Metal-free synthesis of quinolines by direct condensation of amides with alkynes: revelation of N-aryl nitrilium intermediates by 2D NMR techniques

Article abstract of DOI:10.1007/s11426-017-9160-1

Employing triflic anhydride/2-fluoropyridine as an activation system, the coupling reactions of secondary N-aryl amides with terminal alkynes yielded substituted quinolines in moderate to excellent yields. The reaction tolerated both electron-donating and electron-withdrawing groups at the benzamide moiety. Electron-rich aryl acetylenes served as excellent coupling partners, and aliphatic terminal alkynes such as cyclopropyl and conjugate vinyl acetylenes could also be used as reaction partners. By means of 2D NMR techniques (heteronuclear multiple bond correlation (HMBC), heteronuclear single quantum correlation (HSQC)), nitrilium ions were probed as reactive intermediates which are in contrast with that suggested by Movassaghi on the basis of in situ IR monitoring experiments. On the basis of these results, a plausible mechanism for the formation of quinolines was suggested.

Full text of DOI:10.1007/s11426-017-9160-1

SCIENCE CHINA
Chemistry
•ARTICLES• . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . https://doi.org/10.1007/s11426-017-9160-1
Metal-free synthesis of quinolines by direct condensation of amides
with alkynes: revelation of N-aryl nitrilium intermediates by 2D
NMR techniques
Jian-Liang Ye, Ya-Nan Zhu, Hui Geng & Pei-Qiang Huang*
Department of Chemistry, Fujian Provincial Key Laboratory of Chemical Biology, Collaborative Innovation Center of Chemistry for Energy
Materials, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, China
Received September 27, 2017; accepted October 25, 2017; published online December 28, 2017
Employing triflic anhydride/2-fluoropyridine as an activation system, the coupling reactions of secondary N-aryl amides with
terminal alkynes yielded substituted quinolines in moderate to excellent yields. The reaction tolerated both electron-donating and
electron-withdrawing groups at the benzamide moiety. Electron-rich aryl acetylenes served as excellent coupling partners, and
aliphatic terminal alkynes such as cyclopropyl and conjugate vinyl acetylenes could also be used as reaction partners. By means
of 2D NMR techniques (heteronuclear multiple bond correlation (HMBC), heteronuclear single quantum correlation (HSQC)),
nitrilium ions were probed as reactive intermediates which are in contrast with that suggested by Movassaghi on the basis of in
situ IR monitoring experiments. On the basis of these results, a plausible mechanism for the formation of quinolines was
suggested.
amide activation, alkynes, quinolines, 2D NMR, nitrilium
Citation:
Ye JL, Zhu YN, Geng H, Huang PQ. Metal-free synthesis of quinolines by direct condensation of amides with alkynes: revelation of N-aryl nitrilium
intermediates by 2D NMR techniques. Sci China Chem, 2017, 60, https://doi.org/10.1007/s11426-017-9160-1
1 Introduction
[2j] and arenes [2k] could be used as effective nucleophiles
which resulted in a highly chemoselective conversion of
amides to α,β-unsaturated ketones [2j] and aromatic ketones
[2k].
Amide is a classical functional group. Unexpectedly, its
chemistry is underdeveloped. In recent years, the direct
transformation of amides has attracted considerable atten-
tion. The efforts have resulted in a host of valuable synthetic
transformations of amides [1–3]. Among the methods thus
developed, nucleophilic addition to amide carbonyl group
occupies the central position [1]. In this regard, direct use of
weakly nucleophilic alkenes and alkynes as nucleophiles is
attractive for the promise of conducting chemoselective re-
actions [4] that are difficult when using highly reactive or-
ganometallic reagents. Very recently, we have demonstrated
that by means of activation of amide carbonyl with tri-
fluoromethanesulfonic anhydride (Tf2O) [5], both alkenes
As a logic extension, the use of alkynes as nucleophiles
was envisioned. A survey of literature showed that very few
examples have been reported on the use of alkynes as nu-
cleophiles in the reaction with amides [2b–2f,2h]. In 2006,
Movassaghi et al. [2b] reported that by activating with Tf2O/
2-chloropyridine (2-ClPyr.), N-phenyl benzamides reacted
with copper trimethylsilylacetylide to yield α-trimethylsily-
lethynyl imines (2-I, Scheme 1) in excellent yields. Sub-
jection of the latter to ruthenium-catalyzed cycloisomeri-
zation produced pyridine and quinoline derivatives (3-I,
Scheme 1). Following this two-step synthesis, an elegant
single-step synthesis of pyridine derivatives employing π-
nucleophiles was developed by the same group [2c,2h].
*Corresponding author (email: pqhuang@xmu.edu.cn)
© Science China Press and Springer-Verlag GmbH Germany 2017 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . chem.scichina.com link.springer.com

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1H NMR and 13C NMR spectra were recorded at 500, 125 or
214 MHz, respectively. Chemical shifts (δ) are reported in
ppm and respectively referenced to internal standard Me4Si
1
and solvent signals (Me4Si, 0 ppm for H NMR and CDCl3,
77.0 ppm for 13C NMR). Mass spectra were recorded on a
Bruker Dalton ESquire 3000 plus LC-MS apparatus (ESI
direct injection; Germany). HRMS spectra were recorded on
a 7.0T FT-MS apparatus (Bruker, USA). Silica gel (300–400
mesh) was used for flash column chromatography, eluting
with EtOAc/n-hexane mixture. Reactions were performed in
oven-dried glassware under an argon atmosphere.
2.2 General procedure for the synthesis of quinolines
Scheme 1 Reported methods for the direct coupling of 1-trimethylsilyl-1-
alkynes with N-aryl amides and our synthetic plan.
Into a dry 10-mL Schlenk tube equipped with a magnetic
stirring bar were added successively a secondary amide
(0.5 mmol, 1.0 equiv.), 5 mL of anhydrous 1,2-dichloroe-
thane (DCE) and 2-fluoropyridine (2-F-Pyr.) (0.6 mmol, 1.2
equiv.) under an argon atmosphere. After being cooled to
−40 °C, trifluoromethanesulfonic anhydride (Tf2O) (155 mg,
93 μL, 0.55 mmol, 1.1 equiv.) was added dropwise via a
syringe and the reaction was stirred for 5 min. Then the
reaction mixture was warmed to 0 °C and maintained for
10 min. Alkynes (3.0 equiv.) in 1 mL of DCE was added
dropwise at 0 °C, and the mixture was heated to 70 °C and
stirred for 4 h. The reaction was quenched with a saturated
NaHCO3 aqueous solution (5 mL) and extracted with di-
chloromethane (3×5 mL). The combined organic layers were
washed with brine (5 mL), dried over anhydrous Na2SO4,
filtered, and concentrated under reduced pressure. The re-
sidue was purified by flash column chromatography (FC) on
silica gel to afford the corresponding quinoline and α-alkynyl
imine.
Among the many π-nucleophiles used, in two cases, 1-
methoxy-4-(prop-1-yn-1-yl)benzene and 1-ethynyl-4-meth-
oxybenzene, have been used as nucleophiles to yield qui-
nolines [2c,2h]. In the same year, Yao [2d,2e] developed a
concise total synthesis of the antitumor alkaloid camp-
tothecin. Central to that synthesis is a highly efficient and
mild cascade reaction of an acetylenic aniline amide trig-
gered by bis(triphenyl)oxodiphosphonium trifluoromethane-
sulfonate (Hendrickson reagent) [6]. Following that dis-
covery, the first metal-free synthesis of N-aryl α-alkynyl
imines (2-II, Scheme 1) from benzanilide derivatives and 1-
trimethylsilyl-1-alkynes was developed [2f]. During that
study, they observed that only 1-silylated 1-alkynes are ef-
fective alkynylation agents. Moreover, in the alkynylation
reactions, variable amounts of quinoline derivatives were
formed as by-products. Thus, it is desirable to develop a
reliable approach to quinoline derivatives by direct coupling
of terminal alkynes with secondary amides. In particular,
such an approach is in high demand in view of the im-
portance of quinolines as a class of important pharmaco-
phores [7,8]. In connection with our work on the use of Tf2O/
2-F-Pyr. [2g] as an activation system for secondary amides
[2j–2l,3g], we decided to explore the direct synthesis of
quinolines from secondary amides and terminal alkynes. We
report herein that Tf2O/2-F-Pyr.-promoted condensation of
N-aryl amides with terminal alkynes allows a direct access to
quinoline derivatives.
The detailed synthesis procedures and characteristics of
quinolines can be seen in the Supporting Information online.
3 Results and discussion
We opted for benzanilide (1a) as a substrate and the condi-
tions that we previously established for the activation of
secondary amides [2j–2l] for investigating the coupling with
phenylacetylene. In the event, a solution of 1a (1.0 equiv.)
and 2-F-Pyr. (1.2 equiv.) in dichloromethane (DCM) was
exposure to Tf2O (1.1 equiv.) at −78 °C for 30 min, then
phenylacetylene (4a, 1.1 equiv.) was added. After running at
room temperature for 4 h, the desired quinoline 3a was
formed in 37% yield, along with N-aryl α-alkynyl imine
intermediate 2a in 5% yield. Increasing the molar equiva-
lents of 4a (Table 1, entries 2–5) to 3.0 resulted in an im-
provement of yield (3a: 60% yield) (entry 5). Further
increase the amount of 4a was unrewarding (entry 6). The
temperature for the activation of amide can be increased
2 Experimental
2.1 Reagents and materials
Melting points were determined on a Büchi M560 Automatic
Melting Point apparatus (Switzerland) and are uncorrected.
Infrared spectra (IR) were measured with a Nicolet Avatar
360 FT-IR spectrometer (USA) using film pellet techniques.

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Table 1 Optimization of reaction conditions in DCM
Table 2
Optimization of the reaction conditions in DCE
b)
Yield (%) b)
Yield (%)
a)
a)
Entry
T (°C)
Time (h)
Entry
n
3a
63
52
70
74
82
83
2a
16
10
10
6
3a
37
54
55
58
60
62
60
30
62
2a
5
1
2
3
r.t.
70
70
70
70
70
4
2
4
4
4
8
1
2
3
4
5
6
1.1
1.5
2.0
2.5
3.0
5.0
3.0
3.0
3.0
10
11
11
13
13
11
/
c)
4
5 d)
6 d)
5
5
c)
a) Tf2O (1.1 equiv.), 2-F-Pyr. (1.2 equiv.), 1a (1.0 equiv., 0.1 M), −40 °C,
5 min; 0 °C, 10 min; then 4a (3.0 equiv.) was added, the reaction was run at
the reported temperature; b) yields determined by 1H NMR using 1,3,5-
trimethoxybenzene as an internal standard; c) the concentration of 1a was
0.25 M; d) 4a (3.0 equiv., 1.5 M in DCE) was added dropwise.
7
8 d)
e)
9
10
a) Tf2O (1.1 equiv.), 2-F-Pyr. (1.2 equiv.), 1a (1.0 equiv.) −78 °C,
30 min; 4a was added and run at room temperature for 4 h; b) yields
determined by 1H NMR using 1,3,5-trimethoxybenzene as an internal
standard; c) exposured to Tf2O at −40 °C; d) exposured to Tf2O at 0 °C; e)
after addition of 4a, the reaction was run at 40 °C.
reaction: only moderate yield was obtained. The coupling of
N-(3-methoxyphenyl)benzamide (1h) with phenylacetylene
afforded a mixture of two regioisomers 3h-a and 3h-b in a
combined yield of 65%. The reaction of N-naphthyl benza-
mide 1i produced the desired product 3i in only 38% yield
and alkyne imine 2i was not detected. The reactions of
electron-rich heteroaryl carboxamides 1j and 1k gave cor-
responding quinolines 3j and 3k in 65% and 74% yield,
respectively. Surprisingly, in both cases, alkyne imines 2j
and 2k were not observed. In addition to aromatic amides,
aliphatic amides such as 1l, 1m and 1n are also suitable
substrates, which reacted with phenylacetylene 4a to afford
the corresponding quinolines 3l, 3m and 3n in 73%, 64%,
and 64% yield, respectively. In addition, The structures of
both quinoline 3m and α-alkynyl imine 2b were determined
by single crystal X-ray diffraction analysis (Figure 1) [9].
Next, scope of alkyne was surveyed (Table 4). Arylacety-
lenes bearing a methoxy group at either para- or ortho-
position of the aryl ring afforded the desired quinolines 3o
and 3p in excellent yields. The alkyne bearing a meta-sub-
stituted methoxyl group (4q) also reacted smoothly to give
3q in 74% yield. A similar yield (3r, 70%) was obtained
from the reaction of (p-tolyl)acetylene (4r). The reaction of
electron-rich heteroaryl acetylene 4t also afforded a good
yield (84%). To our good surprise, in the absence of an
additional base, electron-deficient p-nitrophenylacetylene
(4s) also reacted with benzanilide to give the corresponding
quinoline 3s, albeit in only 46% yield. While aliphatic
alkynes bearing a cyclopropyl group and an alkenyl group
(4u and 4v) served well as reaction partners, low yields were
obtained from the reactions of simple 1-octyne (4w) and that
bearing an electron-withdrawing group (Cl) at α-position
from −78 to −40 °C without affecting yield (entry 7).
However, further elevating the temperature to 0 °C resulted
in a drop of yield (entry 8). On the other hand, elevating
reaction temperature at the second stage of the reaction (after
addition of 4a) seemed to be beneficial for the reaction (entry
9).
In the light of the latter result, DCE was employed as a
solvent to replace dichloromethane (Table 2). When the re-
action with 4a was run at 70 °C for 4 h, yield of 3a increased
to 70% (entry 1), which was further improved to 74% by
running the reaction at a concentration of 0.25 M (entry 4).
Moreover, mode of addition of 4a has an impact on the
reaction: by dropwise addition of a solution of 4a in DCE
(1.5 M), yield of 3a was further improved to 82% (entry 5).
In addition, prolonging reaction time to 8 h was unrewarding
(entry 6). Thus the optimal conditions for condensation re-
action of secondary amides and alkynes were determined as
treating 1a (1.0 equiv., 0.25 M) and 2-F-Pyr. (1.2 equiv.) with
Tf2O (1.1 equiv.) in DCE at −40 °C (5 min; 0 °C, 10 min),
following by addition of 4a (3.0 equiv., 1.5 M in DCE), and
stirred at 70 °C for 4 h.
After optimizing reaction conditions, the substrate scope
was investigated and the results are summarized in Table 3.
The reaction tolerated both electron-donating (Table 3, 1b
and 1c) and electron-withdrawing groups (1d) at the benzoyl
moiety. However, moderate yield was obtained from ben-
zamides bearing a strong electron-donating (1c) or a strong
electron-withdrawing group (1d). Substituents at para-po-
sition of the N-aryl moiety (1e–1g) are detrimental for the

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Table 3 Condensation reactions of N-aryl sec-amides with phenylace-
tylene
Figure 1 X-ray structures of quinoline 3m (a) and α-alkynyl imine
2b (b).
4 Mechanistic investigation by means of in situ
2D NMR techniques
In Yao’s work [2f] utilizing the Hendrickson’s reagent as an
activator of N-aryl amides, the intermolecular Diels-Alder
reaction between the putative imidate diene A (Figure 3) and
an alkyne has been suggested to account for the formation of
quinolines. To gain an insight into the mechanism of our
Tf2O/2-F-Pyr.-mediated condensation of secondary N-aryl
amides with terminal alkynes, we proceeded to probe the
reactive intermediates. Previously, Movassaghi and co-
workers have undertaken in situ IR monitoring experiments
to examine the intermediates generated from N-aryl benza-
mides by activation with Tf2O in the presence of either 2-
ClPyr. or 2-F-Pyr. That no detection of an IR absorption
consistent with a nitrilium ion (2370 cm−1) [2g] and the ob-
servation of an IR absorption at 1621 cm−1, led them to
suggest an amidinium ion B (Figure 3) [2c,2g] as the inter-
mediate. However, in our previous in situ IR monitoring of
the reaction between N-2,6-dimethylphenyl benzamides and
alkenes, an absorption appeared at 2310 cm−1 was observed,
suggesting the formation of a nitrilium ion intermediate C
(Figure 3) [2j]. To clarify on this issue, we undertook an
investigation by means of in situ 2D NMR techniques.
For this purpose, we selected N-acetyl aniline (1m) as a
substrate, and examined the Tf2O/acetyl aniline (1m) and
a) Isolated yield; b) yields determined by 1H NMR using 1,3,5-tri-
methoxybenzene as an internal standard; c) performed at 7.3 mmol (1.55 g)
scale of 1b; d) not detected.
(4x). Interestingly, the reaction of allene 5 at 40 °C resulted
in the formation of the unexpected quinoline 3y in 60% yield.
The structure of quinoline 3y was elucidated by single crystal
X-ray diffraction analysis (Figure 2) [9]. Quinoline 3y is a
product incorporated two molecules of phenylallene 5 into
benzanilide.
1
Tf2O/2-F-Pyr./1m combinations [10]. In the H NMR spec-
trum of a mixture of Tf2O and 1m, five methyl peaks ap-
peared at δH 3.27, 2.67, 2.37, 2.033 and 2.029, respectively.
These methyl assignments also were confirmed by multi-
plicity-edited heteronuclear single quantum correlation
To demonstrate synthetic utility of the reaction, gram-scale
synthesis was examined. The gram-scale reaction of 1b with
4a proceeded smoothly to give 3b (1.53 g) in 71% yield
along with 2b in 6% yield (Table 3).

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Table 4 Condensation reactions of benzanilide with alkynes
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
Figure 2 X-ray structure of quinoline 3y.
Figure 3 Structures of the activated intermediates generated from sec-
amides previously proposed by Yao (A), Movassaghi (B), and Huang (C).
(Chart 1), the corresponding species were determined as M1
(δH 2.033, 2.029; 40%) and M2 (δH 2.37; 2%). The multi-
bond correlation between residue methyl δH 3.27 and δC
116.6 (within the range of the characteristic resonance of
C≡N around δC 115–120) explicitly indicated the formation
of nitrilium ion M3 (27%) [2j]. Notably, the unusual 4-bond
correlation δH 3.27/δC 123.3 and 5-bond correlation δH 3.27/
δC 128.0 also suggested a conjugated-plane structure for the
nitrilium ion. It is worthy to notice that although the re-
sonances at δC2 116.6, δC4 123.3 were readily detected
through HMBC correlations, in the 13C NMR, they were
scarcely observable which can be ascribed to an enhanced
13C-14N spin-spin coupling and a quadrupolar broadening of
14N in the conjugated structure.
Interestingly, in the 13C NMR spectrum of a mixture of
Tf2O/2-F-Pyr./1m, recorded under the same conditions, only
the resonances of the nitrilium M3, CF3SO3H (TfOH), and 2-
F-pyridinium M4 were observed. Thus, nitrilium ion M3
was the predominant species in the activation system Tf2O/2-
F-Pyr./1m (Chart 2). This result suggested that nitrilium ion
M3 was readily formed in this activation system and 2-F-Pyr.
promoted the transformation of the iminium M1 to nitrilium
M3 [2j].
In addition, at this point the yield of nitrilium ion M3 was
only 47% as determined by 1H NMR [11]. This may be due
to the high activity of nitrilium. Indeed, the amount of ni-
trilium M3 sharply decreased to 9% and more undetermined
a) Isolated yield; b) Tf2O (1.1 equiv.), 2-F-Pyr. (2.4 equiv.), 1a (1.0
equiv., 0.1 M in CH2Cl2), −78 °C, 5 min; 0 °C, 10 min; then 5 (3.0 equiv.)
was added, and the reaction was run at the 40 °C for 8 h; c) not detected.
1
species were recorded in H NMR while continued to keep
(HSQC) experiment. The resonance at δH 2.67, attributable to
unconsumed 1m, indicated a 69% conversion. In the het-
eronuclear multiple bond correlation (HMBC) spectrum
(Chart 1), the resonances at δH 2.37, 2.033, 2.029 correlated
with δC 178.6, 171.1, 178.6, respectively. Because the latter
are characteristic resonances of sp2 carbon attached to N
the mixture in NMR tube at room temperature for 24 h.
Based on these results, the Diels-Alder-type concerted
process can be ruled out because of the constrained linear
geometry of nitrilium ion [2j], and a nucleophilic addition
mechanism can be suggested (Scheme 2). The scenario may

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Chart 1 Regional HMBC spectrum of a mixture of 1m (0.20 mmol) and Tf2O (0.22 mmol) in CDCl3 (1 mL).
Chart 2 Regional 13C NMR spectrum of a mixture of 1m (0.20 mmol), 2-F-Pyr. (0.24 mmol) and Tf2O (0.22 mmol) in CDCl3 (1 mL).

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To verify the proposed mechanism, the cyclization of α-
alkynyl imine 2b was attempted. Under the standard condi-
tions, quinoline 3b was not observed, and 2b was recovered
in 96% yield (Scheme 3). Furthermore, treating α-alkynyl
imine 2b with TfOH did not produce 3b. These results allow
suggesting that quinoline 3 can not be produced via Path B-2
(Scheme 2).
5 Conclusions
In summary, we have demonstrated that terminal alkynes
could serve as effective nucleophiles in the reaction with
Tf2O/2-F-Pyr.-activated secondary N-aryl amides, which
provided a facile access to functionalized quinolines. This
method is complementary with those developed by Mo-
vassaghi and Yao that yielded N-aryl α-alkynyl imines as the
major products. By means of 2D techniques (HMBC and
HSQC), nitrilium ions were detected as reactive inter-
mediates generated from Tf2O/2-F-Pyr. and sec-amides. On
the basis of this result, a plausible mechanism involving
nucleophilic addition of alkynes to nitrilium ion inter-
mediates, tandem intramolecular Friedel-Crafts-type reac-
tion was suggested. To the best of our knowledge, this
constitutes the first utilization of 2D NMR techniques to
probe nitrilium ion intermediates. We believe that this would
find more applications as an advantageous alternative to the
in situ IR technique in probing reactive intermediates. In
view of the versatility of amides in organic synthesis [12],
our method is of synthetic value.
Scheme 2 Proposed mechanism for the condensation reaction of alkynes
with secondary amides.
Scheme 3 The reaction of α-alkynyl imine 2b under standard conditions.
Acknowledgements This work was supported by the National Key R&D
Program of China (2017YFA0207302), the National Natural Science
Foundation of China (21332007, 21672176), the Natural Science Founda-
tion of Fujian Province, China (2017J01021) and the Program for Chang-
jiang Scholars and Innovative Research Team in University of Ministry of
Education, China.
involve the addition of an alkyne with nitrilium ion inter-
mediate M3 to generate the cation intermediate M6, which is
captured by the highly nucleophilic enamine/aryl moiety to
give, via a Friedel-Crafts process, quinoline 3 as the major
product (Path A). On the other hand, a base-promoted β-
elimination gave the α-alkynyl imine 2 as a minor product
(Path B-1). It is worth mentioning that the addition of al-
kynes to preformed N-aryl nitrilium ions similar to M3 has
been reported to give quinolines [8c].
Conflict of interest The authors declare that they have no conflict of
interest.
Supporting information The supporting information is available
online at http://chem.scichina.com and http://link.springer.com/
journal/11426. The supporting materials are published as submitted,
without typesetting or editing. The responsibility for scientific ac-
curacy and content remains entirely with the authors.
The effects of substituents on alkynes towards the reaction
can be accounted for by the proposed mechanism. Alkynes
bearing a MeO group at either para- or ortho-position of a
phenylacetylene (4o and 4p in Table 4), being able to provide
a strong resonance stabilization effect to the carbocation M6,
afforded quinolines 3o and 3p in excellent yields. Thiophe-
nyl, being a strong electron-donating and heteroaromatic
group, can efficiently stabilize the carbocation group to af-
ford 3t in a good yield. Cyclopropyl and vinyl groups being
able to stabilize α-carbocation, the corresponding alkynes 4u
and 4v (Table 4) can be employed as nucleophiles.
1
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3
9
The crystallographic data of compounds 3m, 2b, and 3y (CCDC:
1574872, 1574871, and 1575066) can be obtained free of charge from
the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.
uk/data_request/cif
10 Experimental procedure: To a dry NMR tube were sequentially added
amide 1m (27 mg, 0.20 mmol), CDCl3 (1 mL), Tf2O (39 μL, 0.22
mmol), and 2-F-Pyr. (24 μL, 0.24 mmol, for Tf2O/2-F-Pyr./1m com-
bination) at −40 °C under Ar. Then the NMR tube was kept at same
temperature for 5 min before allowing warm up to rt. Then NMR
spectra were recorded during consecutive 5 h
11 The yield was calculated on the basis of the molar ratio of acetyl
aniline (1m, 1.0 equiv.) and 2-F-Pyr. (1.2 equiv.). Assuming that the
aryl hydrogen is 9.8 (5+4×1.2), when yield of nitrilium ion M3 is
100%, integration of the methyl portion should have a value of 3. The
observed relative integration value of 1.41 corresponds to a 47% yield
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