supervision of Dr. Frédéric Taran at CEA
Saclay. Her Ph. D. work was dedicated to the chemistry of iminosydnones and their applications
in biology. Her current research interests combine the development of new methodologies for
synthesis and the design of molecular objects for live cell imaging.

Nuno Maulide

Professor, Ph.D.

Institute of Organic Chemistry, University of Vienna

Nuno Maulide is a Full Professor and Chair of Organic Synthesis at the

University of Vienna. He obtained a Ph.D. in 2007 at the Université catholique
de Louvain under the supervision of Prof. István E. Markó. Subsequently, he joined the group
of Prof. Barry M. Trost at Stanford University for a post-doctoral stay in 2007-2008. In 2009, he
started his independent career as a Max-Planck-Research Group Leader at the Max-Planck
Institut für Kohlenforschung. In 2013, he moved to his current position as a Full Professor at the
University of Vienna. Since 2018, he is an Adjunct PI at CeMM. He is a member of the Board of
Editors for Organic Synthesis (2018) as well as an Associate Editor of Organic Letters (2018)
and JACS AU (2020). For his research, he received numerous awards, including the recent
Tetrahedron Young Investigator Award (2020), Springer Heterocyclic Chemistry Award (2018)
and 3 ERC Grants. Nuno Maulide was named Scientist of the Year in Austria (2019) and is an
elected Corresponding Member of the Austrian Academy of Sciences (2018).

Related Products
Trifluoromethanesulfonic Anhydride (Tf2O) 10g 25g 250g T1100
2-Chloropyridine (2-Cl-Pyr) 25g 100g 500g C0279
2-Methoxypyridine (2-MeO-Pyr) 25mL M0788
2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) 25g 250g D1070
N,N-dimethyl trifluoroacetamide (DTA) 5g 25g T3262
2-Fluoropyridine (2-F-Pyr) 25g 100g F0217
2,6-Dichloropyridine (2,6-diCl-Pyr) 25g 500g D0410
2-Iodopyridine (2-I-Pyr) 5g 25g I0533
2,4-Dichloroquinoline (2,4-diCl-quinoline) 5g 25g D4452
2,6-Di-tert-butylpyridine (DTBP) 5g 25g D1804

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