Halo-1,2,3-triazolium salts as halogen bond donors for the activation of imines in dihydropyridinone synthesis

Article abstract of DOI:10.1021/acs.joc.9b00248

In the past decade halogen bond (XB) catalysis has gained considerable attention. Halo-triazoles are known XB donors, yet few examples detail their use as catalysts. As a continuation of our previous work the catalytic properties of substituted enantiomerically pure halo-triazolium salts were explored in the reaction between an imine and Danishefsky's diene leading to the formation of dihydropyridinone. The catalytic activity of the XB donors was highly dependent on the choice of the halogen atom and on the counterion. Also, it was found that impurities in the diene affected the rate of the reaction.

Full text of DOI:10.1021/acs.joc.9b00248

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Article
Halo-1,2,3-triazolium salts as halogen bond donors for
the activation of imines in dihydropyridinone synthesis
Mikk Kaasik, Andrus Metsala, Sandra Kaabel, Kadri Kriis, Ivar Järving, and Tonis Kanger
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00248 • Publication Date (Web): 11 Mar 2019
Downloaded from http://pubs.acs.org on March 13, 2019
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Halo-1,2,3-triazolium salts as halogen bond donors for the
activation of imines in dihydropyridinone synthesis
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Mikk Kaasik, Andrus Metsala, Sandra Kaabel, Kadri Kriis, Ivar Järving and Tõnis Kanger*
Department of Chemistry and Biotechnology, Tallinn University of Technology, Tallinn 12618, Estonia
*E-mail: tonis.kanger@taltech.ee
Abstract: In the past decade halogen bond (XB) catalysis has gained considerable attention. Halo-triazoles are known XB donors, yet
few examples detail their use as catalysts. As a continuation of our previous work the catalytic properties of substituted
enantiomerically pure halo-triazolium salts were explored in the reaction between an imine and Danishefsky`s diene leading to the
formation of dihydropyridinones. The catalytic activity of the XB donors was highly dependent on the choice of the halogen atom and
on the counterion. Also, it was found that impurities in the diene affected the rate of the reaction.
Introduction
Halogen bonding is the process in which a Lewis acidic halogen atom interacts with a Lewis base.1 It has been applied mainly in
supramolecular chemistry and its use in solution is also growing.2,3,4 Halogen bonds (XBs) are similar to hydrogen bonds (HBs), which
have been extensively used in catalysis.5 On the other hand, some properties of XBs can be considered more advantageous than
HBs in catalysis, namely the high directionality of XBs and the use of soft donor atoms.6,7 In 2008 Bolm et al. showed the potential of
XBs in organocatalysis.8 Since then there have been several reports describing the use of XBs to catalyse Diels-Alder,9 Michael
addition,10 halogen abstraction11 and other miscellaneous reactions.12 In addition, computational studies have explored the catalytic
potential of XB donors.13 Nevertheless, the field is only starting to expand and even more importantly no examples of asymmetric
catalysis based solely on XB activation have been reported. There are some examples of enantioselective reactions in which
simultaneous different interactions, including XBs, are involved to achieve asymmetric induction.14 Surprisingly, there are a limited
number of examples utilizing halo-1,2,3-triazoles and their salts as catalysts, although these compounds are known XB
donors,9a,11b,11e,15 even more so, considering the ease of triazole synthesis via a copper-catalysed click reaction between alkyne and
azide.16 Easy access to a wide variety of chiral azides and the opportunities to modify the triazole ring make these compounds very
attractive potential catalysts. The catalytic activity of the triazoles can be increased via quaternization, making the core of the triazole
more electronegative and increasing the magnitude of the  hole on the halogen atom.15c,17 We have previously shown that chiral
halogen substituted triazolium salts form complexes with imines and thioureas, and are additionally capable of enantiodiscrimination in
solution.18 To evaluate the catalytic potential of the triazolium salts, we used them in an aza-Diels-Alder19 reaction between imine 1
and Danishefsky`s diene 2 (Scheme 1).
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Scheme 1. The model reaction under study.
4
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O
Ph
OMe
N
XB-catalyst
7
8
9
N
OTMS
MeO
Ph
MeO
1
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In this paper we demonstrate the high catalytic activity of the triazolium salts and describe how the catalytic activity is affected by the
structure of the XB donor. In addition, an alternative mechanistic pathway for product formation is proposed and the importance of
diene quality is described.
Results and Discussion
First, the set of synthesised XB donors was expanded compared to the one described in our previous publication18 using the same
general synthetic scheme (Figure 1).20
CuI
TTTA
Y
N
I
N
I
N
N
N
N
N3
Ph
Ar
I
Ar
Ar
+
Ph
Ph
THF
4
5
6(a-d)
7(a-d
): Y = OTf
a
8(a;c)
: Y = BF4
: Ar = Ph
b
9a
: Y = BARF
: Ar = C6F5
c
: Ar = 4-NO2-C6H4
d
: Ar = 3,5-(CF3)2-C6H3
CF3
N
N
N
OTf
Ph
N
N
N
10
11
12
: X = Br
: X = Cl
: X = H
B
N
Ph
3
X
CF3
BARF
4
TTTA
Figure 1.Triazolium salts used in the study.
The reaction of azide 4 derived from (R)-α-methyl benzyl amine and differently substituted aromatic 1-iodoalkynes 5 in the presence of
copper(I)iodide and tris(1-tert-butyl-1H-1,2,3-triazolyl)methylamine (TTTA) afforded 5-iodo-1,2,3-triazole derivatives 6, which were
converted into triazolium salts 7 or tetrafluoroborate salts 8. In addition, tetrakis-3,5-bis(trifluoromethyl)phenylborate (BARF) salt 9a
was also synthesised. Bromotriazole 10 was obtained starting from the corresponding bromoalkyne,21 chloro derivative 11 via
halogen exchange from 6a22 and hydrogen analogue 12 from the terminal alkyne (see Experimental Section for details). The
substitution pattern of the phenyl ring involves various electronegative groups (6b-d).
The electrostatic potential surfaces (ESP) of the triazoles and corresponding cationic structures (Table 1) were modelled to find
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Table 1. The most positive electrostatic potential value VS,max (a.u.) (mapped on electron density isosurface of 0.001 a.u.)
on the halogen atom X in the XB donor structure.a
6
7
Ph
N
Ph
N
N
N
N
N
Ar
8
Ar
X
X
9
Entry
Ar
X
I
VS,max
Entry
7
Ar
X
I
VS,max
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4-NO2C6H4
0.1644
0.1642
0.1646
0.1565
0.1443
0.1350
4-NO2C6H4
0.0597
0.0589
0.0570
0.0479
0.0370
0.0287
3,5-(CF3)2C6H3
I
8
3,5-(CF3)2C6H3
I
C6F5
Ph
I
9
C6F5
Ph
I
I
10
11
12
I
Ph
Br
Cl
Ph
Br
Cl
Ph
Ph
aThe ESP values were modelled only for the cationic part of the XB donors 7a-d, 10 and 11 to avoid the anion having an influence on the VS,max value on X and to
evaluate the effect of the halogen atom, aromatic substituent and positive charge on the VS,max value.
structural factors that most influenced the  hole. The DFT calculations were carried out with the Gaussian09 program23 using the
CAM-B3LYP24 and M062X25 functional with the DEF2TZVP26 basis set. ESP values were calculated with the help of the Multiwfn
program27 and visualisation was made with the MOLEKEL28 program. Charge has the most influence on the magnitude of the  hole
and similarly to previous results a positive charge of the triazole core increased the size of the  hole on the halogen atom (Table 1,
comparing entries 1-6 to entries 7-12).15c,17 Next, the polarisability of the halogen atom had a smaller influence on the size of the 
hole (Table 1, comparing entries 4-6 or entries 10-12). The aromatic substituent of the triazole ring had a more subtle influence on the
 hole and can thus be used for the fine tuning of the properties of the catalyst (Table 1, entries 1-4).
Calculations show, in addition to the previously obtained affinity constant of Ka(CDCl3) = 8,18 that halogen bonding between
imine 1 and iodo-triazolium salt 7d is plausible. Interestingly, in the minimum energy structure of 7d the triflate counterion is not
halogen bonded to the iodine atom (Figure 2, A). Based on
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B)
A)
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Å
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Figure 2. A) The most stable conformer of the XB donor 7d; B) the most stable conformer of 7d + 1 adduct.
solid state data we assumed that a XB to the counterion would be favoured.18 This conformer is stable, but higher in energy (For
further details, see SI Figure S2 and Table S1). When imine 1 is added to the 7d system a stable adduct is formed containing an
almost linear XB with an angle of 169.4° and a bond length of 2.943 Å (Figure 2, B). This data reveal that the activation of imine 1 by
triazolium salt 7d using a XB is plausible.
Based on previous results by Minakata et al., the aza-Diels-Alder reaction between imine 1 and Danishefsky’s diene 2 was
chosen as a model reaction (Scheme 1).9b Since neutral triazoles 6 showed no catalytic activity in this reaction, they were omitted from
the later part of the study. Proceeding to catalytic experiments, we also had to take into account the solubility of the donors in
dichloromethane. Compounds 7d and 8a were not used as catalysts because of their poor solubility. Based on the previous, triflate 7a
was chosen as the reference catalyst in the study. A pentafluorophenyl group and a 4-nitrophenyl group have an influence on the 
hole comparable to that of a 3,5-bistrifluormethylphenyl group (Table 1, entries 1-3). Fortunately, the corresponding salts 7b and 7c
were soluble in dichloromethane and could thus be used to probe the influence of the aromatic substituent on the reaction. Also, salts
8c, 9a, 10, 11 and 12 were included in the study to evaluate the influence of the counterion and halogen atom.
The reaction in the presence of triazolium salt 7a gave promising results showing high conversion of imine 1 in a reasonable
time. Although the triazolium salts were enantiomerically pure we observed no stereoselectivity in any of the following reactions. To
get a better understanding of the reaction, we decided to run it in CD2Cl2 with 20 mol% of the catalyst and follow it by 1H NMR, using
p-xylene as an internal standard to determine the conversion. This change helped to reveal an unexpected lag period that preceded a
rapid period of conversion of imine 1 to product 3 (Figure 3, purple line).
100%
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50%
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Figure 3. The dependence of the conversion of the model reaction on the halogen/hydrogen atom on the triazole ring of the
catalyst.
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Control experiments supported the idea that the reaction proceeded by XB activation. The hydrogen analogue 12 was
markedly less active than 7a (Figure 3, comparing purple and grey lines). After a few days only a moderate level of conversion was
achieved. Also, no reaction took place if TBA-Cl was added to the reaction mixture with catalyst 7a.29 Bases have been successfully
used to exclude the possibility of Brønsted acid catalysis.9b,11f Unfortunately, the product was not formed if K2CO3, Et3N or Hünig’s
base was added to the reaction mixture. However, in all instances we observed the decomposition of 6a into 12. This indicates
towards an unwanted interaction between the base and the XB catalyst. Therefore, the reactions in the presence of an added base
were inconclusive and the possibility of hidden Brønsted acid catalysis could not be ruled out. Bromotriazole derivative 10 (Figure 3,
magenta line) exhibited a similar reaction profile to 7a with a gentler slope. The conversion of imine remained below 20% in the
presence of chloro derivative 11 (Figure 3, green line) during the first eight hours. This is in agreement with our computations and
previous results that have reported on the dependence of the XB donor ability on halogen atom polarisability.11c,30 Elemental halogens
might form in solution and act as the true catalysts. To rule this out, the reaction with bromotriazolium salt 10 was run in the presence
of cyclohexene, which should quench free Br2 and HBr.10b,11d Fortunately, we observed no change in reaction profile compared to the
reaction with only 10 (For further details see SI Figure S4). In our opinion these results show that the catalytic activity comes from the
halogen and the rest of the structure is relatively inactive.
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The rate of the reaction was highly dependent on the quality and on the batch of the diene 2 used. The delay present in the
reaction with 7a was different in the case of various batches of diene (Figure 4, comparing the purple line to the others).
100%
90%
80%
batch I
70%
batch II:
60%
0 days
50%
40%
7 days
30%
20%
11 days
10%
0%
0
60
120 180 240 300 360 420 480
Time (min)
Figure 4. The influence of different batches of Danishefsky`s diene 2 and time after opening on the model reaction with
catalyst 7a.
Also, the reaction was slower when the diene was used sometime after its first use (Figure 4, comparing the brown, orange and blue
lines). Therefore all comparable studies were carried out with the same batch of diene in a minimal time frame. Although these
findings significantly complicate the interpretation of data, we feel confident that general observations can still be made. The lag
period, although shorter, was still present when different batches of diene were used with the catalyst 7a. It was assumed that self-
aggregation of the catalyst may also reduce its effective concentration in solution. We have observed the dependence of the chemical
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shift values of the catalyst on its concentration (For further details, see SI Figure S5). Therefore the delay may have been caused by
the kinetics of deaggregation to achieve sufficient concentration of the catalyst to activate imine 1. Initially we assumed that product
formation could increase the speed of deaggregation. To determine the influence of other reaction components on the catalyst, we
incubated imine 1, diene 2, and product 3 in separate experiments with the catalyst for 30 minutes before adding the second reactant
(For further details, see SI Figure S6).31 Only in the case of incubation with the diene 2 was the reaction slower than the reference
reaction and hence compounds 1 and 3 do not accelerate the reaction through facilitating deaggregation and exclude the possibility of
autocatalysis.32 On the other hand, diene 2 or its decomposition products might inhibit the catalyst. It is known that trimethylsilyl
trifluoromethanesulfonate (TMSOTf) can catalyse Mannich33 reaction and Diels-Alder reaction.34 However, we did not detect the
formation of TMSOTf by HRMS during the course of the reaction. Also, if TMSOTf is the actual catalyst then we should not observe
any dependency of the reaction on the choice of halogen atom.
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Next, the influence of the counterion on the catalytic activity was investigated (Figure 5). Surprisingly, compound 8c
100%
90%
80%
70%
60%
7a - OTf
8c - BF4
9a - BARF
50%
40%
30%
20%
10%
0%
0
60 120 180 240 300 360 420 480
Time (min)
Figure 5. The dependence of the conversion of the model reaction on the counterion of the catalyst.
containing the tetrafluoroborate counterion was completely inactive (Figure 5, red line). The BARF counterion containing compound 9a
(Figure 5, green line) exhibited no delay at the start of the reaction. However, the reaction did not go to completion within eight hours.
Both of these counterions are considered to be less coordinating than the triflate counterion and therefore compounds 8c and 9a
should give a stronger XB with the imine.35 Hence, these compounds should be more active than the triflate salt 7a. Unusual and
unpredictable influence of the counterion on the catalytic activity of the XB donors has also been described in earlier papers.11c,36,37
The inactivity of 8c can partly be explained by its lower stability in the reaction mixture compared to the others salts (For further
details, see SI Figure S8). On the other hand, the absence of product formation again implies that the decomposition products were
not catalytically active.
The influence of the aromatic substitution pattern of triflate salts 7a-c on the reaction was investigated (Figure 6).
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0%
7a batch II
7b
7c
7b 2mol%
0
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180
Time (min)
Figure 6. The influence of the aromatic substituent of the catalyst on the conversion of the model reaction.
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Pentafluorophenyl derivative 7b was a very efficient catalyst. The reaction was complete in almost 30 minutes (Figure 6, orange line).
The lag period could not be observed but also not excluded on such a short time-scale with the better XB donor 7b compared to donor
7a. When we lowered the catalyst loading of 7b from 20 to 2 mol% (Figure 6, yellow line), the lag period was again detected and the
reaction profile was similar to that of the reaction with catalyst 7a. The reaction was almost complete within 2 hours indicating high
efficiency of the catalyst. p-nitrophenyl derivative 7c was as active as catalyst 7a.38
Finally, a more thorough study of NMR spectra revealed the formation of some new peaks that were converted into peaks
corresponding to the product 3 during the course of the reaction (Figure 7). Based on HRMS and NMR analysis,
HMe
HCH2
HCHH
HMe(ref)
485 min
422 min
368 min
305 min
239 min
181 min
121 min
60 min
8 min
0 min
3.95 3.90 3.85 2.95 2.90 2.85 2.80 2.75 2.70 2.65
f1 (ppm)
2.35 2.30 2.25
Figure 7. Outtake of 1H NMR spectra (CD2Cl2, 297 K, 400 MHz) from the reaction catalysed by 7a showing the methyl protons
HMe of 1, the methylene protons HCH2 of 14, one of the methylene protons HCHH of 3, and the methyl protons HMe(ref) of p-
xylene.
this compound could correspond to the Mannich intermediate 14 (Scheme 2, A).39 It is assumed that the iodotriazolium salt 7 activates
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Scheme 2. A) Mannich/Michael path to product 3; B) 4+2 cycloaddition path to product 3.
4
5
A) Mannich-Michael mechanism
Ar
N
6
7
8
9
N
Ar
N
Silyl
transfer
N
N
I
N
*R
Ph
I
OTMS
N
OTMS
*R
Ph
N
7
`Ar
`Ar
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OMe
OMe
13
1
2
HCH2
O
O
O
O
N
H
H
`Ar
`Ar
N
N
`Ar
TMS
N
OMe
`Ar
OMe
MeO
Si
Ph
Ph
Ph
Ph TMS
3
14
15
16
Based on HMBC
14 15 17
or - TMS + 2H) observed by HRMS
MW (
,
B) Pericyclic mechanism
Ar
N
N
N
*R
TMS
I
O
O
OTMS
Ph
N
7
`Ar
N
`Ar
`Ar
N
OMe
OMe
Ph
Ph
17
1
2
3
imine 1 towards a nucleophilic attack of silyl enol ether. Preliminary results by Minakata et al. also showed the feasibility of using a XB
donor to catalyse the Mannich reaction.9b The intermediate 16 is formed by cyclization via an aza-Michael reaction followed by
demethoxylation. The target compound 3 is obtained after desilylation. The initially expected 4+2 cycloaddition pathway could also be
at work in parallel (Scheme 2, B).40
Conclusions
Halo-1,2,3-triazole-based XB donors were successfully used as catalysts to obtain dihydropyridinone 3, although no enantioenriched
products were formed. By modifying the structure of triazolium salts we were able to tune the catalytic properties of the XB donors to
varying degrees. By introducing a pentafluorophenyl substituent, the catalyst loading could be lowered from 20 to 2 mol% without
significant loss in activity. Both the choice of halogen atom and the counterion had a significant impact on the catalytic activity of the
XB donors. Yet again, the counterion affected catalytic activity in an inexplicable way and therefore counterion effects in XB catalysis
should receive closer examination. From a catalyst design perspective we are now interested in using different azides in the click
reaction to move towards stereoselective XB catalysis. As the product might form through a tandem Mannich-Michael pathway, the
catalytic potential of these compounds in the Mannich reaction could be of interest.
Experimental Section
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All commercially available reagents were used without further purification. MeOH was dried by distillation over sodium metal. All air or
moisture sensitive reactions were carried out under argon atmosphere using oven-dried glassware. The reactions were monitored by
thin layer chromatography (TLC) with silica gel-coated aluminum plates (Merck 60 F254) and visualized with KMnO4, anisaldehyde,
vaniline or ninhydrine stain. Yields refer to chromatographically purified or crystallised products. 1H NMR spectra were recorded on a
Bruker Avance III instrument at 400 MHz and are reported in parts per million (δ) referenced to the residual solvent signal (CDCl3 δ =
7.26, CD3OD δ = 3.31 ppm, D6DMSO δ = 2.50 ppm). Data for 1H NMR spectra are as follows: chemical shift δ (ppm), multiplicity (s =
singlet, bs = broad singlet, d = doublet, t = triplet, q = quartet, dd = doublet of doublets, m = multiplet), coupling constant J Hz, and
relative integration. 13C{1H} NMR spectra were recorded at 101 MHz and are reported in parts per million (δ) referenced to the residual
solvent signal (CDCl3 δ = 77.16, CD3OD δ = 49.00 ppm, D6DMSO δ = 39.52 ppm). HRMS spectra were recorded with an Agilent
Technologies 6540 UHD Accurate-Mass Q-TOF LC/MS spectrometer by using AJ-ESI ionization. Optical rotations were obtained with
an Anton Paar GWB Polarimeter MCP500. IR spectra were recorded on a Bruker Tensor 27 FT-IR spectrophotometer. IR absorption
frequencies in wavenumbers are listed, with the relative strength in parentheses (w = weak, m = medium, s = strong).
(Iodoethynyl)benzene,20 4,41 6a,18 6d,18 7a18 and 7d18 are known and were prepared following the literature procedure. A CEM
Discover microwave reactor was used for the microwave assisted synthesis of (R)-5-chloro-4-phenyl-1-(1-phenylethyl)-1H-1,2,3-
triazole. The reaction vessel was sealed with a Teflon cap and the reaction temperature was monitored by a non-contact infrared
sensor.
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(R)-5-iodo-4-(perfluorophenyl)-1-(1-phenylethyl)-1H-1,2,3-triazole
(6b):
1-ethynyl-2,3,4,5,6-pentafluorobenzene:
Bromopentafluoro-benzene (3.0 mL, 24.1 mmol), PdCl2(PPh3)2 (0.342 g, 0.49 mmol), and CuI (0.187 g, 0.46 mmol) were dissolved in
THF (60 mL). Hünig’s base (16.0 mL, 89.9 mmol) was added, followed by ethynyltrimethylsilane (6.8 mL, 49.1 mmol), and the mixture
was stirred for 24 h at 72 °C. The suspension was poured onto a pad of Celite, washed with THF and the filtrate was concentrated
under vacuum. Purification by flash column chromatography on silica gel (100% petroleum ether) afforded the Sonogashira coupling
product and the Glaser coupling product as a mixture. The mixture was concentrated under vacuum and dissolved in MeOH (100 mL)
and KOH (50%, 0.078 mL) was added. The reaction was stirred for 1 h, then quenched with H2O (30 mL) and acidified with HCl (7 mL,
1M). The combined organic phase was dried over MgSO4 and purification by distillation (130 °C, 1 atm) gave 1-ethynyl-2,3,4,5,6-
pentafluorobenzene as an orange oil (0.74 g, 16% yield, solvent impurities were not completely removed). 1H NMR (400 MHz, CDCl3)
δ 3.62 – 3.61 (m, 1H). 1,2,3,4,5-pentafluoro-6-(iodoethynyl)benzene: 1-ethynyl-2,3,4,5,6-pentafluorobenzene (0.30 g, 1.56 mmol),
dissolved in THF (4 mL), was treated with CuI (0.029 g, 0.15 mmol) and 4-iodomorpholine hydroiodide (0.59 g, 2.0 mmol) and the
reaction mixture was stirred for 3.5 h at rt. The suspension was poured onto a pad of neutral alumina, the solid phase was washed
with THF and CH2Cl2, and the filtrate was concentrated under vacuum. The combined organic fractions were pooled and washed with
a solution of Na2S2O3 (100 mL, 5% w/w) and a solution of saturated NaCl (50 mL). The organic phase was dried over Na2SO4,
concentrated and purified by column chromatography on silica gel (100% petroleum ether) to provide 1,2,3,4,5-pentafluoro-6-
(iodoethynyl)benzene as an orange oil (0.35 g, 70% yield). 13C{1H} NMR (101 MHz, CDCl3) δ 150.1 – 147.0 (m), 139.2 – 136.1 (m),
143.5 – 140.4 (m), 100.5 – 99.9 (m), 77.7 (q, J = 3.6 Hz), 21.7 (q, J = 3.9 Hz). 6b: CuI (0.006 g, 0.032 mmol) and TTTA (0.015 mg,
0.035 mmol) were dissolved in freshly distilled THF (3.5 mL) under argon atmosphere and stirred at rt for 30 min. Then (R)-(1-
azidoethyl)benzene (0.097 mL, 0.680 mmol) and 1,2,3,4,5-pentafluoro-6-(iodoethynyl)benzene (0.215 g, 0.676 mmol) were added and
the reaction mixture was stirred at rt for 23 h. The reaction mixture was concentrated, NH4OH (20 mL, 10% w/w) was added and the
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aqueous phase was extracted with CH2Cl2 (2 x 25 mL). The combined organic phase was passed through a phase separator,
concentrated and purified by column chromatography on silica gel (from 10% of EtOAc in petroleum ether) to provide triazole 6b as
colourless crystals (0.271 g, 86% yield). mp 157 – 160 oC; αD20 32.0 (c 0.21, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.43 – 7.28 (m, 5H),
5.79 (q, J = 7.1 Hz, 1H), 2.14 (d, J = 7.1 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 139.7, 129.2, 128.6, 126.7, 82.7, 62.3, 22.4. IR
(KBr) ν=: 1659 (w), 1554 (m), 1495 (s), 1413 (w), 1393 (w), 1238 (m), 1165 (m), 1126 (m), 1046 (m), 987 (s), 917 (w), 841 (s), 765
(m), 698 (s) cm-1. HRMS (ESI/Q-TOF) m/z: M + H+ Calcd for C16H9F5IN3 465.9834; found: 465.9831.
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(R)-5-iodo-4-(4-nitrophenyl)-1-(1-phenylethyl)-1H-1,2,3-triazole (6c): 1-(iodoethynyl)-4-nitrobenzene: Iodoform (4.10 g,
10.42 mmol), triphenylphosphine (2.87 g, 10.94 mmol) and tBuOK (1.11 g, 9.93 mmol) were added to THF (20 mL) under argon
atmosphere. The suspension was stirred at rt for 5 minutes and turned brown. 4-nitrobenzaldehyde (0.75 g, 4.96 mmol) was added.
After 30 minutes, the brown suspension was cooled to -78 °C and tBuOK (2.80 g, 24.95 mmol) was added. After an additional 30
minutes the reaction was quenched with brine (90 mL) at -78 °C. After warming to rt the two layers were separated and the aqueous
phase was extracted with diethylether (3 x 90 mL). The combined organic phase was passed through a phase separator,
concentrated and purified by column chromatography on silica gel (starting from 0% of EtOAc in petroleum ether) to provide the
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product as a yellow solid (1.17 g, 86% yield). H NMR (400 MHz, CDCl3) δ 8.24 – 8.15 (m, 2H), 7.62 – 7.54 (m, 2H). 13C{1H} NMR
(101 MHz, CDCl3) δ 147.5, 133.3, 130.1, 123.7, 92.5, 14.3. 6c: CuI (0.006 g, 0.032 mmol) and TTTA (0.015 mg, 0.035 mmol) were
dissolved in freshly distilled THF (3.5 mL) under argon atmosphere and stirred at rt for 30 min. Then 1-(iodoethynyl)-4-nitrobenzene
(0.186 g, 0.681 mmol) and (R)-(1-azidoethyl)benzene (0.097 mL, 0.680 mmol) were added and the reaction mixture was stirred at rt
for 5 h. The reaction mixture was concentrated, NH4OH (20 mL, 10 % w/w) was added and the aqueous phase was extracted with
CH2Cl2 (2 x 25 mL). The combined organic phase was dried over Na2SO4, filtered, concentrated and purified by column
chromatography on silica gel (from 10% of EtOAc in petroleum ether) to provide triazole 6c as yellow crystals (0.253 g, 88% yield). mp
153 °C dec in the presence of visible light; αD20 25.9 (c 0.16, CHCl3); 1H NMR (400 MHz, CDCl3) δ 8.34 – 8.28 (m, 2H), 8.23 – 8.14 (m,
2H), 7.41 – 7.29 (m, 5H), 5.82 (q, J = 7.1 Hz, 1H), 2.14 (d, J = 7.1 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 147.7, 147.6, 139.8,
136.8, 129.1, 128.6, 128.1, 126.7, 124.0, 78.3, 62.0, 22.5. IR (KBr) ν=: 2992 (w), 2937 (w), 1602 (s), 1521 (s), 1458 (m), 1382 (m),
1346 (s), 1288 (m), 1245 (w), 1110 (m), 989 (m), 977 (m), 855 (s), 712 (s), 604 (w), 540 (w) cm-1. HRMS (ESI/Q-TOF) m/z: M + H+
Calcd for C16H13IN4O2 421.0156; found: 421.0151.
(R)-5-bromo-4-phenyl-1-(1-phenylethyl)-1H-1,2,3-triazole: (bromoethynyl)benzene: To ethynylbenzene (0.75 mL, 6.85
mmol), dissolved in acetone (70 mL), were added NBS (1.35 g, 7.59 mmol) and AgNO3 (0.119 g, 0.70 mmol). The resulting mixture
was stirred at rt for 3.5 hours. The suspension was filtered and the filtrate was concentrated under reduced pressure. Then, the
resulting crude mixture was added to water (50 mL) and extracted with Et2O (3 × 50 mL). The combined organic phase was dried over
K2CO3, concentrated and purified by column chromatography on silica gel (100% petroleum ether) to provide (bromoethynyl)benzene
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as a yellow oli (1.13 g, 91% yield). H NMR (400 MHz, CDCl3) δ 7.54 – 7.42 (m, 2H), 7.42 – 7.28 (m, 3H). 13C{1H} NMR (101 MHz,
CDCl3) δ 132.1, 128.8, 128.5, 122.8, 80.2, 49.9. The triazole: Cu(OAc)2 (0.024 g, 0.132 mmol), CuBr (0.019 g, 0.132 mmol) and TTTA
(0.058 mg, 0.135 mmol) were dissolved in freshly distilled THF (6.0 mL) under argon atmosphere and stirred at rt for 30 min.
(bromoethynyl)benzene (0.239 g, 1.32 mmol) and (R)-(1-azidoethyl)benzene (0.194 g, 1.32 mmol) were added and the reaction
mixture was stirred at 60 °C for two weeks. The reaction mixture was concentrated, NH4OH (28 mL, 18 % w/w) was added and the
aqueous phase was extracted with CH2Cl2 (3 x 30 mL). The combined organic phase was dried over anhydrous Na2SO4, concentrated
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and purified by column chromatography on silica gel (from 10% of EtOAc in petroleum ether) to provide the Br-triazole as colourless
crystals (0.176 g, 41% yield). αD20 27.0 (c 0.18, CHCl3); 1H NMR (400 MHz, CDCl3) δ 8.00 – 7.95 (m, 2H), 7.48 – 7.41 (m, 2H), 7.41 –
7.28 (m, 6H), 5.78 (q, J = 7.1 Hz, 1H), 2.11 (d, J = 7.2 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 144.8, 140.0, 129.8, 129.0, 128.7,
128.6, 128.4, 127.0, 126.6, 108.1, 60.0, 22.0. IR (KBr) ν=: 3031 (w), 2988 (m), 2943 (w), 1607 (w), 1494 (m), 1477 (m), 1447 (m),
1374 (m), 1306 (w), 1280 (m), 1232 (s), 1049 (m), 989 (m), 975 (m), 771 (s), 733 (s), 698 (s), 536 (m) cm-1. HRMS (ESI/Q-TOF) m/z:
M + H+ Calcd for C16H14BrN3 328.0444; found: 328.0439 (79Br). The assignment is supported by an X-ray crystallographic structure.
(R)-5-chloro-4-phenyl-1-(1-phenylethyl)-1H-1,2,3-triazole: 6a (0.186 g, 0.496 mmol) was suspended in MeCN (1.5 mL)
and EtOAc (0.5 mL) in a microwave vial, water (1.0 mL) and KCl (0.110 g, 1.47 mmol) were added to the mixture and the vial was
sealed with a Teflon cap. The suspension of the reaction mixture was heated until most of the triazole 6a was dissolved. The vial was
placed into a microwave reactor and heated at 150 °C for 30 min. The reaction mixture was cooled, diluted with water and the
aqueous phase was extracted with EtOAc (2 x 10 mL) and with DCM (3 x 10 mL). The combined organic phase was dried over
anhydrous MgSO4, concentrated and purified with column chromatography on silica gel (starting from 5% of EtOAc in petroleum
ether) to provide the Cl-triazole as pale yellow crystals (0.115 g, 81% yield). mp 115 – 116 °C; αD20 22.6 (c 0.37, CHCl3); 1H NMR (400
MHz, CDCl3) δ 8.00 – 7.94 (m, 2H), 7.49 – 7.41 (m, 2H), 7.40 – 7.28 (m, 6H), 5.75 (q, J = 7.1 Hz, 1H), 2.11 (d, J = 7.1 Hz, 3H). 13C{1H}
NMR (101 MHz, CDCl3) δ 142.1, 139.7, 129.5, 129.1, 128.8, 128.6, 128.5, 126.6, 126.5, 121.6, 59.1, 21.6. HRMS (ESI/Q-TOF) m/z:
M + H+ Calcd for C16H14ClN3 284.0949; found: 284.0954.
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(R)-4-phenyl-1-(1-phenylethyl)-1H-1,2,3-triazole: CuI (0.010 g, 0.053 mmol) and TTTA (0.021 mg, 0.049 mmol) were
dissolved in freshly distilled THF (3.5 mL) under argon atmosphere and stirred at rt for 30 min. Phenylacetylene (0.231 g, 1.013 mmol)
and (R)-(1-azidoethyl)benzene (0.150 g, 1.019 mmol) dissolved in THF (2.0 mL) were added and the reaction mixture was stirred at rt
for 21 h. The reaction mixture was concentrated, NH4OH (20 mL, 10 % w/w) was added and the aqueous phase was extracted with
CH2Cl2 (4 x 20 mL). The combined organic phase was dried over anhydrous Na2SO4, concentrated and purified by column
chromatography on silica gel (starting from 0% of EtOAc in petroleum ether) to provide the H-triazole as colourless crystals (0.320 g,
84% yield). mp 115 – 116 °C; αD20 -48.9 (c 0.20, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.85 – 7.75 (m, 2H), 7.64 (s, 1H), 7.47 – 7.28
(m, 8H), 5.87 (q, J = 7.1 Hz, 1H), 2.03 (d, J = 7.1 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 147.9, 140.0, 130.8, 129.2, 128.9, 128.7,
128.2, 126.7, 125.8, 118.5, 60.4, 21.5. IR (KBr) ν=: 3121 (m), 3091 (w), 2985 (m), 1606 (w), 1496 (m), 1481 (m), 1463 (m), 1449 (m),
1356 (m), 1232 (m), 1219 (m), 1153 (m), 1075 (s),1026 (m), 992 (m), 916 (w), 818 (m), 764 (s), 714 (s), 692 (s), 521 (m) cm-1. HRMS
(ESI/Q-TOF) m/z: M + H+ Calcd for C16H15N3 250.1339; found: 250.1336.
(R)-5-iodo-3-methyl-4-(perfluorophenyl)-1-(1-phenylethyl)-1H-1,2,3-triazol-3-ium
trifluoromethanesulfonate
(7b):
Triazole 6b (0.200 g, 0.230 mmol) was dissolved in CH2Cl2 (9.0 mL) under argon atmosphere. Methyl triflate (0.073 mL, 0.645 mmol)
was added dropwise and the reaction mixture was stirred at rt for 21 h. After removal of the solvents under reduced pressure the solid
was dissolved in CH2Cl2 (6.0 mL) and Et2O (10.0 mL) was added to the solution and after 10 minutes a fine precipitate formed which
was filtered to provide triflic salt 7b as colourless crystals (0.231 g, 85% yield). mp 134 – 137 °C; αD20 12.6 (c 0.21, CHCl3); 1H NMR
(400 MHz, CDCl3) δ 7.49 – 7.37 (m, 5H), 6.10 (q, J = 6.9 Hz, 1H), 4.39 (s, 3H), 2.18 (d, J = 7.0 Hz, 3H). 13C{1H} NMR (101 MHz,
CDCl3) δ 136.2, 130.0, 129.8, 127.2, 120.6 (q, J = 320.4 Hz), 77.5, 67.5, 40.6, 21.7. IR (KBr) ν=: 3034 (w), 1661 (m), 1505 (s), 1450
(m), 1246 (s), 1161 (s), 1078 (m), 1030 (s), 994 (s), 867 (m), 754 (m), 699 (m), 638 (s), 574 (w), 518 (m) cm-1. HRMS (ESI/Q-TOF)
m/z: M - CF3O3S+ Calcd for C17H12F5IN3 479.9991; found: 479.9998; OTf- Calcd for CF3O3S 148.9526; found 148.9550.
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(R)-5-iodo-3-methyl-4-(4-nitrophenyl)-1-(1-phenylethyl)-1H-1,2,3-triazol-3-ium trifluoromethanesulfonate (7c): Triazole
6c (0.102 g, 0.243 mmol) was dissolved in CH2Cl2 (5.0 mL) under argon atmosphere. Methyl triflate (0.041 mL, 0.363 mmol) was
added dropwise and the reaction mixture was stirred at rt for 23 h. The reaction mixture was concentrated and dissolved in CH2Cl2
(1.5 mL). Et2O (10.0 mL) was added to the reaction mixture and a precipitate formed after 20 minutes, which was filtered to provide
triflic salt 7c as colourless crystals (0.123 g, 87% yield). mp 84 – 87 °C; αD20 34.8 (c 0.25, MeOH); 1H NMR (400 MHz, CDCl3) δ 8.48 –
8.36 (m, 2H), 8.01 – 7.89 (m, 2H), 7.51 – 7.37 (m, 5H), 6.02 (q, J = 6.9 Hz, 1H), 4.32 (s, 3H), 2.19 (d, J = 7.0 Hz, 3H). 13C{1H} NMR
(101 MHz, CDCl3) δ 149.8, 145.4, 136.4, 132.1, 129.7, 129.6, 128.4, 127.1, 124.6, 120.5 (q, J = 320.0 Hz), 88.7, 67.0, 39.9, 21.6. IR
(KBr) ν=: 3107 (w), 1605 (m), 1527 (s), 1488 (w), 1454 (w), 1349 (s), 1277 (s), 1158 (s), 1030 (s), 856 (m), 757 (w), 704 (m), 638 (s),
600 (w), 574 (w) cm-1. HRMS (ESI/Q-TOF) m/z: M - CF3O3S+ Calcd for C17H16IN4O2 435.0312; found 435.0327; OTf- Calcd for
CF3O3S 148.9526; found 148.9549. The assignment is supported by an X-ray crystallographic structure.
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(R)-5-iodo-3-methyl-4-phenyl-1-(1-phenylethyl)-1H-1,2,3-triazol-3-ium tetrafluoroborate (8a): Triazole 6a (0.124 g,
0.330 mmol) was dissolved in CH2Cl2 (6.5 mL) under argon atmosphere. Trimethyloxonium tetrafluoroborate (0.061 mg, 0.412 mmol)
was added and the reaction mixture was stirred at rt for 24 h. The reaction was quenched by adding MeOH (10.0 mL) and stirred for 1
h. After removal of the solvents under reduced pressure the crude produce was dissolved in MeOH (10.0 mL) and Et2O (5.0 mL) was
added to the solution and a fine precipitate formed which was filtered. The crystallisation was repeated a second time using MeOH
(5.0 mL) and Et2O (25.0 mL) to provide tetrafluoroboronic salt 8a as colourless crystals (in total: 0.140 g, 89% yield). mp 193 – 195 °C;
αD20 36.0 (c 0.16 in MeOH); 1H NMR (400 MHz, CD3OD) δ 7.77 – 7.57 (m, 5H), 7.55 – 7.37 (m, 5H), 6.23 (q, J = 6.9 Hz, 1H), 4.27 (s,
3H), 2.12 (d, J = 6.9 Hz, 3H). 13C{1H} NMR (101 MHz, CD3OD) δ 148.6, 138.8, 133.1, 131.4, 130.7, 130.4, 130.3, 128.2, 124.3, 91.3,
67.4, 39.8, 22.0. HRMS (ESI/Q-TOF) m/z: M – BF4+ Calcd for C17H17IN3 390.0462; found 390.0455; BF4- Calcd for BF4: 86.0071;
found 86.0072 (10B), 87.0037 (11B). The assignment is supported by an X-ray crystallographic structure.
(R)-5-iodo-3-methyl-4-(4-nitrophenyl)-1-(1-phenylethyl)-1H-1,2,3-triazol-3-ium tetrafluoroborate (8c): Triazole 6c
(0.112 g, 0.267 mmol) was dissolved in CH2Cl2 (5.5 mL) under argon atmosphere. Trimethyloxonium tetrafluoroborate (0.055 mg,
0.372 mmol) was added and the reaction mixture was stirred at rt for 3 days. The reaction was quenched by adding MeOH (5.5 mL)
and stirred for 40 min. After removal of the solvents under reduced pressure the solid was dissolved in CH2Cl2 (2.0 mL) and Et2O (5.0
mL) was added to the solution and a precipitate formed after 20 minutes, which was filtered to provide tetrafluoroboronic salt 8c as
pale yellow crystals (0.132 g, 95% yield). mp 98 – 101 °C; αD20 39.4 (c 0.19, MeOH); 1H NMR (400 MHz, CD3OD) 8.56 – 8.45 (m, 2H),
8.01 – 7.88 (m, 2H), 7.56 – 7.36 (m, 5H), 6.25 (q, J = 6.9 Hz, 1H), 4.32 (s, 3H), 2.13 (d, J = 6.9 Hz, 3H). 13C{1H} NMR (101 MHz,
CD3OD) δ 151.3, 146.9, 138.7, 133.2, 130.38, 130.37, 130.3, 128.2, 125.5, 92.1, 67.6, 40.0, 22.0. IR (KBr) ν=: 1605 (w), 1526 (s),
1487 (w), 1453 (w), 1348 (s), 1287 (w), 1061 (s), 855 (m), 763 (w), 704 (m), 600 (w) cm-1. HRMS (ESI/Q-TOF) m/z: M – BF4+ Calcd
for C17H16IN4O2 435.0312; found 435.0315; BF4- Calcd for BF4 86.0071; found: 86.0089 (10B), 87.0054 (11B). The assignment is
supported by an X-ray crystallographic structure.
(R)-5-iodo-3-methyl-4-phenyl-1-(1-phenylethyl)-1H-1,2,3-triazol-3-ium
tetrakis3,5-bis(trifluoromethyl)phenylborate
(9a): Sodium tetrakis3,5-bis(trifluoromethyl)phenylborate: A three-neck round bottom flask fitted with a reflux condenser was
evacuated, flame dried and filled with argon prior to use. Magnesium (1.11 g, 45.7 mmol), NaBF4 (0.71 g, 6.4 mmol) and Et2O (150
mL) were added to the flask. To start the reaction dibromoethane (0.49 mL, 5.7 mmol) was added and the flask was heated for 5
minutes followed by the dropwise addition of 3,5-bis(trifluoromethyl)bromobenzene (5.0 mL, 35.9 mmol) dissolved in Et2O (40 mL)
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over 70 min. The solution was then stirred over night at rt. As all of the magnesium had not reacted the reaction was refluxed for an
additional 24 h. Then the reaction mixture was quenched by the addition of Na2CO3 (16.2 g, 153 mmol) dissolved in H2O (200 mL) and
stirred for 1 h and filtered. The aqueous phase was extracted three times with Et2O (50 mL), the combined organic phase was dried
over Na2SO4. The solvent was removed and the remaining crude product was dissolved in toluene (50 mL) and concentrated to
remove remaining traces of water, this was repeated three more times. The product was dried under reduced pressure with heating
(100 °C) for 10 h to yield a brown solid. This solid was washed with CH2Cl2 and toluene, dried under reduced pressure with heating
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(100 °C) in the presence of P2O5 for 2 days to yield the NaBARF as a pale grey solid (2.70 g, 47% yield). H NMR (400 MHz,
D6DMSO) δ 7.64 (s, 4H), 7.61 (s, 8H). 13C{1H} NMR (101 MHz, D6DMSO) δ 161.0 (q, J = 49.9 Hz), 134.9, 129.1 – 127.9 (m), 124.0
(q, J = 272.2 Hz), 118.0 – 117.1 (m). Tetramethylammonium tetrakis3,5-bis(trifluoromethyl)-phenylborate: NaBARF (1.76 g, 1.99
mmol) was suspended in CH2Cl2 (100 mL) and tetramethylammonium iodide (0.60 g, 2.98 mmol) was added and the reaction mixture
was stirred at rt for 3 days open to air (moisture helps to increase the solubility of NaBARF). Then the mixture was filtered and the
filtrate concentrated under reduced pressure. The obtained solid was suspended in Et2O and then filtered (to remove excess Me4NI).
The filtrate was concentrated under reduced pressure and the resulting solid was recrystallised from CH2Cl2 at 0 °C for three times to
yield the tetramethylammonium BARF salt as a colourless powder (in total: 1.49 g, 80% yield). 1H NMR (400 MHz, D6DMSO) δ 7.66
(s, 4H), 7.64 – 7.57 (m, 8H), 3.10 (s, 12H). 13C{1H} NMR (101 MHz, D6DMSO) δ 161.0 (q, J = 49.9 Hz), 134.0 (s), 129.1 – 127.9 (m),
124.0 (q, J = 272.4 Hz). 117.9 – 117.27 (m), 54.7 – 54.0 (m). 9a: Triazolium 7a (0.153 g, 0.284 mmol) was dissolved in a mixture of
CH2Cl2 (17.4 mL) and MeOH (5.8 mL), tetramethylammonium BARF (0.293 g, 0.313 mmol) was added and the reaction mixture was
stirred at rt for 22 h. After removal of the solvents under reduced pressure the precipitate was suspended in Et2O (11.5 mL) and stirred
for 45 minutes at 0 °C. The precipitate was removed by filtration and the filtrate was concentrated. The obtained solid was suspended
in CHCl3 (11.5 mL) and stirred for 30 minutes at 0 °C. The precipitate was removed by filtration and the filtrate was concentrated
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under reduced pressure to provide BARF salt 9a as colourless crystals (0.342 g, 96% yield). mp 173 – 174 °C; αD 12.5 (c 0.37,
CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.67 – 7.56 (m, 9H), 7.53 – 7.47 (m, 2H), 7.43 (s, 4H), 7.39 – 7.30 (m, 3H), 7.30 – 7.25 (m, 2H),
7.24 – 7.19 (m, 2H), 5.87 (q, J = 7.0 Hz, 1H), 4.04 (s, 3H), 1.99 (d, J = 7.0 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 161.8 (q, J =
49.9 Hz), 147.9, 135.1 – 134.8 (m), 135.0, 133.5, 130.7, 130.5, 130.0, 129.7 – 128.5 (m), 129.3, 127.0, 124.63 (q, J = 272.6 Hz),
120.6, 117.8 – 117.5 (m), 86.4, 67.7, 39.5, 21.3. IR (KBr) ν=: 1610 (m), 1355 (s), 1277 (s), 1131 (s), 888 (m), 839 (m), 763 (w), 745
(m), 715 (m), 697 (m), 683 (m), 670 (m) cm-1. HRMS (ESI/Q-TOF) m/z: M – C32H12BF24+ Calcd for C17H17IN3 390.0462; found
390.0460; BARF-: Calcd for C32H12BF24 862.0691; found 862.0696 (10B).
(R)-5-bromo-3-methyl-4-phenyl-1-(1-phenylethyl)-1H-1,2,3-triazol-3-ium trifluoromethanesulfonate (10): The Br-
triazole (0.096 g, 0.29 mmol) was dissolved in CH2Cl2 (6.0 mL) under argon atmosphere. Methyl triflate (0.050 mL, 0.439 mmol) was
added dropwise and the reaction mixture was stirred at rt for 22 h. After removal of the solvents under reduced pressure the product
was purified by column chromatography on silica gel (from 5% of MeOH in CH2Cl2) to provide triflic salt 10 as an off colourless oil
(0.049 g, 34% yield). αD20 -1.6 (c 0.18, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.70 – 7.55 (m, 5H), 7.49 – 7.37 (m, 5H), 6.06 (q, J = 7.0
Hz, 1H), 4.31 (s, 3H), 2.19 (d, J = 7.0 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 143.2, 136.6, 132.4, 130.2, 129.8, 129.8, 129.7,
127.1, 122.4, 120.8 (q, J = 320.4 Hz), 116.5, 65.4, 39.9, 21.3. IR (film) ν=: 3063 (w), 1566 (w), 1493 (m), 1455 (m), 1266 (s), 1225 (m),
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1154 (s), 1031 (s), 795 (w), 760 (m), 702 (s), 638 (s), 573 (w) cm-1. HRMS (ESI/Q-TOF) m/z: M - CF3O3S+ Calcd for C17H17BrN3
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342.0600; found 342.0601 (79Br); OTf- Calcd for CF3O3S 148.9526; found 148.9525.
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(R)-5-chloro-3-methyl-4-phenyl-1-(1-phenylethyl)-1H-1,2,3-triazol-3-ium trifluoromethanesulfonate (11): Triazole 11
(0.1005 g, 0.354 mmol) was dissolved in CH2Cl2 (6.0 mL) under argon atmosphere. Methyl triflate (0.060 mL, 0.531 mmol) was added
dropwise and the reaction mixture was stirred at rt for 23 h. After removal of the solvents under reduced pressure the product was
mixed overnight in MeOH (1 mL) in the presence of activated charcoal (0.025 g) to remove some of the coloured impurities. In addition
11 was purified by column chromatography on silica gel (from 5% of MeOH in CH2Cl2) to provide triflic salt 11 as a colourless oil
(0.132 g, 83% yield. αD20 -15.5 (c 0.27, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.63 – 7.49 (m, 5H), 7.43 – 7.28 (m, 5H), 6.00 (q, J = 7.0
Hz, 1H), 4.24 (s, 3H), 2.14 (d, J = 7.0 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 140.5, 136.4, 132.5, 130.1, 129.9, 129.8, 129.7,
129.2, 127.0, 120.7, 64.4, 40.0, 20.9. IR (film) ν=: 1494 (w), 1455 (w), 1266 (s), 1225 (m), 1155 (s), 1032 (s), 761 (m), 701 (m), 638
(s), 574 (w) cm-1. HRMS (ESI/Q-TOF) m/z: M - CF3O3S+ Calcd for C17H17ClN3 298.1106; found 298.1110; OTf- Calcd for CF3O3S
148.9526; found 148.9544.
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(R)- 3-methyl-4-phenyl-1-(1-phenylethyl)-1H-1,2,3-triazol-3-ium trifluoromethanesulfonate (12): (R)-4-phenyl-1-(1-
phenylethyl)-1H-1,2,3-triazole (0.050 g, 0.201 mmol) was dissolved in CH2Cl2 (4.0 mL) under argon atmosphere. Methyl triflate (0.045
mL, 0.401 mmol) was added dropwise and the reaction mixture was stirred at rt for 21 h After removal of the solvents under reduced
pressure the product was purified by column chromatography on silica gel (from 3% of MeOH in CH2Cl2) to provide triflic salt 12 as a
colourless oil (0.074 g, 89% yield). αD20 -27.6 (c 0.09, CHCl3); 1H NMR (400 MHz, CDCl3) δ 8.54 (s, 1H), 7.63 – 7.50 (m, 7H), 7.48 –
7.38 (m, 3H), 6.17 (q, J = 7.1 Hz, 1H), 4.26 (s, 3H), 2.11 (d, J = 7.0 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 143.6, 136.7, 132.1,
130.0, 129.8, 129.7, 129.6, 128.0, 127.7, 122.0, 120.9 (q, J = 320.3 Hz), 65.4, 38.8, 20.3. HRMS (ESI/Q-TOF) m/z: M - CF3O3S+
Calcd for C17H18N3 264.1495; found 264.1502; OTf- Calcd for CF3O3S: 148.9526; found 148.9551.
General procedure for the reactions with 1H NMR monitoring between 1 and 2: All of the crystallised XB donors were
additionally purified by column chromatography (from 5% of MeOH in CH2Cl2) before their use in the catalytic experiments.
Danishefsky`s diene of purity 96% was purchased from Alfa Aesar and used as received. (E)-1-(4-methoxyphenyl)-N-
phenylmethanimine 1: MgSO4 (6.8 g, 56.4 mmol) was suspended in CH2Cl2 (13 mL), then p-anysaldehyde (1.8 mL, 13.8 mmol) and
aniline (1.2 mL, 13.1 mmol) were added. The reaction mixture was stirred at rt for 24 h and filtered. After removal of the solvent under
reduced pressure, the crude product was purified by crystallisation from a mixture of CH2Cl2 and Et2O to yield imine 1 as colourless
crystals (1.94 g, 70% yield). 1H NMR (400 MHz, CDCl3) δ 8.40 (s, 1H), 7.93 – 7.79 (m, 2H), 7.40 (dd, J = 8.7, 6.9 Hz, 2H), 7.22 (td, J =
7.6, 7.2, 1.5 Hz, 3H), 7.04 – 6.93 (m, 2H), 3.87 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 162.3, 159.8, 152.5, 130.6, 129.4, 129.2,
125.7, 121.0, 114.3, 55.5.
The XB donor (0.052 mmol, 0.2 equiv.) was dissolved in a stock solution of CD2Cl2 (0.650 mL) containing imine 1 (0.4 M, 1.0 equiv.)
and p-xylene (0.2 M, 0.5 equiv.). Then 0.600 mL of the solution was transferred to a NMR tube and the 1H spectrum was measured.
1
Then Danishefsky`s diene 2 (0.063 mL, 1.3 equiv.) was added and the H spectra were measured at approximately 8, 15 and 30
minute intervals for at least the first 8 h of the reaction. In certain cases the product 3 was isolated by purification with column
chromatography on silica gel (from 20% of EtOAc in petroleum ether) to provide 3 as a yellow oil with yields usually 10% lower than
the corresponding conversion.
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Parameters specific to the experiment: T = 297 K, Relaxation delay = 36 s, Number of Scans = 8. Data Processing was performed
using MestreNova. The spectra were phased, baseline-corrected and zero-filled (To spectrum size 128K). Then line fitting function
(deconvolution) was used to more accurately integrate the peaks corresponding to the protons of the methoxy group of imine 1 and
methyl group of p-xylene.
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2-(4-methoxyphenyl)-1-phenyl-2,3-dihydropyridin-4(1H)-one (3): H NMR (400 MHz, CDCl3) δ 7.64 (dd, J = 7.8, 1.2 Hz, 1H), 7.35 –
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7.27 (m, 2H), 7.21 – 7.15 (m, 2H), 7.15 – 7.07 (m, 1H), 7.07 – 7.00 (m, 2H), 6.90 – 6.81 (m, 2H), 5.32 – 5.26 (m, 1H), 5.24 (dd, J =
6.9, 3.2 Hz, 1H), 3.76 (s, 3H), 3.26 (dd, J = 16.3, 7.0 Hz, 1H), 2.75 (ddd, J = 16.3, 3.3, 1.2 Hz, 1H). 13C{1H} NMR (101 MHz, CDCl3) δ
190.5, 159.2, 148.3, 144.8, 129.9, 129.6, 127.5, 124.5, 118.8, 114.4, 102.9, 61.4, 55.4, 43.7.
Acknowledgements
The authors thank the Estonian Ministry of Education and Research (Grant Nos. IUT 19-32, IUT 19-9, PUT692 and PUT1468) and the
Centre of Excellence in Molecular Cell Engineering 2014-2020.4.01.15-0013 for financial support. This work has been partially
supported by ASTRA “TUT Institutional Development Programme for 2016-2022” Graduate School of Functional Materials and
Technologies" (2014-2020.4.01.16-0032). We thank Dr. Marina Kudrjašova for the 19F NMR measurmetns, Dr. Riina Aav for advice on
the NMR experiments, Dr. Aleksander-Mati Müürisepp for IR and Ms. Jevgenija Martõnova for the X-ray measurements.
Supporting Information
Copies of 1H and 13C{1H} spectra, spectra and chromatograms used for the mechanistic study, computational details and
crystallographic details.
REFERENCES
1 Desiraju, G. R.; Ho, P. S.; Kloo, L.; Legon, A. C.; Marquardt, R.; Metrangolo, P.; Politzer, P.; Resnati, G.; Rissanen, K. Definition of
the halogen bond (IUPAC Recommendations 2013). Pure Appl. Chem. 2013, 85, 1711–1713.
2
For general reviews see: b) Montaña, Á. M. The σ and π Holes. The Halogen and Tetrel Bondings: Their Nature, Importance and
Chemical, Biological and Medicinal Implications. ChemistrySelect 2017, 2, 9094–9112; b) Cavallo, G.; Metrangolo, P.; Milani, R.;
Pilati, T.; Priimagi, A.; Resnati, G.; Terraneo, G. The Halogen Bond. Chem. Rev. 2016, 116, 2478–2601; c) Wang, H.; Wang, W.; Jin,
W. J. σ-Hole Bond vs π-Hole Bond: A Comparison Based on Halogen Bond. Chem. Rev. 2016, 116, 5072–5104; d) Gilday, L. C.;
Robinson, S. W.; Barendt, T. A.; Langton, M. J.; Mullaney, B. R.; Beer, P. D. Halogen Bonding in Supramolecular Chemistry. Chem.
Rev. 2015, 115, 7118–7195.
3 For reviews focusing on the use of XBs in crystal engineering: a) Christopherson, J.-C.; Topić, F.; Barrett, C. J.; Frisčič, T. Halogen-
Bonded Cocrystals as Optical Materials: Next-Generation Control over Light–Matter Interactions. Cryst. Growth Des. 2018, 18,
1245−1259; b) Li, B.; Zang, S.-Q.; Wang, L.-Y.; Mak, T. C. W. Halogen bonding: A powerful, emerging tool for constructing high-
dimensional metal-containing supramolecular networks. Coord. Chem. Rev. 2016, 308, 1–21; c) Berger, G.; Soubhyea, J.; Meyer, F.
Halogen bonding in polymer science: from crystal engineering to functional supramolecular polymers and materials. Polym. Chem.
2015, 6, 3559–3580; d) Mukherjee, A.; Tothadi, S.; Desiraju, G. R. Halogen Bonds in Crystal Engineering: Like Hydrogen Bonds yet
Different. Acc. Chem. Res. 2014, 47, 2514–2524.
4 For reviews focusing on the use of XBs in solution: a) Tepper, R.; Schubert, U. S. Halogen Bonding in Solution: Anion Recognition,
Templated Self‐Assembly, and Organocatalysis. Angew. Chem. Int. Ed. 2018, 57, 6004–6016; b) Brown, A.; Beer, P. D. Halogen
bonding anion recognition. Chem. Commun. 2016, 52, 8645–8658; c) Jentzsch, A. V. Applications of halogen bonding in solution.
Pure Appl. Chem. 2015, 87,15–41; d) Carlsson, A.-C.C.; Vega, A.X.; Erdélyi, M. Halogen Bonding in Solution. Top. Curr.Chem. 2015,
359, 49–76; e) Beale, T. M.; Chudzinski, M. G.; Sarwar, M. G.; Taylor, M. S. Halogen bonding in solution: thermodynamics and
applications. Chem. Soc. Rev. 2013, 42, 1667–1680.
5 For reviews, see: a) Nishikawa, Y. Recent topics in dual hydrogen bonding catalysis. Tetrahedron Lett. 2018, 59, 216-223; b) Zhao,
B.-L.; Li, J.-H.; Du, D.-M. Squaramide‐Catalyzed Asymmetric Reactions. Chem. Rec. 2017, 17, 994–1018; c) Fang, X.; Wang, C.-J.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 17
1
2
3
4
5
6
7
8
9
Recent advances in asymmetric organocatalysis mediated by bifunctional amine–thioureas bearing multiple hydrogen-bonding
donors. Chem. Commun. 2015, 51, 1185–1197; d) Chauhan, P.; Mahajan, S.; Kaya, U.; Hack, D.; Enders, D. Bifunctional
Amine‐Squaramides: Powerful Hydrogen‐Bonding Organocatalysts for Asymmetric Domino/Cascade Reactions. Adv. Synth. Catal.
2015, 357, 253–281; e) Albrecht, Ł.; Jiang, H.; Jørgensen, K. A. Hydrogen‐Bonding in Aminocatalysis: From Proline and Beyond.
Chem. Eur. J. 2014, 20, 358–368.
6 a) Rissanen, K. Halogen bonded supramolecular complexes and networks. CrystEngComm 2008, 10, 1107–1113; b) Lommerse, J.
P. M.; Stone, A. J.; Taylor, R.; Allen, F. H. The Nature and Geometry of Intermolecular Interactions between Halogens and Oxygen or
Nitrogen. J. Am. Chem. Soc. 1996, 118, 3108–3116.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
7
a) Riel, A. M. S.; Jessop, M. J.; Decato, D. A.; Massena, C. J.; Nascimento, V. R.; Berryman, O. B. Experimental investigation of
halogen-bond hard–soft acid–base complementarity. Acta Crystallogr., Sect. B: Struct. Sci., Cryst. Eng. Mater. 2017, 73, 203–209; b)
Robertson, C. C.; Perutz, R. N.; Brammer, L.; Hunter, C. A. A solvent-resistant halogen bond. Chem. Sci. 2014, 5, 4179–4183.
8 Bruckmann, H. A.; Pena, M. A.; Bolm, C. Organocatalysis through Halogen-Bond Activation. Synlett 2008, 900–902.
9
a) Haraguchi, R.; Hoshino, S.; Sakai, M.; Tanazawa, S.; Morita, Y.; Komatsu, T.; Fukuzawa, S. Bulky iodotriazolium
tetrafluoroborates as highly active halogen-bonding-donor catalysts. Chem. Commun. 2018, 54, 10320–10323; b) Takeda, Y.;
Hisakuni, D.; Lin, C.-H.; Minakata, S. 2-Halogenoimidazolium Salt Catalyzed Aza-Diels–Alder Reaction through Halogen-Bond
Formation. Org. Lett. 2015, 17, 318–321; c) Jungbauer, S. H.; Walter, S. M.; Schindler, S.; Rout, L.; Kniep, F.; Huber, S. M. Activation
of a carbonyl compound by halogen bonding. Chem. Commun. 2014, 50, 6281–6284.
10 a) von der Heiden, D.; Detmar, E.; Kuchta, R.; Breugst, M. Activation of Michael Acceptors by Halogen-Bond Donors. Synlett 2018,
29, 1307–1313; b) Gliese, J.-P.; Jungbauer, S. H.; Huber, S. M. A halogen-bonding-catalyzed Michael addition reaction. Chem.
Commun. 2017, 53, 12052–12055.
11 a) Benz, S.; Poblador-Bahamonde, A. I.; Low-Ders, N.; Matile, S. Catalysis with Pnictogen, Chalcogen, and Halogen Bonds. Angew.
Chem. Int. Ed. 2018, 57, 5408–5412; b) Dreger, A.; Engelage, E.; Mallick, B.; Beer, P. D.; Huber, S. M. The role of charge in 1,2,3-
triazol(ium)-based halogen bonding activators. Chem. Commun. 2018, 54, 4013–4016; c) Jungbauer, S. H.; Huber, S. M. Cationic
Multidentate Halogen-Bond Donors in Halide Abstraction Organocatalysis: Catalyst Optimization by Preorganization. J. Am. Chem.
Soc. 2015, 137, 12110–12120; d) Kniep, F.; Walter, S. M.; Herdtweck, E.; Huber, S. M. 4,4′‐Azobis(halopyridinium) Derivatives:
Strong Multidentate Halogen‐Bond Donors with a Redox‐Active Core. Chem. Eur. J. 2012, 18, 1306–1310; e) Kniep, F.; Rout, L.;
Walter, S. M.; Bensch, H. K. V.; Jungbauer, S. H.; Herdtweck, E.; Huber, S. M. 5-Iodo-1,2,3-triazolium-based multidentate halogen-
bond donors as activating reagents. Chem. Commun. 2012, 48, 9299–9301; f) Walter, S. M.; Kniep, F.; Herdtweck, E.; Huber, S. M.
Halogen‐Bond‐Induced Activation of a Carbon–Heteroatom Bond. Angew. Chem. Int. Ed. 2011, 50, 7187–7191.
12
For reviews, see: a) Breugst, M.; von der Heiden, D. Mechanisms in Iodine Catalysis. Chem. Eur. J., 2018, 24, 9187–9199; b)
Bulfield, D.; Huber, S. M. Halogen Bonding in Organic Synthesis and Organocatalysis. Chem. Eur. J., 2016, 22, 14434–14450; c)
Schindler, S.; Huber, S. M. Halogen Bonds in Organic Synthesis and Organocatalysis. Top. Curr. Chem., 2014, 359, 167–203.
13 a) von der Heiden, D.; Bozkus, S.; Klussmann, M.; Breugst, M. Reaction Mechanism of Iodine-Catalyzed Michael Additions. J. Org.
Chem. 2017, 82, 4037–4043; b) Kee, C. W.; Wong, M. W. In Silico Design of Halogen-Bonding-Based Organocatalyst for Diels–Alder
Reaction, Claisen Rearrangement, and Cope-Type Hydroamination. J. Org. Chem. 2016, 81, 7459–7470; c) Nziko, V. de P. N.;
Scheiner, S. Catalysis of the Aza-Diels–Alder Reaction by Hydrogen and Halogen Bonds. J. Org. Chem. 2016, 81, 2589–2597; d)
Breugst, M.; Detmar, E.; von der Heiden, D. Origin of the Catalytic Effects of Molecular Iodine: A Computational Analysis. ACS Catal.
2016, 6, 3203 – 3212.
14 a) Kuwano, S.; Suzuki, T.; Hosaka, Y.; Arai, T. A chiral organic base catalyst with halogen-bonding-donor functionality: asymmetric
Mannich reactions of malononitrile with N-Boc aldimines and ketimines. Chem. Commun. 2018, 54, 3847–3850; b) Arai, T.; Suzuki, T.;
Inoue, T.; Kuwano, S. Chiral Bis(imidazolidine)iodobenzene (I-Bidine) Organocatalyst for Thiochromane Synthesis Using an
Asymmetric Michael/Henry Reaction. Synlett 2017, 28, 122–127; c) Lindsay, V. N. G.; Charette, A. B. Design and Synthesis of Chiral
Heteroleptic Rhodium(II) Carboxylate Catalysts: Experimental Investigation of Halogen Bond Rigidification Effects in Asymmetric
Cyclopropanation. ACS Catal. 2012, 2, 1221–1225.
15 a) Robinson, S. W.; Beer, P. D. Halogen bonding rotaxanes for nitrate recognition in aqueous media. Org. Biomol. Chem., 2017, 15,
153–159; b) Lim, J. Y. C.; Marques, I.; Ferreira, L.; Félix, V.; Beer, P. D. Enhancing the enantioselective recognition and sensing of
chiral anions by halogen bonding. Chem. Commun. 2016, 52, 5527–5530; c) Tepper, R.; Schulze, B.; Jäger, M.; Friebe, C.; Scharf, D.
H.; Görls, H.; Schubert, U. S. Anion Receptors Based on Halogen Bonding with Halo-1,2,3-triazoliums. J. Org. Chem. 2015, 80, 3139–
3150.
16
For recent reviews, see: a)H. B. Jalani, A. C. Karagöz, S. B. Tsogoeva, Synthesis 2017, 49, 29-41; b) B. Schulze, U. S. Schubert,
Chem. Soc. Rev. 2014, 43, 2522-2571.
17
Nepal, B.; Scheiner, S. Competitive Halide Binding by Halogen Versus Hydrogen Bonding: Bis‐triazole Pyridinium. Chem. Eur. J.
2015, 21, 13330–13335.
18
Kaasik, M.; Kaabel, S.; Kriis, K.; Järving, I.; Aav, R.; Rissanen, K.; Kanger, T. Synthesis and Characterisation of Chiral
Triazole‐Based Halogen‐Bond Donors: Halogen Bonds in the Solid State and in Solution. Chem. Eur. J. 2017, 23, 7337–7344.
19 For reviews on asymmetric aza-Diels-Alder reactions, see: a) Eschenbrenner‐Lux, V.; Kumar, K.; Waldmann, H. The Asymmetric
Hetero‐Diels–Alder Reaction in the Syntheses of Biologically Relevant Compounds. Angew. Chem. Int. Ed. 2014, 53, 11146–11157;
b) Masson, G.; Lalli, C.; Benohouda, M.; Dagousset, G. Catalytic enantioselective [4 + 2]-cycloaddition: a strategy to access aza-
hexacycles. Chem. Soc. Rev. 2013, 42, 902–923.
20
Hein, J. E.; Tripp, J. C., Krasnova, L. B.; Sharpless, K. B.; Fokin, V. V. Copper(I)‐Catalyzed Cycloaddition of Organic Azides and
1‐Iodoalkynes. Angew. Chem. Int. Ed. 2009, 48, 8018-8021.
21
Kuijpers, B. H. M.; Dijkmans, G. C. T.; Groothuys, S.; Quaedflieg, P. J. L. M.; Blaauw, R. H.; van Delft, F. L.; Rutjes, F. P. J. T.
Copper(I)-Mediated Synthesis of Trisubstituted 1,2,3-Triazoles. Synlett. 2005, 3059–3062.
22 Worrell, B. T.; Hein, J. E.; Fokin, V. V. Halogen Exchange (Halex) Reaction of 5‐Iodo‐1,2,3‐triazoles: Synthesis and Applications of
5‐Fluorotriazoles. Angew. Chem. Int. Ed. 2012, 51, 11791–11794.
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Gaussian 09, Revision D.01, Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.;
Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H. P.; Izmaylov, A. F.; Bloino,
J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.;
Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, J. A., Jr.; Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin, K. N.;
Staroverov, V. N.; Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.;
Rega, N.; Millam, J. M.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.;
Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.;
Salvador, P.; Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas, Ö.; Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J.
Gaussian, Inc., Wallingford CT, 2009.
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Yanai, T.; Tew, D.; Handy, N. A new hybrid exchange–correlation functional using the Coulomb-attenuating method. Chem. Phys.
Lett. 2004, 393, 51-57.
25 Zhao, Y.; Truhlar, D. G. The M06 suite of density functionals for main group thermochemistry, thermochemical kinetics, noncovalent
interactions, excited states, and transition elements: two new functionals and systematic testing of four M06-class functionals and 12
other functionals. Theor. Chem. Acc. 2008, 120, 215-241.
26
Weigend, F.; Ahlrichs, R. Balanced basis sets of split valence, triple zeta valence and quadruple zeta valence quality for H to Rn:
Design and assessment of accuracy. Phys. Chem. Chem. Phys. 2005, 7, 3297-3305.
27 Lu, T.; Chen, F. Multiwfn: A multifunctional wavefunction analyzer. J. Comput. Chem. 2012, 33, 580-592.
28 Varetto, U. Molekel 5.4.
29 The 7a + TBACl complex precipitates at 0.4 M concentration, if the reaction was run under ten times diluter conditions the complex
was still in solution, however no reaction took place
30 Surprisingly, Minakata et al. observed a reverse trend between halogen atom polarisability and catalytic activity in reference 9a.
31 This was in addition to the 20 minute delay in adding the diene 2 after solubilising the catalyst present in the other reactions
32 Zhang, X.; Hao, X.; Liu, L.; Pham, A.-T.; López-Andarias, J.; Frontera, A.; Sakai, N.; Matile, S. Primary Anion−π Catalysis and
Autocatalysis. J. Am. Chem. Soc. 2018, 140, 17867-17871.
33
Pilli; R. A.; Russowsky. D. Secondary Mannich bases via trimethylsilyl trifluoromethanesulphonate promoted addition of silyl enol
ethers to Schiff bases. Chem. Commun., 1987, 1053-1054.
34 Kawęcki. R. Aza Diels–Alder reactions of sulfinimines with the Rawal diene. Tetrahedron: Asymmetry 2006, 17, 1420–1423.
35 For reviews see: a) Krossing, I.; Raabe, I. Noncoordinating Anions—Fact or Fiction? A Survey of Likely Candidates, Angew. Chem.
Int. Ed. 2004, 43, 2066–2090; b) Strauss, S. H. The Search for Larger and More Weakly Coordinating Anions. Chem. Rev. 1993, 93,
927-942.
36 Saito, M.; Tsuji, N.; Kobayashi, Y.; Takemoto, Y. Direct Dehydroxylative Coupling Reaction of Alcohols with Organosilanes through
Si–X Bond Activation by Halogen Bonding. Org. Lett. 2015, 17, 3000–3003;
37
Surprisingly, in reference 9a tetrafluoroborate containing triazolium salts were used to catalyse aza-Diels-Alder reaction. The
authors claim that steric bulk of the substituents on the triazolium ring influence significantly the catalytic activity of the salts. In the
paper, the less sterically crowded catalysts (that are more comparable to our compounds 8) gave lower yields than those that were
more crowded.
38We were able to recover 80% of the catalyst after the reaction, see SI Figure S45B.
39 Compounds with m/z ratios corresponding to intermediates 13/14/17 and 15/16 were detected by HRMS in the reaction mixture. By
HMBC we infer that a methylene group is nearby to a carbonyl group in the intermediate, which cannot be possible in the case of
intermediate 16. We speculate that the TMS substituent is located on the nitrogen atom in 14 based on the observation that 14 is quite
persistant in the reaction medium in the case of hydrogen containing triazole salt 12. All attempts at isolating the intermediate were
unsucsessful. For furter details see SI.
40 Girling, P. R.; Kiyoi, T.; Whiting, A. Mannich–Michael versus formal aza-Diels–Alder approaches to piperidine derivatives. Org.
Biomol. Chem. 2011, 9, 3105–3121.
41 Freitas, L. B. de O.; Eisenberger, P.; Crudden, C. M. Mesoionic Carbene–Boranes. Organometallics 2013, 32, 6635–6638.
For Table of Contents Only
OTf
N
N
O
Ar
Ph
N
Ph
OMe
N
I
N
XB-catalyst
OTMS
Ph
MeO
as low as 2 mol%
MeO
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