N-triflyl-propiolamides: Preparation and transamidation reactions

Article abstract of DOI:10.1016/j.tet.2019.05.027

N-Trifluoromethylsulfonyl-propiolamides have been prepared by two methods: a) N-triflation of secondary acetylenic carboxanilides, prepared in two steps from terminal alkynes, with triflic anhydride (Tf₂O) and b) from terminal alkynes and an aryl or alkyl isocyanate followed by Tf₂O in a consecutive one-pot reaction. The title compounds are bench-stable and insensitive to water and alcohols but amenable to transamidation reactions with a wide range of amine nucleophiles. Conversely, they are excellent reagents for the propynoylation of ammonia, primary and secondary amines, anilines, and hydrazines.

Full text of DOI:10.1016/j.tet.2019.05.027

Accepted Manuscript
N-triflyl-propiolamides: Preparation and transamidation reactions
Vito A. Fiore, Gerhard Maas
PII:
S0040-4020(19)30565-4
https://doi.org/10.1016/j.tet.2019.05.027
TET 30348
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 23 April 2019
Revised Date: 10 May 2019
Accepted Date: 11 May 2019
Please cite this article as: Fiore VA, Maas G, N-triflyl-propiolamides: Preparation and transamidation
reactions, Tetrahedron (2019), doi: https://doi.org/10.1016/j.tet.2019.05.027.
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N-Triflyl-propiolamides: Preparation and
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Vito A. Fiore, Gerhard Maas
Institute of Organic Chemistry I, Ulm University, Albert-Einstein-Allee 11, D-89081 Ulm, Germany

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Tetrahedron
journal homepage: www.elsevier.com
N-Triflyl-propiolamides: Preparation and transamidation reactions
Vito A. Fiorea and Gerhard Maasa,
aInstitute of Organic Chemistry I, Ulm University, Albert-Einstein-Allee 11, D-89081 Ulm, Germany
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
N-Trifluoromethylsulfonyl-propiolamides have been prepared by two methods: a)
N-triflation of secondary acetylenic carboxanilides, prepared in two steps from
terminal alkynes, with triflic anhydride (Tf2O) and b) from terminal alkynes and an
aryl or alkyl isocyanate followed by Tf2O in a consecutive one-pot reaction. The title
compounds are bench-stable and insensitive to water and alcohols but amenable to
transamidation reactions with a wide range of amine nucleophiles. Conversely, they
are excellent reagents for the propynoylation of ammonia, primary and secondary
amines, anilines, and hydrazines.
Available online
Keywords:
Carboxamides
Sulfonamides
Transamidation
Acetylenes
2009 Elsevier Ltd. All rights reserved
.
N-acylation
Corresponding author. Tel.: +0-049-731-22791; fax: +0-049-731-22803 e-mail: gerhard.maas@uni-ulm.de

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ACCEPTED MANUSCRIPT
as N-sulfonyl carboxamides (N-SO2Me,13 N-tosyl,11a,13a
N-4-nitrophenylsulfonyl,14 N-SO2CF315) are suitable
substrates for these purposes. Reaction of an activated
amide with R1R2NH/LiHMDS further facilitates the
transamidation, even for weakly nucleophilic and
sterically hindered anilines.11b
1. Introduction
The amide bond is the most fundamental functional
group in organic compounds. It is not only an essential
structural moiety in peptides and proteins as well as in
certain synthetic polymers (polyamides), but it is also
present in quite a number of pharmaceuticals and
biologically active compounds. Therefore, it is not
surprising that a number of strategies and methods for
the construction of the amide bond have been
established in the past and continue to be developed
up to present. Several recent reviews reflect the
ongoing activities to improve existent methods and to
put to work novel ideas with the goals of efficiency,
atom economy and environmental benign synthesis.1−5
Concerning medicinal chemistry synthesis, analyses of
a limited set of papers published in 1984, 2008 and
2014 have shown, that amide bond formation was and
still is by far the most frequently encountered reaction
type.6
Scheme 1. Transamidation of carboxamides.
The abovementioned amide forming reactions have
been performed with a wide range of aliphatic and
(hetero)aromatic carboxylic acids and carboxamides.
On the other hand, in connection with other studies on
α,β-acetylenic carboxamides, we realized that only
few approaches to such compounds are in common
use (see section 2.1). This situation may be caused by
several different factors, such as the commercial
availability and eventually high price of propiolic
acids and their 3-substituted derivatives, limited
stability of the corresponding acid chlorides, or
competing Michael addition of the amine reagent in
direct transamidation reactions. Furthermore, only a
few types of N-activated propiolic amides (N-Ac, N-
Ts, N-Ms) are known.16 Encouraged by the report of
Hendrickson and Bergeron,15a showing that N-triflyl
anilides (R−CO−N(Ph)−SO2CF3) are easy-to-prepare,
bench-stable, and excellent transamidation reagents,
we decided to synthesize so far unknown α,β-
acetylenic N-triflyl carboxanilides (or N-aryl-N-
propynoyl triflamides) and to study their
transamidation potential.
Major synthetic approaches to carboxamides are
provided by: the direct condensation of carboxylic
acids and amines (thermally induced, Lewis acid
catalyzed), by N-acylation of amines using carboxylic
acids and stoichiometrically applied coupling reagents,
and reaction of amines with common carboxylic acid
derivatives (e.g. acid halides, mixed anhydrides and
unactivated esters) or amine surrogates (e.g. azides,
isocyanates, nitriles), and the transamidation of other
carboxamides. The last-mentioned strategy can also be
considered as an amine acylation process (Scheme 1).
In contrast to reactive carboxylic acid derivatives, the
electrophilicity of non-activated primary, secondary
and tertiary carboxamides is low and harsh reaction
conditions are often required. Moreover, the
transamidation is, in principle, an equilibrium
reaction. Depending on the individual transamidation
reaction, these difficulties may be overcome by using
“traditional” variations, such as a large excess of the
amine substrate, use of primary amides (RCONH2,
leading to extrusion of volatile ammonia) or taking
advantage of different nucleophilicities of the involved
amines. More recently, catalytic methods have been
developed,4b,7,8 which include the use of Brønsted
2. Results and discussion
2.1. Syntheses of triflamides 4
The title compounds, N-triflyl propiolic amides 4,
were prepared from terminal alkynes 1 on two routes,
one via N-triflation of secondary propiolic amides
(Scheme 2, method A), and the other via triflation of
acetylenic amidate intermediates (isocyanate route,
method B). Following method A, propiolic amides
3a−e were prepared from alkynes 1 in two steps via
esters 2 using conventional methods. When secondary
amides 3 were treated with a molar excess of triflic
anhydride and diisopropylethylamine at low
temperature, the acetylenic N-triflyl amides 4a-e were
obtained in fair to good yields (Table 1). The terminal
acetylenic amide 3f was obtained by desilylation17 of
3d and N-triflated to give triflamide 4f in good yield.
In contrast, several attempts of fluoride- or proton-
induced desilylation of TMS-alkyne 4d ended in
acids,
boron-based
Lewis
acids
such
as
B(OCH2CF3)3,9a and of Cu,9b Fe,9c Ni9d,e or Pd9f,g based
catalysts, to name just a few.
Catalyst-free transamidation procedures involving
reaction partners of low reactivity are not easy to
achieve. It has just been reported that uncatalyzed
formylations of weakly nucleophilic aromatic amines
with comparably reactive formamide (HCONH2) and
of primary or secondary aliphatic amines with DMF
can be brought about in high yields, but under harsh
conditions (150 °C, reaction time ≥ 24 h).10 In contrast,
N-activated primary and secondary amides can react
effectively with a broad range of amines (NH3,
primary and secondary aliphatic amines) under much
milder conditions. N-Boc and N,N-(Boc)2,11−13 as well
undefined
product
mixtures.

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Scheme 2. Preparation of N-triflyl propiolamides 3 in this study. Method A: a) 1. alkyne 1 in THF, -78 °C, then n-BuLi/hexane, 2. ClCO2Me, -78 °C,
3 h → r.t. b) PhNH2, n-BuLi/THF, -78 °C, 30 min; 2. propiolic ester 2a-e,g, -78 °C, 3 h → r.t. See Tables 1 and 2 for substituents and yields. DIPEA =
N,N-diisopropyl-N-ethylamine.
(Table 2). It is obvious that the isocyanate route
(method B) is more attractive than method A, since it
is an operationally simple and in general high-
yielding, consecutive two-step reaction, which gives
access to a variety of triflamides 4 from terminal
Table 1
Preparation of N-triflyl-propiolamides 4 from
acetylenic amides 3 (Scheme 2, method A)
alkynes 1 and isocyanates 5.
Yield (%)
for 3 → 4
Amide 3
R1
R2
Table 2
a
Ph
Ph
68
71
47
35
60
75
69
Preparation of N-triflyl-propiolamides 4 on the
isocyanate route (Scheme 2, method B)
b
c
cyclopropyl
Ph
4
a
b
c
d
e
h
i
R1
R2
Yield (%)
n-Bu
SiMe3
Ph
Ph
d
e
fa
gb
Ph
Ph
Ph
94
88
89
82
76
96
79
70
mesityl
Ph
cyclopropyl
n-Bu
SiMe3
Ph
Ph
H
Ph
I
Ph
Ph
aPrepared by desilylation of 3d (1. MeOH, KF/Al2O3
mesityl
Ph
(5%);17
2. HCl aq. (5%); quant.).
t-Bu
bPrepared from 3f (1. NaOH, MeOH, 10 min; 2. I2, 3
h; quant.).
4-Cl-C6H4
Ph
Ph
j
Et
Method A has several drawbacks, as it requires
three steps with isolation and purification of 2 and 3,
and a significant excess (1.2−2 equiv) of expensive
Tf2O was found to enhance the reaction times and also
the yields of triflamides 4. In addition, we found that
optimal yields were obtained when the batch size was
not larger than 15 mmol. On the other hand, it is well
known that amides can be prepared directly from
alkynyl metals (RLi, RMgBr) and isocyanates via
amidate adducts, which are usually quenched with a
proton donor to deliver secondary amides. This
approach has also been applied to the direct synthesis
of secondary propiolamides from metalated terminal
alkynes and isocyanates.16b,18,19,20a Moreover, the
amidate intermediate has been trapped with other
electrophiles instead of H+ (e.g. propargyl bromide21
and mesyl chloride16b), resulting in the formation of
tertiary amides. In our case, we have trapped imidate 6
(Scheme 2) with triflic anhydride and obtained the
desired N-acyl triflamides 4 in good to high yields
The N-selective triflation of amides 3 with triflic
anhydride/amine base under the given conditions is
remarkable. In quite a number of studies, it has been
found that secondary amides react with Tf2O/base
(base = DIPEA,22 pyridine, non-nucleophilic 2-halo-
pyridines23,24) by O-triflation, leading to intermediate
iminium salts [R1−C(OTf)=N+HR2 TfO-] or neutral
imidoyl triflates, which can react with a variety of
nucleophiles either under displacement of the triflate
substituent23 or via nitrilium intermediates that result
from β-elimination of triflic acid.24 N-triflation of
secondary amides with Tf2O is rarely mentioned as a
minor side-reaction,25, and the same can be said for
tertiary amides.26 Interestingly, both O- and N-
triflation of NH-lactams with Tf2O/pyridine has been
observed, but only in the case of piperidin-2-one, the
N-triflyl-lactam is the major product.27 While the
selective N-triflation of acetylenic secondary amides 3

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according to our method A stands in contrast to most
of the discussed reports, the high-yielding N-triflation
of N-benzyl-benzamide and of piperidin-2-one with
Tf2O was achieved after NH-deprotonation with a
strong base (NaH, t-BuLi).15a In this case, an amidate
intermediate similar to 6 was generated, the N-
triflylation of which is in agreement with our method
B. Anyway, the molecular structures of 4a and 4f were
confirmed by XRD analyses (see section 2.2). All
acetylenic triflamides 4 are bench-stable solids and
insensitive to water and aliphatic alcohols under
ambient conditions.
analysis and are shown in Figures 1 and 2a. While the
general molecular features of both molecules are
similar and need no further comment, some geometric
details of the amide bond (Table 3) deserve a closer
look. Amide bond geometries in N-Boc, N-Ts and
other activated aliphatic and aromatic carboxamides
have been studied just recently in order to uncover
correlations between their structure and reactivity in
uncatalyzed
and
transition-metal
catalyzed
transamidation reactions (for selected references, see
lit.28).
2.2. Solid-state structures of triflamides 4a and 4g
Fig. 1. Molecular structure of 4a in the crystal. Selected bond
lengths [Å]: C2−C3 1.195(3), C1−N 1.438(3), C1−O1 1.194(3),
N−S 1.645(1).
The molecular structures of acetylenic triflamides
4a,g have been determined by X-ray diffraction
Fig. 2. Solid-state structure of 4g. Selected bond lengths [Å]: C2−C3 1.193(4), C1−N 1.413(3), C1−O1 1.211(3), N−S 1.661(2). Halogen
bond: C3−I 1.995(3), I−O1’(0.5 + x, 1.5 − y, 1 − z) 2.941(3); angle C3−I···O1’(-0.5 + x, 1.5 – y, 1 − z) 178.3(3)o. Left: Molecular structure
with iodine−oxygen halogen bonds (Mercury plot), bond distances and angles are given in blue color. Right: One-dimensional infinite chain
in the crystal, projection along the b axis (Mercury plot).
Table 3
Selected geometric data of the amide bond in 4a,g
Amide
C=O [Å]
Torsion angles [deg]
τa
Sum of bond
angles at N
360.0
N−C(O) [Å]
S-N-C1-O1
-13.3(3)
-8.5(4)
CPh-N-C1-C2
S-N-C1-C2
167.2(2)
CPh-N-C1-O1
165.3(2)
4a
4g
1.438(3)
1.413(3)
1.194(3)
1.211(3)
-14.1(3)
-9.5(4)
13.7
9.0
171.9(2)
170.2(3)
360.0
aTwist angle τ, as defined by Winkler and Dunitz.29

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It can be seen that in both structures, the torsion
angle at the N−C bond is small and the N atom is
trigonal-planar (i. e., sp2-hybridized), as in
Ph−C(=O)−N(Ts)Ph (τ = 18.8°; N−C(O) 1.410 Å,
C=O 1.215 Å).28a It can be expected that a less twisted
amide bond allows a better nN → π*C=O electron
delocalization, and this would explain the bond length
variations between 4a and 4g. It can be questioned,
however, whether the marginal twist difference at the
C−N bond could influence the bond length changes
that much. A more reasonable explanation is the
presence of a C=O···I halogen bond in the solid-state
structure, where the carbonyl oxygen atom acts as an
electron donor.
comprehensively, and the influence of I···O and other
halogen bonds on crystal structure architectures has
also been addressed in several recent publications.32
Molecules of 4g contain both an XB donor and an XB
acceptor, and therefore they can function as self-
complementary tectons in supramolecular aggregates.
The nearly planar backbone of the infinite chains has a
sawtooth shape with a repeat distance of only 9.267 Å
(the length of the crystallographic a axis). This
compactness results from the E configuration at the
(N)C=O(···I) bond and the comparably small C−O···I
angle (114.3o). We have investigated earlier the solid-
state structures of several 3-iodopropiolamides
containing cyclic dialkylamino groups, which also
form 1D infinite chains, partly with similar structural
motifs as in the crystal of 4g (see Table 4).33 The I···O
distance (2.941(3) Å) in 4g, as in other
propiolamides,33,34 is distinctly shorter than the sum of
van der Waals radii (rI + rO = 3.50 Å). The known
range for C≡C−I···O=C halogen bond distances,
according to a recent compilation (CSD data search in
2016, 13 structures34), amounts to 2.754–3.241 Å.
The crystal structure of 3-iodopropiolamide 4g is of
interest, because it is built on non-covalent
iodine−oxygen halogen bonds (XB), which connect
the molecular tectons into one-dimensional infinite
chains (Figure 2b). The nature of the halogen bond30,31
and its significance in many different areas of
chemistry (organic, biological, macromolecular,
material and others)30 have been reviewed
Table 4
Characteristic bond geometry data of iodine−oxygen halogen bonds in some acetylenic amides
[a]
Amide
Space
group
d(I···O’) (Å)
RIO
Angle
Angle
Configuration at
C1=O1 bond [b]
Ref.
C3−I···O’ (o)
178.3(3)
175.6(4)
C1−O···I’’ (o)
114.3(3)
150.6(4)
4g
Pbca
2.941(3)
2.762(4)
0.840
0.789
E (170.9)
Z (-2.0)
This work
33
3-iodopropiol- C2/c
pyrrolidinide
3-iodopropiol- P21/c
piperidide
2.754(2)
0.787
172.6(3)
130.8(3)
33
E (-142.8)
a RIO =dIO/(rvdW(I) + rwdW(O)).
b C1−N and O···I bond on the same side; in parentheses: torsion angle N−C1−O1···I (deg).
with a wide range of amines under mild conditions
and in high yields (Scheme 3 and Table 5, only results
for 4a are shown). Notably, a conjugate addition of the
amine at the acetylenic bond of 4 (Michael addition)
has not been observed at all. For better comparison, all
reactions were performed at room temperature. The
progress of a reaction could be followed conveniently
by 19F NMR spectroscopy, which indicated the
2.3. Triflamides 4 as propynoylation reagents
N-Triflyl-carboxamides are known as excellent
reagents for the acylation of amines.15 These
transamination reactions can be performed under
milder conditions when the leaving group is the N-
phenyl-triflamide rather than the unsubstituted
triflamide ([TfNH]-) anion. We report now that
acetylenic N-phenyl-N-triflyl propiolamides 4 are
excellent amine acylation reagents, too, which react
.
disappearance of 4a (δF
= -72.9 ppm) with
concomitant formation of HN(Tf)Ph (δF = -76.6 ppm)
Scheme 3. N- and O-propynoylation with acetylenic N-triflylamide 4a.

6
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Table 5
Acetylenic amides 7 prepared from triflamide 4a and various amines (see Scheme 3)
Entry
Amine
Amide
no.
t a
Yield [%][b]
96
1
Ammonia
7a
10 min
2
3
4
5
6
Dimethylamine
Diethylamine
Allylamine
7b
7c
7d
7e
7f
1–2 min
1–2 min
1–2 min
1–2 min
1–2 min
93
89
88
92
91
Propargylamine
Piperidine
7
Morpholine
7g
1–2 min
91
8
9
Diisopropylamine
7h
7i
11 (4) days 89
1,2-Ethylenediamine
1–2 min
6 h
90
97
89
10
N,O-Dimethyl-
hydroxylamine
7j
11
12
2-Aminoethanol
Aniline
7k
7l
1–2 min
60 (15) min 96
13
14
4-Aminobenzoic acid
7m
7n
10 (2) h
97
1,3-Phenylenediamine
Perfluoroaniline
30 (10) min 93
15
16
7o
7p
3 months
8 h
0
Methyl phenyl-
alaninate
98
17
Glycylglycine
7q
5 (3.5) h
97
a In parentheses: reaction time with added NEt3 (5 mol %).
b Acetonitrile as solvent, no NEt3. Synthesis of 7a in water, of 7b,d,g,p,q in CH3OH−H2O (1:1 v/v).
The effectiveness and scope of acylation reactions
with 4a as a N-propynoylation reagent is illustrated in
Table 5. A significant solvent effect (CH3CN, CH3OH,
CH2Cl2, Et2O) on reaction times and yields could not

7
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be observed. Due to the stability of triflamides 4
toward water and alcohols, some of the reactions were
performed in the almost “green chemistry” mixed
solvent methanol/water (1:1)35 without yield losses
(amine = NH3, allylamine, Me2NH, morpholine,
methyl phenylalaninate, glycylglycine). Acylation of
ammonia, primary aliphatic, secondary acyclic and
cyclic amines with no α-branched substituents was
finished almost instantaneously; longer reaction times
were required for sterically demanding (N(i-Pr)2) and
less nucleophilic primary amines (phenylalaninate,
N,O-dimethylhydroxylamine, glycylglycine). These
characteristics are in agreement with the generally
accepted mechanism of an SN reaction that includes
nucleophilic addition at the carbonyl group with
form 3-hydroxypyrazole 9a (lit.;36 no yield and
spectroscopic data were given). Analogously,
hydrazides 8b−e underwent cyclization with formation
of 9b−e on brief thermal treatment in the molten state.
In contrast, SiMe3-hydrazide 8f resisted cyclization
under these conditions and decomposition set in above
200 °C. The NMR spectra of 8f indicated the presence
of two sets of signals at 294 K, with beginning
coalescence around 350 K. By analogy with other
hydrazides, the two species are assigned to E/Z
isomerism at the amide bond.37
formation of
a sterically demanding tetrahedral
intermediate. Gratifingly, even the less nucleophilic
class of anilines can be acylated, albeit with extended
reaction times. Only perfluorophenylaniline withstood
acylation even after three months. For comparison,
anilines are not amenable to uncatalyzed (metal-free)
N-acylation by N-Ts and N-Boc activated
carboxamides.9f The known rate-enhancing influence
of added triethylamine could be used to accelerate the
otherwise slow reactions. A comparison with the
preparation of morpholide 7g from 1-(3-
phenylpropynoyl)-1H-1,2,3-benzotriazole
and
morpholine (THF, r.t., 12 h, 53% yield19) shows that
4a is a far more reactive and effective propynoylation
reagent.
Scheme 4. Two-step synthesis of 3-hydroxypyrazoles
9 from acetylenic triflamides 4.
Chemo- and
reactions became evident in some examples, too.
Thus, 2-aminoethanol underwent N-acylation
exclusively, and the amide and carboxyl groups in the
dipeptide (entry 17) as well as in benzoic acid (entry
13) were not affected. 1,2-Ethylenediamine was
susceptible to a fast diacylation, while selective
monoacylation occurred on phenylene-1,3-diamine.
regioselective propynoylation
Based on several previous studies on the
tautormerism of N-substituted 3-hydroxypyrazoles
versus 1,2-dihydro-3H-pyrazol-3-ones,38,39 it was to be
expected that the cyclization products in solution exist
as the hydroxy tautomers 9 rather than the keto forms
9’. In the IR spectra, the absence of amide valence
vibrations in the range 1600−1700 cm-1 and the
presence of several broad absorptions in the range
2500−2900 cm-1 point to the hydroxy tautomer 9 and
O−H···O hydrogen-bonded complexes thereof. In the
1H NMR spectra recorded in [D6]DMSO, one-proton
signals in the δ range 9.63−10.24 ppm speak in favor
of OH rather than NH protons, which are usually
found at lower δ values. The chemical shifts of the
oxygenated ring carbon C-3 of 9a−e were found at δ =
160.0–161.7 ppm in DMSO solution, which is very
close to the value for 3-hydroxy-1-phenylpyrazole
(162.8 ppm39). In the non-polar solvent [D6]benzene,
δ(OH) was found in the range 12.33−12.71 ppm and
δ(C(OH) at 162.9−164.2 ppm; the significant
deshielding of the OH signal compared to DMSO as
solvent is in agreement with NMR data of other 3-
hydroxypyrazoles.39
The stability of triflamides 4 toward alcohols
(MeOH, EtOH, 1,2-aminoethanol, see above) is in
agreement with their lower nucleophilicity compared
to amines. When the reactions were tried at 80 °C,
some decomposition of 4 but no ester formation was
observed. On the other hand, the methoxide ion was
efficiently acylated by triflamides 4 (Scheme 3).
While this reaction is of some interest in mechanistic
terms, the so formed esters 2a,c,d are more
conveniently
accessible
by
the
direct
methoxycarbonylation of the alkynes 1 (see Scheme 1,
method A) and other methods. In competition
experiments, triflamide 4a was exposed to NaOMe
and dimethylamine (or allylamine, aniline) in
methanol solution. In each case, only N-acylation but
no O-acylation was observed. Furthermore, no S-
acylation could be achieved, when nucleophilic
Derivatives of pyrazolones and hydroxypyrazoles
are of interest because of their biological activities in
various areas, and therefore, several different synthetic
approaches to these heterocyclic systems have been
developed.40 One pathway uses the combination of
acetylenic esters and alkyl- or arylhydrazines, but
because of the ambident reactivity of both reactants,
the result is not generally predictable and depends on
the nature of substituents and reaction conditions such
alkanethiols (R-SH,
R = cyclohexyl, tert-butyl;
ethane-1,2-dithiol) and thiolates were applied.
Returning to N-propynoylation, we found that
triflamides 4a−f reacted with phenylhydrazine readily
at room temperature to give hydrazides 8 in high
yields (Scheme 4). Hydrazide 8a has been prepared
earlier
from
ethyl
3-phenylpropiolate
and
phenylhydrazine and has been cyclized thermally to

8
ACCEPTED MANUSCRIPT
as solvent, temperature and others.40,41 For example,
the reaction of ethyl phenylpropiolate and
phenylhydrazine in ethanol at room temperature
afforded hydrazide 8a, (which was thermally
converted into 9a, see above), but 2,5-diphenyl-2,3-
dihydro-1H-pyrazol-3-one in hot EtOH;36 furthermore,
when the reaction was performed in the presence of an
alkoxide base, 3-hydroxypyrazole 9a was obtained
(NaOEt/EtOH, rfx, 42% yield or KOt-Bu/t-BuOH, rfx,
79% yield42). The strength of the triflamide
transamidation pathway outlined in Scheme 4,
although not as atom-economical as the acetylenic
ester pathway, is given by the completely
regioselective, fast and high-yielding hydrazide
formation under mild and base-free conditions.
hexane, 20 mL, 50 mmol, 1 equiv) was added. The
mixture was brought to -30 °C, stirred for 1 h, a
solution of an isocyanate 5 (50 mmol, 1 equiv) in ether
(6 mL) was added and stirring was continued for 3 h.
After addition of Tf2O (15.52 g, 55 mmol, 1.1 equiv)
in ether (6 mL), the mixture was brought to room
temperature and stirred for additional 4 hours. Then it
was extracted with several portions of water until the
water phase was neutral, the organic phase was dried
(Na2SO4), and the solvent was evaporated. The residue
was triturated with ice-cold methanol (5−10 mL)
while scratching with
a glass rod, to induce
crystallization of N-triflyl-propiolamide 4, which was
filtered off and washed with another portion of cold
methanol. Reported yields refer to the amount of
isocyanate.
3. Conclusions
4.1.1.
N,3-Diphenyl-N-((trifluoromethyl)sulfonyl)-
propiolamide (4a). Method A: From amide 3a (3.40 g,
15 mmol), DIPEA (2.33 g, 3.1 mL, 18 mmol) and
Tf2O (5.08 g, 3.0 mL, 18 mmol). Yield: 3.69 g (68%).
Method B: From phenylacetylene (1a, 5.62 g, 6.04
mL, 55 mmol), n-BuLi (2.5 M in hexane, 20 mL, 50
mmol), isocyanate 5a (5.96 g, 5.4 mL, 50 mmol) and
Tf2O (15.52 g, 9.1 mL, 55 mmol) Yield: 16.61 g
(94%). − Colorless solid, m.p. 119.1−119.3 °C. 1H
NMR (CDCl3, 400.1 MHz): δ 7.13–7.15 (m, 2H, HPh),
7.28–7.32 (m, 2H, HPh), 7.42–7.46 (m, 3H, HPh), 7.53–
In this study, we have used the excellent leaving
group property of the N-phenyltriflamide anion for the
transfer of acetylenic carbonyl (propynoyl) structural
moieties from N-triflyl propiolanilides (N-propynoyl-
triflylanilides) onto a wide range of aliphatic amines
and anilines. The acetylenic N-triflyl-carboxamides
can be easily prepared in a two-step one-pot reaction
from terminal alkynes and isocyanates followed by
triflic anhydride. Studies of their solid-state structure
reveal that there is only little torsional distortion at the
C(O)−N amide bond and this does not enhance the
carbonyl activity toward nucleophilic substitution. The
title compounds are reagents of choice for N-
propynoylation reactions, because they are bench-
stable solids, insensitive to water and alcohols, and
have a significantly higher N-acylation potential than
other N-activated carboxamides known so far.
7.62 (m, 3H, HPh) ppm. 13C NMR (CDCl3, 100.6
1
MHz): δ 80.91 (C-2), 97.85 (C-3), 115.05 (q, JC,F
=
324.5 Hz, CF3); 118.48, 128.80, 129.97, 130.70,
131.05, 131.85, 133.40, 134.63 (all CPh); 151.85
(NC=O) ppm. 19F NMR (CDCl3): δ -72.94 ppm. IR
(KBr): ꢀꢁ 2190 (s), 1710 (s), 1591 (m), 1489 (m), 1412
(s), 1283 (s), 1250 (s), 1200 (s), 1114 (m) cm-1. MS
(CI): m/z 354 [M+H]+. Anal. calcd. for C16H10F3NO3S
(353.03): C 54.39, H 2.85, N 3.96; found: C 54.68, H
3.00, N 3.70.
4. Experimental
For a full set of experimental procedures, physical
and spectroscopic data, see supplementary data.
4.1. Typical procedures for preparation of N-
triflyl-propiolamides 4
Method A: A propiolamide 3 (15 mmol) was dissolved
in anhydrous Et2O (100 mL), N,N-diisopropyl-N-
ethylamine (DIPEA, 2.33 g, 3.1 mL, 18 mmol) was
added, and the mixture was cooled at -78 °C. After
addition of triflic anhydride (Tf2O, 5.08 g, 3.0 mL, 18
mmol, 1.2 equiv) in one portion, the mixture was
stirred for 3 h. The colorless precipitate (LiOTf,
[HNEtiPr2]OTf) was filtered off and extracted with
Et2O (3 × 75 mL), then discarded. The filtrate and the
ether extracts were combined, dried (Na2SO4), and
evaporated to dryness at 20 mbar/40 °C. After
recrystallization of the resulting brownish solid from
methanol at -25 °C, product 4 was obtained as a
colorless or yellowish solid.
Method B: A solution of a terminal alkyne 2 (55
mmol, 1.1 equiv) in anhydrous Et2O (75 mL) was
cooled at -78 °C and n-butyl lithium (2.5 M in n-

9
ACCEPTED MANUSCRIPT
4.1.2. 3-Cyclopropyl-N-phenyl-N-((trifluoromethyl)-
sulfonyl)propiolamide (4b). Method A: From
propiolamide 3b (2.79 g, 15 mmol), DIPEA (2.33 g,
3.1 mL, 18 mmol) and Tf2O (5.08 g, 3.0 mL, 18
mmol): Yield: 3.39 g (71%). Method B: From
cyclopropylacetylene (1b, 11.7 M in toluene, 4.70 mL,
3.64 g, 55 mmol), n-BuLi (2.5 M in hexane, 20 mL,
50 mmol), isocyanate 5a (5.96 g, 5.4 mL, 50 mmol)
and Tf2O (15.52 g, 9.1 mL, 55 mmol). Yield: 14.02 g
(88%). − Colorless solid, m.p. 42 °C. 1H NMR
(CDCl3, 400.1 MHz): δ 0.47–0.51 (m, 2H, CH2), 0.83–
0.88 (m, 2H, CH2), 1.14–1.21 (m, 1H, CH), 7.34 (d, 3J
4.1.4.
N-Phenyl-N-((trifluoromethyl)sulfonyl)-3-
(trimethylsilyl)propiolamide (4d). Method A: From
propiolamide 3d (3.12 g, 14 mmol), DIPEA (2.21 g,
2.89 mL, 17 mmol) and Tf2O (4.75 g, 2.8 mL, 17
mmol): Yield: 1.77 g (35%). Method B: From
trimethylsilyl-acetylene (1d, 5.40 g, 7.8 mL, 55
mmol), n-BuLi (2.5 M in hexane, 20 mL, 50 mmol),
isocyanate 5a (5.96 g, 5.4 mL, 50 mmol) and Tf2O
(15.52 g, 9.1 mL, 55 mmol). Yield: 14.34 g (82%). −
1
Colorless solid, m.p. 79 °C. H NMR (CDCl3, 400.1
MHz): δ 0.01 (s, 9H, SiCH3), 7.36−7.38 (m, 2H, HPh),
7.48−7.55 (m, 3H, HPh) ppm. 13C NMR (CDCl3, 100.6
MHz): δ -1.32 (SiCH3), 93.77 and 106.95 (C≡C),
119.82 (1JC,F = 324.6 Hz, CF3); 129.82, 130.59,
131.00, 134.46 (all CPh); 150.93 (NC=O) ppm. 19F
NMR (CDCl3) δ -72.95 ppm. (KBr): ꢀꢁ 1713 (s), 1593
(w), 1489 (m), 1421 (s), 1258 (s), 1223 (s), 1204 (s),
1127 (s), 1076 (w), 1028 (w), 1003 (w), cm-1. MS
= 7.45 Hz, 2H, HPh), 7.47–7.55 (m, 3H, HPh) ppm. 13
NMR (CDCl3, 100.6 MHz): δ -0.25 (CH), 10.27
(CH2), 69.03 (C-2) and 106.40 (C-3), 119.85 (1JC,F
C
=
324.7 Hz, CF3); 129.75, 130.54, 130.81, 134.69 (all
CPh); 151.40 (NC=O) ppm. 19F NMR (CDCl3): δ -
72.99 ppm. IR (KBr): ꢀꢁ 2209 (s), 1715 (s), 1594 (m),
1491 (s), 1417 (s), 1358 (m), 1223 (s), 1131 (s), 1033
(m), 1003 (s), 955 (s), 917 (s) cm-1. MS (CI): m /z 318
[M+H]+. Anal. calcd. for C13H10F3NO3S (317.03): C
49.21, H 3.18, N 4.41; found: C 49.18, H 3.37, N 4.60.
(CI): m /z
=
350 [M+H]+. Anal. calcd. for
C13H14F3NO3SSi (349.40): C 44.69, H 4.04, N 4.01;
found: C 44.60, H 4.14, N 3.97.
4.1.5.
N-(2,4,6-Trimethylphenyl)-3-phenyl-N-
4.1.3. N-Phenyl-N-((trifluoromethyl)sulfonyl)hept-2-
ynamide (4c). Method A: From propiolamide 3c (3.35
g, 18 mmol), DIPEA (2.71 g, 3.6 mL, 21 mmol) and
Tf2O (5.97 g, 4.1 mL, 21 mmol): Yield: 2.78 g (47%).
Method B: From 1-hexyne (1c, 3.61 g, 5.1 mL, 44
mmol), n-BuLi (2.5 M in hexane, 16 mL, 40 mmol),
isocyanate 5a (4.76 g, 4.33 mL, 40 mmol) and Tf2O
(12.41 g, 7.3 mL, 44 mmol). Yield: 11.91 g (89%). −
Pale yellow solid, m.p. 42 °C. 1H NMR (CDCl3, 400.1
MHz): δ 0.78 (t, J = 7.25 Hz, 3H, CH3), 0.97–1.14 (m,
2H, CH2), 1.16–1.29 (m, 2H, CH2), 2.15 (t, J = 6.89
Hz, 2H, CH2), 7.32–7.38 (m, 2HPh), 7.44–7.56 (m,
3HPh). 13C NMR (CDCl3, 100.6 MHz): δ 13.47 (CH3),
18.73 (CH2), 21.67 (CH2), 29.04 (CH2), 73.64 (C-2),
102.19 (C-3), 119.85 (1JC,F = 324.6 Hz, CF3); 129.82,
130.51, 130.85, 134.55 (all CPh); 151.66 (NC=O) ppm.
19F NMR (CDCl3): δ -72.83 ppm. IR (KBr): ꢀꢁ 2223
(s), 1711 (s), 1595 (w), 1490 (m), 1414 (s), 1208 (s),
1130 (s), 1060 (m), 1032 (s) cm-1. MS (CI): m /z 334
[M+H]+. Anal. calcd. for C14H14F3NO3S (333.33); C
50.45, H 4.23, N 4.20; found: C 50.60, H 4.02, N 4.20.
((trifluoromethyl)sulfonyl)propiolamide (4e). Method
A: From propiolamide 3e (4.00 g, 15 mmol), DIPEA
(2.33 g, 3.09 mL, 18 mmol) and Tf2O (5.08 g, 3.0 mL,
18 mmol): Yield: 3.63 g (60%). Method B: From
phenylacetylene (1a, 1.40 g, 1.5 mL, 13.8 mmol), n-
BuLi (2.5 M in hexane, 5 mL, 12.5 mmol), 2,4,6-
trimethylphenyl isocyanate (5e, 2.02 g, 12.5 mmol)
and Tf2O (3.88 g, 2.3 mL, 13.8 mmol). Yield: 3.76 g
(76%). − Colorless solid, m.p. 71 °C. 1H NMR
(CDCl3, 400.1 MHz): δ 2.35 (s, 6H, CH3), 2.37 (s, 3H,
CH3), 7.05 (s, 2H, HAr), 7.10–7.12 (m, 2H, HPh), 7.28–
7.32 (m, 2H, HPh), 7.42–7.46 (m, 1H, HPh) ppm. 13C
NMR (CDCl3, 125.77 MHz): δ 18.73 (CH3), 21.26
(CH3), 80.38 (C-2), 95.20 (C-3), 119.85 (1JC,F = 325.74
Hz, CF3);118.55, 128.79, 130.16, 130.62, 131.79,
133.58, 138.86, 141.13 (all CAr); 152.87 (NC=O) ppm.
19F NMR (CDCl3): δ -71.05 ppm. IR (KBr): ꢀꢁ 2203
(s), 1703 (s), 1605 (w), 1488 (m), 1442 (m), 1405 (s),
1287 (s), 1210 (s), 1166 (s), 1120 (s), 1033 (w), 1000
(w) cm-1. MS (CI): m /z 396 [M+H]+. Anal. calcd. for
C19H16F3NO3S (395.40): C 57.72, H 4.08, N 3.54;
found: C 57.72, H 4.18, N 3.47.
4.1.6. N-Phenyl-N-((trifluoromethyl)sulfonyl)propiol-
amide (4f). Method A: From N-phenyl-propiolamide17
(3d) (1.47 g, 10 mmol), DIPEA (2.75 g, 3.6 mL, 21
mmol) and Tf2O (5.71 g, 4.9 mL, 20 mmol). Yield:
1
2.10 g (75%). − Colorless solid, m.p. 43 °C. H NMR
(CDCl3, 400.1 MHz): δ 3.22 (s, 1H, CH), 7.36–7.38
(m, 2H, HPh), 7.49–7.58 (m, 3H, HPh) ppm. 13C NMR
(CDCl3, 100.6 MHz): δ 74.08 (C-2), 85.71 (C-3),
1
119.79 (q, JC,F = 324.8 Hz, CF3); 130.08, 130.44,
131.34, 133.76 (all CPh); 150.83 (NC=O) ppm. 19F
NMR (CDCl3: δ -72.78 (CF3). IR (KBr): ꢀꢁ 3278 (m),
2115 (m), 1715 (s), 1595 (w), 1416 (s), 1216 (s), 1168
(s), 1128 (s), 1024 (w) cm-1. MS (CI): m /z = 278

10
ACCEPTED MANUSCRIPT
[M+H]+. Anal. calcd. for C10H6F3NO3S (277.22): C
43.33, H 2.18, N 5.05; found: C 43.34, H 2.20, N 5.02.
(m), 1456 (m), 1419 (s), 1367 (m), 1270 (s), 1223 (s),
1161 (s), 1029 (w), 997 (s), 954 (s) cm-1. MS (CI): m/z
= 334 [M+H]+. Anal. calcd. for C14H14F3NO3S
(333.33): C 50.45, H 4.23, N 4.20; found: C 50.58, H
4.31, N 4.25.
4.1.7. 3-Iodo-N-phenyl-N-
((trifluoromethyl)sulfonyl)propiolamide (4g)
4.1.7.1. 3-Iodo-N-phenylpropiolamide (3g). N-phenyl-
propiolamide17 (3d) (1.50 g, 10.34 mmol) was added
to a solution of sodium hydroxide (0.55 g, 13.68
mmol) in methanol (10 mL) and the mixture was
stirred for ten minutes. After addition of iodine (2.64
g, 10.39 mmol), stirring was continued for three hours.
The solution was concentrated at reduced pressure
until a solid precipitated, which was filtered off and
extracted with ethyl acetate. The organic extract was
concentrated and purified by column chromatography
(100 g of silica gel Merck Si 60, 0.063−0.2 mm,
cyclohexane/ethyl acetate 1:1, Rf = 0.80). After
evaporation of the solvent, the product was dissolved
in CH2Cl2 and precipitated with an equal volume of n-
pentane. A colorless solid was obtained (2.76 g, 10.3
mmol, 99% yield). Decomposition at 141 °C –1H
NMR (CDCl3, 400.1 MHz): δ 7.13–7.16 (m, 1H, HPh),
7.31–7.35 (m, 2H, HPh), 7.50–7.51 (m, 2H, HPh), 7.67
(s, 1H, NH) ppm. 13C NMR (CDCl3, 100.6 MHz): δ
12.48 (C≡CI), 90.19 (C≡CI); 120.17, 125.30, 129.28,
137.08 (all CPh); 149.68 (NHC=O) ppm. IR (KBr):
2157 (m), 1636 (s), 1602 (s), 1547 (s), 1494 (m), 1441
(s), 1323 (m), 1249 (m) cm-1. MS (CI): m /z 272
[M+H]+. Anal. calcd. for C9H9INO (271.06): C 39.88,
H 2.23, N 5.17; found: C 40.08, H 2.22, N 5.22.
4.1.9.
3-(4-Chlorophenyl)-N-phenyl-N-
((trifluoromethyl)sulfonyl)propiolamide (4i). Method
B: From(4-chlorophenyl)acetylene (1i, 6.01 g, 44
mmol), n-BuLi (2.5 M in hexane, 16 mL, 40 mmol),
phenyl isocyanate (5a, 4.76 g, 4.3 mL, 40 mmol) and
Tf2O (12.41 g, 7.3 mL, 44 mmol). Yield: 12.31 g
1
(79%). − Beige solid, m.p. 118 °C. H NMR (CDCl3,
400.1 MHz): δ 7.09–7.11 (m, 2H, HPh), 7.30–7.32 (m,
2H, HPh), 7.45–7.48 (m, 2H, HPh), 7.56–7.64 (m, 3H,
HPh) ppm. 13C NMR (CDCl3, 100.6 MHz): δ 81.57 (C-
1
2), 96.37 (C-3), 116.91 (CAr), 119.87 (d, JC,F = 324.9
Hz, CF3); 129.34, 130.00, 130.68, 131.09, 134.52,
138.43 (7 CAr, two signals coincide); 151.64 (NC=O)
ppm. 19F NMR (CDCl3): δ -72.95 ppm. IR (KBr): ꢀꢁ
2210 (s), 1713 (s), 1591 (m), 1490 (s), 1413 (s), 1287
(s), 1217 (s), 1130 (s), 1031 (w), 1012 (w) cm-1. MS
(CI): m/z
=
388 [M+H]+. Anal. calcd. for
C16H9ClF3NO3S (387.76): C 49.56, H 2.34, N 3.61;
found: C 49.70, H 2.24, 3.43.
4.1.10.
nyl)propiolamide
phenylacetylene (1a, 7.90 g, 8.5 mL, 77 mmol), n-
BuLi (2.5 M in hexane, 28 mL, 70 mmol), ethyl
isocyanate (5j, 5.00 g, 5.5 mL, 70 mmol) and Tf2O
(21.83 g, 12.8 mL, 77 mmol). Yield: 4.98 g (70%). −
Colorless solid, m.p. 39 °C, decomp. at 145 °C. H
NMR (CDCl3, 400.1 MHz): δ 1.39 (t, J = 7.04 Hz,
3H, CH3), 4.03 (q, J = 7.05 Hz, 2H, CH2), 7.36–7.38
N-Ethyl-3-phenyl-N-((trifluoromethyl)sulfo-
(4j). Method B: From
1
4.1.7.2. Conversion 3g
→ 4g. Prepared from
3
propiolamide 3g (2.54 g, 9 mmol), DIPEA (1.40 g,
1.87 mL, 11 mmol) and Tf2O (3.06 g, 1.8 mL, 11
mmol) according to method A: Yield: 2.61 g (69%). −
3
(m, 2 H, HPh), 7.39–7.43 (m, 2H, HPh), 7.48–7.53 (m,
1H, HPh), 7.60–7.63 (m, 2H, HPh) ppm. 13C NMR
(CDCl3, 100.6 MHz): δ 15.10 (CH3), 44.56 (CH2),
1
Colorless solid, m.p. 122 °C (dec.). H NMR (CDCl3,
400.1 MHz): δ 7.34–7.37 (m, 2H, HPh), 7.49–7.55 (m,
3H, HPh) ppm. 13C NMR (CDCl3, 125.77 MHz): δ
27.26 (≡C−I), 86.94 (IC≡C), 119.76 (1JC,F = 324.7 Hz,
CF3); 130.02, 130.41, 131.27, 133.81 (all CPh); 150.11
(NC=O) ppm. 19F NMR (CDCl3): δ -72.88 ppm. IR
(KBr): ꢀꢁ 2171 (s), 1593 (w), 1489 (m), 1414 (s), 1211
(s), 1185 (s), 1027 (w) cm-1. MS (CI): m /z = 404
[M+H]+. Anal. calcd. for C10H5F3INO3S (403.11): C
29.80, H 1.25, N 3.47; found: C 29.76, H 1.35, N 3.64.
1
80.63 (C-2), 95.55 (C-3), 119.64 (q, JC,F = 323.8 Hz,
CF3); 119.01, 128.88, 131.73, 133.33 (all CPh); 151.17
(NC=O) ppm. 19F NMR (CDCl3): δ -75.15 ppm. IR
(KBr): ꢀꢁ 2212 (s), 1689 (s), 1598 (w), 1445 (m), 1414
(s), 1365 (m), 1329 (m), 1293 (s), 1210 (s), 1123 (s),
1038 (m), 962 (s) cm-1. Anal. calcd. for C12H10F3NO3S
(305.27): C 47.21, H 3.30, N 4.59; found: C 47.10, H
3.38, N 4.59.
4.1.8.
4,4-Dimethyl-N-phenyl-N-((trifluoromethyl)-
4.2.
Transamidation
of
N-phenyl-N-triflyl-
sulfonyl)pent-2-ynamide (4h). Method B: From 3,3-
dimethylbut-1-yne (1h, 5.42 g, 8.1 mL, 66 mmol), n-
BuLi (2.5 M in hexane, 24 mL, 60 mmol), phenyl
isocyanate (5a, 7.15 g, 6.5 mL, 60 mmol) and Tf2O
(18.62 g, 10.9 mL, 66 mmol). Yield: 19.28 g (96%). −
Light yellow solid, m.p. 93 °C. 1H NMR (CDCl3,
400.1 MHz): δ 0.94 (s, 9H, CH3), 7.32 (dd, J = 8.16
and 1.67 Hz, 2H, HPh), 7.36–7.61 (m, 3H, HPh) ppm.
13C NMR (CDCl3, 100.6 MHz): δ 27.82 (Cq), 29.24
(CH3), 77.40 (C-2), 108.63 (C-3), 119.85 (1JC,F = 324.6
Hz, CF3); 129.78, 130.54, 130.81, 134.84 (all CPh);
151.77 (NC=O) ppm. 19F NMR (CDCl3): δ -72.91
ppm. IR (KBr): ꢀꢁ 2218 (s), 1719 (s), 1593 (m), 1490
propiolamides 4
General procedure: To a stirred solution of an
acetylenic triflamide 4 (1.0 mmol) in 3−5 mL of
acetonitrile, water, or methanol/water (1:1) was added
a solution of an amine (1.0 mmol) in acetonitrile (2
mL). After complete consumption of 4 (see Table 5
for reaction time; monitoring by 19F NMR
spectroscopy), the solvent was evaporated at reduced
pressure and the residue was recrystallized from Et2O
or, in the case of 7c and 7d, submitted to kugelrohr
distillation. When methanol was used as the reaction

11
ACCEPTED MANUSCRIPT
solvent, the co-product N-phenyl-triflamide separated
in solid form and could be removed by filtration.
(NC=O) ppm. IR (KBr): ꢀꢁ 3061 (br), 2943 (br), 2883
(br), 2218 (s), 1660 (s), 1490 (s), 1310 (s), 1200 (s),
1055 (s) cm-1. MS (CI): m/z 190 [M+H]+. Anal. calcd.
for C11H11NO2 (189.21): C 69.83, H 5.86, N 7.40;
found: C 69.93, H 5.96, N 7.45.
4.2.1. N-Allyl-3-phenylpropiolamide (7d). Prepared
from triflamide 4a (707 mg, 2.0 mmol) and allylamine
(114 mg, 150 µL, 2.0 mmol), in MeOH/H2O (1:1, 5
mL) for two minutes. The co-product N-phenyl-
triflamide was removed by filtration. After solvent
evaporation under reduced pressure, the remaining oil
was submitted to kugelrohr distillation (0.1 mbar, 210
°C); light yellow oil (326 mg, 1.76 mmol, 88% yield).
4.2.4. Methyl (3-phenylpropioloyl)-L-phenylalaninate
(7p). Prepared from triflamide 4a (389 mg, 1.1 mmol),
methyl phenylalaninate hydrochloride (87 mg, 1.1
mmol) and triethylamine (197 mg, 270 µL, 1.1 mmol)
in MeOH/H2O (1:1, 5 mL) for eight hours. The
residue obtained after solvent evaporation was purified
1
– H NMR (CDCl3, 400.1 MHz): δ 3.90 (tt, J = 5.84
Hz, 1.53 Hz, 2H, CH2), 5.11–5.30 (m, 2H, CH=CH2),
5.79 (ddt, J = 17.08 Hz, 10.20 Hz, 5.65 Hz, 1H,
CH=CH2), 6.08 (s, 1H, NH), 7.31–7.38 (m, 3H, HPh),
7.52 (dd, J = 8.31 Hz, 1.47 Hz, 2H, HPh) ppm. 13C
NMR (CDCl3, 100.6 MHz): δ 42.26 (CH2), 82.94 and
84.90 (C≡C), 117.07 (Colef), 120.21 (CPh), 128.50
(CPh), 130.05 (CPh), 132.49 (CPh), 133.23 (Colef),
153.35 (NC=O) ppm. IR (NaCl): ꢀꢁ 3271 (br), 3066
(br), 2917 (s), 2850 (s), 2223 (s), 1628 (s), 1535 (s),
1495 (s), 1438 (s), 1379 (s), 1304 (s), 1211 (s), 1144
(s) cm-1. MS (CI): m/z 186 [M+H]+. Anal. calcd. for
C12H11NO (185.23 g/mol): C 77.81, H 5.99, N 7.56;
found: C 77.66, H 5.97, N 7.54.
chromatographically
(LPLC,
cyclohexane/ethyl
acetate, 2:1, Rf = 0.41) before recrystallization.
Colorless solid (331 mg, 1.08 mmol, 98% yield), m. p.
107 °C. – 1H NMR (CDCl3, 400.1 MHz): δ 3.22 (qd, J
= 13.92 Hz, 5.61 Hz, 2H, CH2), 3.78 (s, 3H, CH3),
5.01 (dt, J = 7.87 Hz, 5.62 Hz, 1H, CH), 6.48 (d, J =
7.76 Hz, 1H, NH), 7.08–7.19 (m, 2H, HPh), 7.23–7.49
(m, 6H, HPh), 7.50–7.60 (m, 2H, HPh) ppm. 13C NMR
(CDCl3, 100.6 MHz): δ 37.83 (CH3), 52.64 (Csp3),
53.66 (Csp3), 82.63 and 85.65 (C≡C); 120.06, 127.38,
128.63, 128.78, 129.42, 130.34, 132.73, 135.54 (all
CPh); 152.83 (NC=O), 171.38 (OC=O) ppm. IR (KBr):
ꢀꢁ 3295 (s), 2216 (s), 1741 (s), 1634 (s), 1530 (s), 1436
(m), 1319 (m), 1210 (m), 1171 (m) cm-1. [ꢃ]ꢄꢆꢅ
+121.69° (ρ = 0.1019, CHCl3). Anal. calcd. for
C19H17NO3 (307.35): C 74.25, H 5.58, N 4.56; found:
C 74.37, H 5.59, N 4.55.
=
4.2.2. 3-Phenyl-N-(prop-2-yn-1-yl)propiolamide (7e).
Prepared from triflamide 4a (707 mg, 2.0 mmol) and
propargylamine (93 mg, 91 µL, 1.0 mmol) in
acetonitrile (3 mL) for 2 minutes. After solvent
evaporation,
the
residue
was
pre-purified
4.2.5.
(3-Phenylpropioloyl)glycylglycine
(7q).
chromatographically (LPLC, CHCl3, Rf = 0.61).
Recrystallization yielded a pale-yellow solid (336 mg,
1.83 mmol, 92% yield). M. p. 64 °C. – 1H NMR
(CDCl3, 400.1 MHz): δ 2.29 (t, J = 2.58 Hz, 1H, CH),
4.16 (dd, J = 5.39 Hz, 2.58 Hz, 2H, CH2), 6.09 (s, 1H,
NH), 7.31–7.46 (m, 3H, HPh), 7.54 (d, J = 9.74 Hz,
2H, HPh) ppm. 13C NMR (CDCl3, 100.6 MHz): δ 29.62
(CH2), 72.43 and 78.30 (C≡C, propargyl), 81.94 and
85.82 (PhC≡C); 119.44, 128.62, 130.48, 132.64 (all
CPh); 153.24 (NC=O) ppm. IR (KBr): ꢂꢁ 3296 (s), 3224
(s), 3036 (s), 2927 (m), 2217 (s), 1631 (s), 1538 (s),
1443 (m), 1411 (m), 1306 (s), 1259 (s), 1218 (s), 1173
(m), 1068 (w), 1024 (m) cm-1. MS (CI): m/z 184
[M+H]+. Anal. calcd. for C12H9NO (183.21): C 78.67,
H 4.95, N 7.65; found: C 78.72, H 4.94, N 7.71.
Prepared from triflamide 4a (353 mg, 1.0 mmol) and
glycylglycine (132 mg, 1.0 mmol) in MeOH/H2O (1:1,
5 mL) for five hours. Colorless solid (253 mg, 0.97
mmol, 97% yield), decomposition at 182 °C. – 1H
NMR (CDCl3, 400.1 MHz): δ 3.76 (d, J = 5.77 Hz,
2H, CH2), 3.81 (d, J = 6.14 Hz, 2H, CH2), 7.45–7.53
(m, 3H, HPh), 7.57–7.61 (m, 2H, HPh), 8.24 (t, J = 5.79
Hz, 1H, NH), 9.04 (t, J = 6.11 Hz, 1H, NH) ppm. 13C
NMR (CDCl3, 100.6 MHz): δ 40.76 (CH2), 41.92
(CH2), 83.67 and 83.85 (C≡C); 119.80, 129.02,
130.35, 132.15 (all CPh); 152.67 (NC=O), 168.41
(NHC=O), 171.11 (NHC=O) ppm. IR (KBr): ꢀꢁ 3360
(s), 3345 (s), 3288 (m), 3225 (m), 3057 (m), 2233 (m),
1738 (m), 1664 (s), 1625 (s), 1550 (s), 1427 (m), 1319
(m), 1210 (s) cm-1. Anal. calcd. for C13H12N2O4
(260.25): C 60.00, H 4.65, N 10.76; found: C 60.21, H
4.66, N 10.22.
4.2.3. N-(2-Hydroxyethyl)-3-phenylpropiolamide (7k).
Prepared from triflamide 4a (370 mg, 1.05 mmol) and
2-aminoethanol (64 mg, 63 µL, 1.05 mmol) in
acetonitrile for two minutes. The residue obtained
after solvent evaporation, was re-dissolved in EtOAc
and passed through a pad of silica gel. After
recrystallization, a colorless solid was obtained (176
4.3. Reaction of triflamides 4 with phenylhydrazine
General procedure: To a solution of a triflamide 4
(1.0 mmol) in CH2Cl2 (5 mL), phenylhydrazine
hydrochloride (1.0 mmol) and triethylamine (1.0
mmol) were added. The reaction progress was
monitored by 19F NMR spectroscopy (cleavage
product N-phenyl-triflamide: δ -76.5 ppm). After the
reaction was completed, the solvent was removed, and
the obtained solid was recrystallized from diethyl
ether. Hydrazide 8 (eventually contaminated with a
small amount of hydroxypyrazole 9), was then heat-
1
mg, 0.93 mmol, 89% yield). M. p. 66 °C. – H NMR
(CDCl3, 400.1 MHz): δ 3.16 (s, 1H, OH), 3.53 (q, J =
5.42, 2H, CH2), 3.75–3.83 (t, J = 5.11 Hz, 2H, CH2),
6.87 (s, 1H, NH), 7.29–7.46 (m, 3H, HPh), 7.46–7.55
(m, 2H, HPh) ppm. 13C NMR (CDCl3, 100.6 MHz): δ
42.67 (CH2), 61.50 (CH2), 82.87 and 85.56 (C≡C);
120.11, 128.64, 130.26, 132.60 (all CPh); 154.45

12
ACCEPTED MANUSCRIPT
148.42/149.0 (all CPh); 152.04/158.0 (NH-C=O) ppm.
IR (KBr): ꢀꢁ 3424 (m), 3333 (m), 3239 (m), 2200 (w),
1642 (s), 1602 (m), 1499 (m), 1249 (m), 848 (s), 748
(m), 689 (m), 663 (m) cm-1. Anal. calcd. for
C12H16N2OSi (232.36): C 62.03, H 6.94, N 12.06;
found: C 61.67, H 7.03, N 12.04.
treated for 1−30 minutes in an open round-bottom
flask at 200 °C with a heatgun. The resulting
hydroxypyrazole 9 was washed with cold diethyl ether
(1 mL).
4.3.1. 1,5-Diphenyl-1H-pyrazol-3-ol (9a). Prepared
from triflamide 4a (353 mg, 1.0 mmol),
PhNHNH2·HCl (145 mg, 1.0 mmol) and NEt3 (101
mg, 139 µL, 1.0 mmol) in CH2Cl2 for one minute. The
product obtained after recrystallization was heat-
treated for three minutes. Colorless solid (215 mg,
4.4. X-Ray Crystallography
Data collection was performed on an Oxford
Diffraction Rigaku instrument (SuperNova, Dual
Source, Atlas CCD, Mo Kα radiation). Structure
solution and refinement: SHELXS/L-9742 and
SHELXL-2014/7.43 Molecule plots: ORTEP-3 for
Windows44 and Mercury, version 3.10.1.45
1
0.94 mmol, 91% yield), m. p. 253 °C. – H NMR
([D6]DMSO, 400.1 MHz): δ 5.93 (s, 1H, CH),
7.15−7.17 (m, 2H, HPh), 7.20−7.27 (m, 3H, HPh),
7.32−7.36 (m, 5H, HPh), 10.19 (s, 1H, OH) ppm. 13C
NMR (CDCl3, 100.6 MHz): δ 94.31 (C-4); 124.54,
126.55, 128.35, 128.56, 128.87, 130.42, 139.90 (all
CPh, two signals coincide); 143.17 (C-5), 161.72
(N=C-OH) ppm. IR (KBr): ꢀꢁ 3058 (m), 2746 (m),
2706 (m), 2591 (m), 1597 (m), 1562 (s), 1518 (s),
1448 (m), 1330 (s), 1273 (m), 1032 (m) cm-1. MS
(CI): m/z = 237 [M+H]+. Anal. calcd. for C15H12N2O
(236.27): C 76.25, H 5.12, N 11.86; found: C 76.22, H
5.14, N 11.77.
Selected data for 4a: Suitable crystals were
obtained as pale yellow rod-shaped prisms by
diffusion crystallization from CH2Cl2/n-pentane at 8
°C. − Data collection at 180(2) K. C16H10F3NO3S, Mw
353.31. Monoclinic space group P21/n, a 16.1122(5),
b 5.64731(15), c 17.8629(6) Å, β 105.592(3)o, V =
1565.55(8) Å3; Z = 4, Dcalcd = 1.499 g cm-3, ꢀ = 0.25
mm-1. Goodness of fit on F2 = 1.053, R = 0.0452 (2535
reflexions with I > 2σ(I)), wR2 = 0.1212 (all 3188
data). Residual electron densities between 0.51 and -
0.43 e Å-3.
4.3.2. 5-Cyclopropyl-1-phenyl-1H-pyrazol-3-ol (9b).
Prepared from triflamide 4b (599 mg, 1.89 mmol),
PhNHNH2·HCl (274 mg, 1.89 mmol) and NEt3 (191
mg, 263 µL, 1.89 mmol) in CH2Cl2 for ten minutes.
The product obtained after recrystallization was heat-
treated for two minutes. Colorless solid (355 mg, 1.77
mmol, 94% yield), m. p. 180 °C. – 1H NMR
([D6]DMSO, 400.1 MHz): δ 0.67−0.71 (m, 2H, CH2),
0.91−0.95 (m, 2H, CH2), 1.77−1.84 (m, 1H, CH), 5.41
(d, J = 0.66 Hz, 1H, CH), 7.27−7.32 (m, 1H, HPh),
7.44−7.48 (m, 2H, HPh), 7.56−7.60 (m, 2H, HPh), 9.93
(s, 1H, OH) ppm. 13C NMR ([D6]DMSO, 100.6 MHz):
δ 8.07 (CH), 8.61 (CH2), 90.00 (C-4); 123.22, 125.98,
129.00, 139.97 (all CPh); 146.32 (C-5), 161.41 (N=C-
OH) ppm. IR (KBr): ꢀꢁ 3008 (m), 2953, (m), 2847 (m),
2794 (m), 2748 (m), 2705 (m), 2632 (m, br), 1594 (s),
1567 (s), 1507 (s), 1415 (m), 1349 (m), 1322 (s), 1252
(m), 1125 (m), 1061 (m), 1030 (m) cm-1. Anal. calcd.
for C12H12N2O (270.72): C 71.98, H 6.04, N 13.99;
found: C 71.82, H 6.06, N 14.10.
Selected data for 4g: Suitable crystals were
obtained as colorless prisms by diffusion
crystallization from CH2Cl2/n-pentane at 8 °C. − Data
collection at 150(2) K. C10H5F3INO3S, Mw = 403.11.
Orthorhombic space group Pbca, a 9.2674(2), b
10.6991(3), c 26.8808(6) Å, V 2665.3(1) Å3; Z 8, Dcalcd
2.009 g cm-3, ꢀ 2.60 mm-1. Goodness of fit = 1.056, R
= 0.0258 (2424 reflexions with I > 2σ(I)), wR2 =
0.0573 (all 2729 data). Residual electron densities
between 0.94 and -0.76 e Å-3.
CCDC 1899511 (4a) and 1899512 (4g) contains the
supplementary crystallographic data for this paper.
These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
Acknowledgments
We gratefully acknowledge support from the
University of Ulm. We thank B. Müller for the X-ray
data collection and Dr. M. Wunderlin for the mass
spectra.
4.3.3. N'-Phenyl-3-(trimethylsilyl)propiolohydrazide
(8f). Prepared from triflamide 4d (629 mg, 1.80
mmol), PhNHNH2·HCl (260 mg, 1.80 mmol) and
NEt3 (182 mg, 251 µL, 1.80 mmol) in CH2Cl2 for 30
minutes. Colorless solid (392 mg, 1.69 mmol, 94%
yield), which did not undergo thermal cyclization. M.
p. 110 °C. Two isomers, I : II = 5 : 1 at 294 K, 4:1 at
Supplementary data
Supplementary material including experimental
procedures, characterization of the products and
spectra can be found in the online version, at
http://dx.doi.org/10.1016/..............
1
330 K). M. p. 110 °C – H NMR ([D6]DMSO, 400.1
MHz), isomer I: δ 0.24 (s, 9H, CH3), 6.65−6.77 (m,
3H, HPh), 7.12−7.20 (m, 2H, HPh), 7.89 (s, 1H, NH),
10.41 (s, 1H, NH) ppm; isomer II: δ 0.06 (s, 9H, CH3),
8.10 (s, 1H, NH), 9.76 (s, 1H, NH) ppm, HPh signals
overlap with those of isomer I. 13C NMR ([D6]DMSO,
100.6 MHz), isomer I/II: δ -0.73/-0.85 (SiCH3), 92.10
and 97.43 (C≡C); 112.16, 118.86, 128.82,
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