Thermal azide-Alkene cycloaddition reactions: straightforward multi-gram access to Δ2-1,2,3-Triazolines in deep eutectic solvents

Article abstract of DOI:10.1039/c8gc01797b

The multi-gram synthesis of a wide range of 1,2,3-Triazolines via azide-Alkene cycloaddition reactions in a Deep Eutectic Solvent (DES) is reported. The role of DES in this transformation as well as the origin of the full product distribution was studied with an experimental/computational-DFT approach.

Full text of DOI:10.1039/c8gc01797b

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Thermal azide–alkene cycloaddition reactions:
straightforward multi-gram access to Δ2-1,2,3-tria-
zolines in deep eutectic solvents†
Cite this: DOI: 10.1039/c8gc01797b
a
Filip Sebest, a Luis Casarrubios, a,b Henry S. Rzepa, a Andrew J. P. White
a
and Silvia Díez-González
*
Received 8th June 2018,
Accepted 29th June 2018
The multi-gram synthesis of a wide range of 1,2,3-triazolines via azide–alkene cycloaddition reactions in a
Deep Eutectic Solvent (DES) is reported. The role of DES in this transformation as well as the origin of the
full product distribution was studied with an experimental/computational-DFT approach.
DOI: 10.1039/c8gc01797b
rsc.li/greenchem
Even when a triazoline can be formed, it often rearranges/
further reacts and other heterocycles (such as triazoles,7 pyra-
Introduction
1,3-Dipolar cycloadditions, also known as Huisgen reactions, zolines,8 isoindoles,9 amidines,10 pyrrol- and indol-izidines11)
are convergent and atom-economical reactions that offer a con- are isolated instead. In consequence, the promise of 1,2,3-tria-
venient synthetic route for five-membered heterocyclic mole- zolines as versatile synthons12 and biologically active com-
cules.1 To date, few reactions can match dipolar cycloadditions pounds remains unfulfilled.13
in the variety of bonds that can be involved and the increase of
A thermal azide–alkene cycloaddition is expected to deliver
molecular complexity in the obtained products. Hence, the two regioisomeric triazolines, either 1,4- or 1,5-disubstituted,
extensive research coverage received by these reactions over the and the product distribution is mainly dictated by electronic
years is more than justified and has notably allowed uncover- factors.14 Thermodynamically, dipolar cycloadditions leading
ing alternative catalytic routes leading to broader and more to either triazoles or triazolines are virtually identical.
selective reactions, including enantioselective ones. A particu- However, while triazoles are aromatic and highly stable, triazo-
larly high-profile example of this is the copper-mediated lines are typically more reactive than the starting materials due
azide–alkyne cycloaddition reaction,2 and this transformation to the numerous decomposition pathways available to them.15
has become the emblem of Click chemistry,3 a concept coined The most commonly encountered products are then imines
by Sharpless in 2001 and closely related to that of Green (often hydrolysed into amines and carbonyl derivatives) and
chemistry.
aziridines. The formation of aziridines upon nitrogen extru-
While the use of metals (mainly copper, but also ruthe- sion from the corresponding triazolines could be a simple
nium, iridium, or silver)4 has been instrumental for the study alternative to metal-mediated aziridination reactions with
and application of triazoles, the preparation of 1,2,3-triazo- azides as nitrene source.16 However, the formation of aziri-
lines from azides and alkenes remains limited to highly acti- dines from the corresponding triazolines depends strongly on
vated alkenes, such as strained and electron-rich alkenes,5 and the position and electronic nature of the substituents on the
therefore out of the scope of Click chemistry. Simple alkenes five-membered ring,12 which has led to apparently conflicting
do not react with azides or react very slowly and reaction times reports over the years.17,18 Unlike the reaction with alkynes, to
of several days or even months are not overly uncommon.6 the best of our knowledge no metal-mediated version of the
azide–alkene cycloaddition has been reported and therefore
the scope of this reaction remains severely limited.
On the other hand, it was recognised early on that the reac-
tion media could play a key role in numerous non-catalysed
dipolar cycloaddition reactions.19 As part of our interest in
developing user-friendly and greener methodologies, we
turned our attention to Deep Eutectic Solvents (DESs). DESs
are combinations of two or three inexpensive, non-toxic and
safe components that produce a non-flammable mixture with
a much lower melting point than any of the individual com-
aDepartment of Chemistry, Imperial College London, Exhibition Road,
South Kensington, London SW7 2AZ, UK. E-mail: s.diez-gonzalez@imperial.ac.uk
bDepartamento de Química Organica I, Facultad de Ciencias Químicas, Universidad
Complutense and Centro de Innovación en Química Avanzada (ORFEO–CINQA),
28040 Madrid, Spain
†Electronic supplementary information (ESI) available: FAIR data for NMR
spectra, computational and crystallographic data, see ref. 48. CCDC
1843142–1843147. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c8gc01797b
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Table 1 Solvent screeninga,b
ponents. These mixtures, which are liquids at the reaction
temperature, are held together via hydrogen bonding inter-
actions. The interesting physico-chemical properties of DESs
are often compared to those of ionic liquids, with the
additional advantages of lower costs and much higher user-
and environment-friendliness (i.e. water tolerance).20 The
benefits of using DESs instead of ionic liquids or standard
organic solvents are obviously dependent on the actual DES
components. Those made of urea, glycerol, water or choline
chloride are particularly promising in Green chemistry.
The applications of DESs are steadily spreading in separ-
ation, materials, organic and organometallic chemistry.21 In
particular, DESs have been applied to several cycloaddition
reactions such as Lewis acid-catalysed Diels–Alder reactions,22
formation of pyrrolidines from the corresponding azomethine
ylides,23 and isoxazoles from nitrile oxides.24 From azides,
either tetrazoles25 or triazoles26 have been prepared in DES. In
many of these examples the beneficial effect of DES as reaction
media was rationalised either through the Lewis acidity of one
of the components, or the formation of hydrogen bonds between
either of the components and the cycloaddition partners.
Entry
Solvent
1ac (%)
3aac (%)
4aac (%)
1
2
3
4
Toluene
MeCN
CHCl3
1,4-Dioxane
THF
25
23
19
30
14
37
0
38
22
16
12
7
5
13
5
7
14
13
10
11
7
<5
0
<5
<5
18
30
11
10
<5
5
5
6
7
8
9
TBME
Diglyme
EtOAc
EtOH
10
11
12
DMSO
Water
DES
<5
0
55
0
18
a Reaction conditions: Azide 1a (1 mmol), styrene 2a (1.3 equiv.) in
mL of solvent. b Observed trace decomposition products:
2
.
Herein we report straightforward azide–alkene cyclo-
addition reactions in Deep Eutectic Solvents to yield 1,2,3-tria-
zoline cycloadducts, or in some cases aziridines, where
organic solvents or ionic liquids only led to disappointing
results. Preliminary studies to ascertain the role of DES in the
azide–alkene cycloaddition reaction and the origin of the aziri-
dine products are also presented.
c 1H NMR yields/recovery are the average of two independent experi-
ments and were determined with respect to 1,3,5-trimethoxybenzene
as internal standard.
Capitalising on this promising result, the optimisation
studies then focused on cycloaddition reactions in deep eutec-
tic solvents and different reaction times and temperatures
were screened. At 80 °C no further conversion was observed
when the reaction mixture was heated for 24 h instead of 16 h.
Results and discussion
Optimisation of the reaction conditions
4-Trifluoromethylphenyl azide and styrene were chosen as Comparable conversions into 3aa and 4aa were observed at
model substrates and they were reacted at 80 °C overnight 90 °C after 8 h, but again the reaction did not proceed further
(Table 1). Mixtures of 1,5-disubstituted triazoline 3aa and aziri- after longer heating periods. Higher reaction temperatures led
dine 4aa were obtained in most reactions. A number of known to significant formation of decomposition products.
decomposition products of triazolines –an imine, aniline or
Next, a number of commonly encountered DESs were tested
acetophenone (Table 1)– were evidenced by NMR in many of (Table 2). In all cases, the starting azide was fully converted
these reactions but only as traces. Disappointing NMR yields when 2 equivalents of styrene were employed and overall
were obtained in all tested organic solvents independently of similar reaction outcomes were obtained with most of the
their characteristics due to severe decomposition of cyclo- tested DESs. The original choice, choline chloride/urea (1 : 2),
adducts and/or the starting azide (up to 80% of the total mass, led to the highest conversion into the desired triazoline 3aa.
Table 1, entries 1–10), which made it virtually impossible to When choline iodide was used instead as the Lewis base
isolate any reaction product. In stark contrast with these partner, significant formation of 4-trifluoromethylaniline
results, a clean reaction was obtained when the model sub- (∼10%) was observed and the resulting DES was only liquid
strates were heated in a mixture 1 : 2 of choline chloride and above 70 °C, which made its manipulation cumbersome. Other
urea (DES, Table 1, entry 12).
DESs remained valuable options, except when a more acidic
It is important to note that both reaction products are partner such as glycolic acid was used as one of the components
stable under the reaction conditions and they were recovered and only a complex mixture of decomposition products was
quantitatively when heated separately at 80 °C in DES for 16 h. obtained (Table 2, entry 6).27 A similar outcome was observed
However, partial decomposition of triazoline 3aa was observed when a popular ionic liquid, BMIM·PF6 (BMIM = N-butyl-
when heated in standard organic solvents (i.e. DMSO, 1,4- N′-methylimidazolium), was used as solvent (Table 2, entry 7).
dioxane) at the same temperature (vide infra). We believe that
After this screening, the term DES in this article will refer
this increased stability of triazolines in DES is key to explain- solely to a 1 : 2 mixture of choline chloride and urea.28 To date,
ing the success of these reactions.
only a handful of 1,2,3-triazolines have been structurally
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Table 2 Screening of deep eutectic solventsa
Entry
Solvent
3aab (%)
4aab (%)
1
2
3
4
5
6
7
Choline chloride/urea (1 : 2)
Choline iodide/urea (1 : 2)
Choline chloride/ethylene glycol (1 : 2)
Choline chloride/water (1 : 2)
Choline chloride/glycerol (1 : 2)
Choline chloride/glycolic acid (1 : 2)
BMIM·PF6
67
60
61
61
61
22
11
13
18
12
Decomposition
Decomposition
a Reaction conditions: Azide 1a (1 mmol), styrene 2a (2 equiv.) in 2 mL
of solvent. b 1H NMR yields are the average of two independent experi-
ments and were determined with respect to 1,3,5-trimethoxybenzene
as internal standard.
characterised,29 and therefore single crystals were grown for
3aa and 4aa to confirm the assigned structures (Fig. 1 and 2).
Crystals of 3aa contained two independent molecules and in
both of them the triazoline ring has a small envelope defor-
mation with C5 lying ca. 0.20 Å out of the {N1,N2,N3,C4} plane
in molecule 3aa-A (0.18 Å in 3aa-B), which atoms are coplanar
to better than 0.01 Å in both instances. In each case, the
4-CF3-phenyl group is almost co-planar to the {N1,N2,N3,C4}
plane, while the phenyl ring on C5 is oriented such that its
plane approaches eclipsed with respect to the N1–C5 bond,
with the N1–C5–C16–C21 torsion angles being ca. 28° in both
molecules. Aziridine scaffolds are far more common, and in
the case of 4aa, the torsion angle between the two substituents
is 138° (Fig. 2).
Fig. 2 Structure of aziridine 4aa (50% probability ellipsoids). Most
hydrogens are omitted for clarity. Selected bond lengths (Å) and angles
(°): N1–C2 1.477(4), N1–C3 1.451(5), C2–C3 1.484(5); C3–N1–C2 60.9
(2), C4–N1–C2 18.3(3).
Scope of the reaction
With a set of optimised conditions in hand, we explored the
scope of the reaction with a range of aryl/heteroaryl azides and
styrene (Table 3). In all cases, the desired 1,5-disubstituted
triazolines were the major product in these reactions and the
1H NMR conversions for the corresponding aziridines ranged
between 6 and 36%. Proportionally, the highest formation of
aziridines was observed when using azides bearing electron-
donating substituent(s) (Table 3, entries 12–15). Reactions
with heteroaryl azides as cycloaddition partners (Table 3,
entries 16–18) were carried at lower temperatures (60–70 °C) as
substantial decomposition of the reaction products was
observed at 80 °C.
Even if the main purpose of this work was the preparation
of 1,2,3-triazolines, many of the formed aziridines 4 were also
isolated and fully characterised due to the inherent impor-
tance of this heterocyclic motif, both in chemistry and
biology.30 Traces of aniline derivatives were observed in many
of these reactions, but such a decomposition product was only
significant when a nitro substituent was present in the starting
1
azide (Table 3, entry 2, 23% by H NMR). On the other hand,
imine formation was only competitive in the reaction of
heteroaryl azide 1r (Table 3, entry 18). Indeed, whereas triazo-
lines bearing ortho-electron-donor groups in their 1-aryl substi-
tuents were found relatively stable, this was not the case when
the ortho substituent was an electron-withdrawing one. For
example, in the reaction with 2-trifluoromethylphenyl azide,
only traces of the desired triazoline were observed together
Fig. 1 Structure of one (3aa-A) of the two independent molecules
present in the crystal of triazoline 3aa (50% probability ellipsoids). Most
hydrogens are omitted for clarity. Selected bond lengths (Å) and angles
(°): N1A–N2A 1.380(6), N2A–N3A 1.241(8), N3A–C4A 1.471(8), C4A–C5A
1.538(8), N1A–C5A 1.462(7); N3A–N2A–N1A 112.2(5), C4A–C5A–C16A
113.2(4).
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Table 3 Reaction scope – aryl and heteroaryl azidesa
decomposition by-products. Finally, purification on neutral
alumina resulted in the substantial decomposition of both
products. Overall, basified silica led to the best separation of
the formed reaction products while minimising their
decomposition during purification.
Benzylic azides were also screened in DES (Table 4),
although lower conversions into cycloadducts were observed in
these reactions, particularly when no electron-withdrawing
groups were present. Longer reactions times could be used in
order to maximise azide conversion, but higher reaction temp-
eratures only led to significant decomposition of the reaction
mixture. The reaction of bis(azide) 1v led to the formation of
four different products, with that bearing a triazoline and an
aziridine ring being the major product (34va, Table 4, entry 4).
The reaction of 1-azido-2-ethoxyethane with styrene has
been reported to yield a mixture of regioisomeric triazolines
after heating neat at 50 °C for 30 days.31 However, when we
tried to reproduce this transformation, we obtained a mixture
Entry
R
3 : 4b (%)
3c (%)
4c (%)
1
4-CF3 (1a)
4-NO2 (1b)
4-CN (1c)
4-COOEt (1d)
4-I (1e)
4-Br (1f)
4-Cl (1g)
72 : 24
68 : 6
58
67
57
57
54
56
58
56
54
76
68
48
46
51
56
18
—
4
2d
3
71 : 14
63 : 24
60 : 27
71 : 31
70 : 30
66 : 29
53 : 30
76 : 21
76 : 10
54 : 35
52 : 33
56 : 36
57 : 29
4
5
6
7
8
9
10
11
12
13
14
15
11
20
24
21
15
23
—
—
28
27
29
11
4-F (1h)
H (1i)
3-CF3 (1j)
3,5-(CF3)2 (1k)
4-Me (1l)
4-iPr (1m)
4-OMe (1n)
2,4,6-(Me)3 (1o)
1
of 1,5-disubstituted triazoline and aziridine (49% and 35% H
NMR yield, respectively). This reaction could also be per-
formed in DES, albeit low conversions were obtained after 16 h
of stirring (Table 4, entry 5). Only starting materials were recov-
ered from the reactions with other aliphatic azides (i.e. decyl
16e
69 : 15
62
14
17
35 : 6
—
—
—
Table 4 Reaction scope – aliphatic azidesa
18f
43 : 11
33
a Reaction conditions: Azide 1X, styrene 2a (2 equiv.) in DES (0.5 M).
b 1H NMR yields are the average of two independent experiments and
were determined with respect to 1,3,5-trimethoxybenzene as internal
standard. c Isolated yields. d Reaction time = 8 h. e Reaction carried out
at 70 °C for 24 h. f Reaction carried out at 60 °C for 32 h.
Entry
1d
Azide
3 : 4b (%)
3c (%)
4c (%)
1s
1t
36 : 34
28
29
2d,e
50 : 30
18 : 8
42
22
with 30% of aziridine, 18% of imine and 6% of aniline. In
the case of 2-nitrophenyl azide, only formation of imine (18%)
and aniline (16%) was evidenced by 1H NMR.
3
1u
—
—
While the optimisation studies were carried out using
1 mmol of aryl azide, the reactions could be easily scaled up
and the scope of the cycloaddition was explored using 3 to 5 g
of azide (15–27 mmol). This led to the multigram isolation of
1,2,3-triazolines, typically by simple precipitation and recrystal-
lisation from the reaction mixture, which minimises the need
for volatile organic compounds. Column chromatography was
still necessary in some cases, as for the isolation of oily triazo-
4e, f
1v
9 : 24 : 42 : 15
n.d.
6 (31va)
20 (33va)
29 (34va)
1 (44va)
5g
1w
16
5
a Reaction conditions: Azide 1X, styrene 2a (2 equiv. per azide group)
in DES (0.5 M). b 1H NMR yields are the average of two independent
experiments and were determined with respect to 1,3,5-trimethoxyben-
lines and aziridines, since the latter remained in the filtrate zene as internal standard. c Isolated yields. d Reaction carried out at
85 °C. e Reaction time = 24 h. f Four reaction products could be isolated
during the first recrystallization step. While triazoline 3aa and
aziridine 4aa could be separated on silica, significant
in this reaction:
decomposition (∼40% of the formed materials) was observed
as expected for products sensitive to acidic conditions. This
could be easily avoided using basified silica (triethylamine),
instead. No decomposition was observed with cellulose either,
although the separation of 3aa and 4aa was poor and required
several columns to obtain an acceptable purity. When basified
alumina or florisil were used as stationary phase only triazo-
g Reaction carried out at 70 °C.
line 3aa was recovered, albeit contaminated with some
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azide and adamantyl azide) at 80 °C. When the reaction temp-
erature was raised to 90 °C, 8% of the desired triazoline was
observed by 1H NMR with decyl azide, but higher temperatures
only led to severe decomposition of the reaction mixture.
Next, the generality of the reaction in terms of alkene sub-
stitution was studied (Table 5). Two other styrene derivatives
were screened bearing either an electron-withdrawing or an
electron-donating group at the para position (Table 5, entries 1
and 2). While only formation of triazoline 3dc was observed in
the reaction with 4-methoxystyrene, a lower ratio of triazoline
formation was observed with the 4-chloro analogue. A similar
triazoline to aziridine ratio was also obtained with a naphthyl
derivative (Table 5, entry 3). The structure of triazoline 3dd
was confirmed by X-ray crystallography (Fig. 3) because several
broad signals were observed in its 1H NMR spectrum, which in
our experience is unusual for this family of compounds.
Interestingly, the reaction of 4-vinylpyridine afforded the
corresponding aziridine 4de as the major reaction product
(Table 5, entry 4). This was also the only product that could be
isolated analytically pure from this reaction.
Fig. 3 Structure of triazoline 3dd (50% probability ellipsoids). Most
hydrogens are omitted for clarity. Selected bond lengths (Å) and angles
(°): N1–N2 1.3724(18), N2–N3 1.2515(19), N3–C4 1.477(2), C4–C5 1.542
(2), N1–C5 1.4681(19); N3–N2–N1 111.97(14), C4A–C5A–C16A 113.99
(12).
Table 5 Reaction scope – monosubstituted alkenesa
We also found that the allylic substituent has a profound
impact on the cycloaddition outcome. Indeed, the reaction of
allyltrimethylsilane delivered triazoline 3dg in good yields and
only traces of the corresponding aziridine. However, allylic
alcohol led to the formation of 30% of aziridine 4dh and only
5% of triazoline (Table 5, entries 6 and 7). Significant aniline
formation (∼25% 1H NMR yield), indicative of product
decomposition, was observed in all reactions with allylic
derivatives. Even an alkene as non-activated as 1-octene could
be successfully used under our reaction conditions (Table 5,
entry 8). As expected,5 electron-richer alkenes led to completely
selective reactions and no aziridine formation was observed
(Table 5, entries 9 and 10). These alkenes were particularly
reactive cycloaddition partners and triazoline 3dk could be
prepared at 65 °C in high yields. This accrued reactivity was
exploited with allyl vinyl ether (Table 5, entry 11), which deli-
vered 5-(allyloxy)triazoline 3dl with only traces of the
triazoline issue of the reaction of the allyl moiety.
Nevertheless, the presence of an allyl group remained proble-
matic and around 30% of the overall mass could not be
accounted for in this case.
Next, the effect of introducing additional substituents on
the alkene partner was explored. In general, longer reaction
times and/or higher reaction temperatures were required to
overcome the increased steric bulk in these reactions (Table 6).
1,1-Disubstituted alkenes led to the exclusive formation of the
corresponding triazolines with the notable exception of 1,1-
diphenylethene (Table 6, entries 1–3). Norbornene yielded tria-
zoline 3dp quantitatively at room temperature (Table 6, entry 4),
as expected for a strained substrate.5a In stark contrast,
unstrained 1,2-disubstituted alkenes led to the stereospecific
formation of the corresponding aziridines (trans-aziridines
from E-alkenes and cis-aziridines from Z-alkenes). The crystal
structure of 4dq confirmed the stereospecificity of the aziri-
Entry
1
Alkene
3 : 4b (%)
3c (%)
4c (%)
2b
2c
2d
2e
2f
53 : 31
39
—
2
3
4
5
86 : 0
70
42
—
41
—
14
31
3
56 : 25
31 : 40
44 : 16
6
2g
2h
2i
67 : <5
5 : 30
62
—
43
—
16
26
7
8d
52 : 15
9e
2j
74 : 0
66
—
10f
11g
2k
2l
90 : 0
56 : 0
85
37
—
—
a Reaction conditions: Azide 1d, alkene 2X (2 equiv.) in DES (0.5 M).
b 1H NMR yields are the average of two independent experiments and
were determined with respect to 1,3,5-trimethoxybenzene as internal
standard. c Isolated yields. d Reaction carried out at 85 °C. e Reaction
carried out at 75 °C. f Reaction carried out at 65 °C. g Reaction carried
out at 60 °C.
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Table 6 Reaction scope – disubstituted alkenesa
Mechanistic studies and origin of the aziridines
(A) The DES effect: As mentioned in the introduction, no metal-
based catalysts have been reported for azide–alkene cyclo-
addition reactions. We could only find two reports evoking the
use of organocatalysts in this reaction. Garcia-Garibay and co-
workers reported the use of dimethylurea as catalyst in the
cycloaddition reaction of aryl azides and electron-poor 1,2-di-
substituted alkenes.35 Alternatively, tetramethylammonium
hydrogen sulfate was used to mediate the cycloaddition of
enones to isolate triazoles after in situ oxidation of the inter-
mediate triazoline.36 When we subjected one of our reactions
to these reported conditions, only disappointing results were
obtained (Table 7, entries 1–3). Little, if any, cycloadducts were
obtained, accompanied by significant decomposition of the
reaction mixture as observed by 1H NMR.
Entry Alkene
1
Conditions
75 °C, 96 h
3 : 4b (%) 3c (%) 4c (%)
92 : 0
66 : 0
87
51
24
—
—
11
2
3
90 °C, 16 h
100 °C, 72 h 30 : 17
4
RT, 16 h
100 : 0
99
—
Furthermore, in previous examples of dipolar cycloaddi-
tions in DES, an organocatalytic effect is often suggested
through H-bonding interactions between the cycloaddition
partners and DES components.23,24,26b While such interactions
might be established with any organic azide through its
internal nitrogen atom, most of the alkenes screened in this
work are not susceptible to forming hydrogen bonds. We
nevertheless tested each of the DES components as organo-
catalysts for cycloaddition. In these tests, THF/water mixtures
and vigorous stirring were required in order to ensure homo-
geneous solutions. Virtually identical results were obtained
with either 15 mol% of choline chloride or urea (Table 7,
5
6
100 °C, 48 h 0 : 60
110 °C, 16 h 0 : 42
—
—
53
36
7
8
90 °C, 32 h
95 °C, 32 h
0 : 26
0 : 26
—
—
21
21
a Reaction conditions: Azide 1d, alkene 2X (2 equiv.) in DES (0.5 M).
b 1H NMR yields are the average of two independent experiments and
were determined with respect to 1,3,5-trimethoxybenzene as internal
standard. c Isolated yields.
dine formation,32 which is in agreement with the expected entries 5 and 6) and even if the conversion of triazoline 3aa
configurational stability of singlet biradicals (vide infra).33
remained modest it should be noted that only decomposition
Aziridines 4dq–4dt were accompanied by decomposition was obtained when the cycloaddition was carried out in THF/
products, which suggests that triazolines bearing substituents water in the absence of an additive. Using both DES com-
on the 4-position are considerably less stable and supports the ponents in sub-stochiometric quantities further improved the
notion of aziridines being formed from 1,4-disubstituted tria- results, but none of these conditions were competitive when
zolines, as discussed below.
From these results, it is clear that the product distribution highest and cleanest conversions (Table 7, entries 4 and 8).
is most strongly influenced by the alkene substitution, while
Overall, it appears plausible that the observed “DES effect”
the nature of the azide has a crucial effect on the overall con- in the azide–alkene reaction is mainly due to the increased
version into cyclised products.
thermal stability of the formed cycloadducts when compared
compared to the developed reactions in DES, which led to the
Finally, we screened a 1,2-diene under our reaction con- to standard organic solvents. However, an organocatalytic
ditions, cyclohexylallene (Scheme 1). In this case, no aziri- effect of one or both DES components cannot be completely
dine formation was observed and instead two conjugated ruled out at this time.
cycloadducts were obtained (together with aniline and
(B) Formation and evolution of triazolines: It is well estab-
other unidentified decomposition products), triazoline 3du lished that the cycloaddition of aryl azides and simple alkenes
and triazole 5du, issue of a double bond migration in proceeds through an asynchronous concerted mechanism.37
3du. The observed regioselectivity is in accordance with In comparison, the factors determining the final reaction
the few reports available on intermolecular azide–allene product distribution are less studied.35,38 Accordingly, we next
cycloadditions.34
carried out a computational mechanistic study to rationalise
No conversion of triazoline 3du into triazole 5du was the obtained experimental results and focused our efforts on
observed during its isolation/purification. However, attempts 1,2,3-triazolines as the origin of the isolated aziridines. The
to grow crystals of 3du from a hot solution in methanol led to formation of the three-membered heterocycles via a nitrene–
the characterisation of peroxide 5du′ instead. While triazole alkene cycloaddition was not considered since formation of
5du′ was not present in the reaction mixture, traces of it nitrenes from the reported aryl azides is highly unlikely at the
could already be evidenced in the 1H NMR of triazoline 3du reaction temperatures employed.39 Indeed, azide 1d was quan-
after a pentane/diethyl ether wash, which shows its high titatively recovered after heating it in DES at 80 °C for 24 h or
reactivity.
at 90 °C for 8 h. Hence, the formation of aziridines 4 from
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Scheme 1 Intermolecular azide–allene cycloaddition reaction in DES. Structures of one (5du’-A) of the two independent molecules present in the
crystal of triazoles 5du’ (left) and triazole 5du (right) are 50% probability ellipsoids. Most hydrogens are omitted for clarity.
Table 7 Organocatalytic testsa
Entry
Conditions (R = –COOEt)
1d (%)
3da (%)
4da (%)
ArNH2 (%)
1
2
3
4
Dimethylurea (10 mol%), toluene, 80 °C, 16 h
[NBu4][HSO4] (20 mol%), toluene, 80 °C, 16 h
[NBu4][HSO4] (20 mol%), DMF, 80 °C, 16 h
Standard conditions: DES, 80 °C, 16 h
12
58
42
5
23
—
9
12
—
5
—
7
10
7
63
24
Entry
Conditions (R = –CF3)
1a (%)
3aa (%)
4aa (%)
ArNH2 (%)
5
6
7
8
Urea (15 mol%), THF/water, 80 °C, 16 h
ChCl (15 mol%), THF/water, 80 °C, 16 h
Urea (30 mol%), ChCl (15 mol%), THF/water, 80 °C, 16 h
Standard conditions: DES, 80 °C, 16 h
20
16
0
19
22
42
72
11
10
16
24
6
6
5
<5
<5
a 1H NMR yields/recoveries are the average of two independent experiments and were determined with respect to 1,3,5-trimethoxybenzene as
internal standard.
transient 1,4-disubstituted triazolines seems to be the most only minor decomposition was observed in other solvents
likely option. However, we could not prepare such a triazoline such as DMSO and dioxane (Table 8, entries 2 and 3). At
even when following literature procedures (vide supra, Table 4, 100 °C, only 58% of the starting triazoline was recovered but
entry 5). On the other hand, we observed that triazoline 3aa the main decomposition product was the corresponding
was stable under our reaction conditions (Table 8, entry 1) and aniline and only small amounts of aziridine were formed in
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Table 8 Thermal stability of triazoline 3aaa
Calculations40 were performed at the B3LYP41+GD3BJ42/6-
311++G(d,p)43 (triple-ζ) SCRF continuum solvation level, using
the CPCM44 model and N-methylformamide mixture level
parameters (ε = 181.56) to simulate the high polarity of the
eutectic solvent used experimentally. Calculations using the
alternative ωB97XD45 functional and/or the Def2-QZVPP46
quadruple-ζ basis set are reported for selected systems. All
transition states were characterised by normal coordinate ana-
lysis, revealing one imaginary mode corresponding to the
intended reaction. IRC47 calculations on these transition states
confirmed the identity and synchronicity of the reactions.
Unless stated otherwise, all energy values are free energies
ΔG‡353 (kcal mol−1) for a standard state of 1 atm (0.041 M), nor-
malized to a relative free energy of 0 kcal mol−1 for the reactant
pre-complex. Full coordinates for all the stationary points,
together with IRC animations and other data are available via
a FAIR data repository.48
3aa 4aa 6aa 7a
(%) (%) (%) (%) (%)
ArNH2
Entry Conditions
1
2
3
4
5
6
DES, 80 °C, 16 h
DMSO, 80 °C, 16 h
1,4-Dioxane, 80 °C, 16 h
DES, 100 °C, 16 h
DMSO, 100 °C, 16 h
1,4-Dioxane, 100 °C, 16 h
>95
89
93
—
—
—
6
—
12
5
—
—
—
7
—
—
—
29
58
7
Complete decomposition
30 <5 <5
—
9
a 1H NMR yields/recoveries are the average of two independent experi-
ments and were determined with respect to 1,3,5-trimethoxybenzene
as internal standard.
The reaction between azide 1d and styrene was chosen for
the computational study. In this reaction, small quantities of
imine 6da and the corresponding aniline were also formed as
minor by-products (Scheme 2). An overview of the located
stationary points and transition states and their corresponding
energies is shown in Scheme 3.
At the B3LYP+GD3BJ/6-311++G(d,p)/SCRF level, two con-
certed asynchronous cycloaddition transition states resulting
in the formation of regioisomeric triazolines 3da and 3da′
were located as TS11,5 and TS11,4, respectively (Scheme 3). The
basis set effect (BSE) on the difference in the activation free
energies ΔΔG‡353 for 6-311++G(d,p) vs. Def-QZVPP was found to
be insignificant, whilst the effect on the barrier is to increase
it by ∼2 kcal mol−1. The regioselectivity ΔΔG‡353 was more sen-
sitive to the DFT functional, ranging from 1.3 for the B3LYP
method with no dispersion included, to 2.2 for the ωB97XD
method which includes a built-in second generation D2 dis-
Scheme 2 Complete product distribution in the model reaction.
comparison (Table 8, entry 4). No triazoline was recovered at
100 °C in either DMSO or dioxane, with imine 6aa being the
major thermolysis product in the latter case (Table 8, entries 5
and 6).
Scheme 3 Complete reaction profile with ΔG‡353 calculated at the B3LYP+GD3BJ/6-311++G(d,p)/SCRF level.
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persion correction and 2.8 kcal mol−1 using B3LYP with expli- mentally observed regioselectivity favouring the formation of
cit inclusion of the third generation GD3BJ correction 3da as the major product (57% isolated yield). The reaction is
(Table 9). These differences qualitatively match the experi- predicted exoenergic by >10 kcal mol−1 but only if dispersion
is included in the model, since this affects both the interaction
energies and the entropies, both of which propagate to the
Table 9 Calculated values of ΔG‡353 for TS1a
free energies.
To understand the origin of the minor products shown in
Scheme 2, we next modelled the nitrogen extrusion processes.
That from 1,5-disubstituted triazoline was investigated just at
the B3LYP+GD3BJ/6-311++G(d,p) level, the reference (resting)
state now being the product of the first reaction 3da
(Table 10). No transition state for aziridine formation could be
located from 3da. Instead, it was computed to evolve into two
Method
TS11,4
TS11,5
ΔΔG‡353
ΔΔG353
c
B3LYP/6-311++G(d,p)
30.8
29.5
1.27
−4.9, −4.1
(0.95)b
3.08
B3LYP+GD3BJ/6-
311++G(d,p)
ωB97XD/6-311++G(d,
p)
24.7
21.6
−11.1,
−11.7
−17.5,
−18.3
(26.7)b
29.0
(24.0)b
26.7
(2.75)b
2.29
(2.22)b
different imines 6da(H) and 8da(Ph) via TS21,5-H and TS21,5-Ph
,
a Bimolecular energetic barriers ΔG3‡53 are reduced by 1.7 kcal mol−1
when corrected for the 0.5 M experimental concentration. b Def2-
QZVPP basis set. c ΔΔG353 product1,4, product1,5. Full FAIR data is
available via a data repository at DOI: 10.14469/hpc/4325.
a process that also involves the migration of either a H or Ph
group to the emerging primary cation via relatively high energy
barriers (Table 10 and Fig. 4). The presence of a dipolar
“hidden intermediate”49 is shown by the large increase in
dipole moment in the region of the transition state (Fig. 4b).
As previously stated, prolonged heating at 80 °C of a pure
sample of a 1,5-disubstituted triazoline led to the corres-
ponding imine as the only decomposition product (see
Table 8). Partial hydrolysis of this imine during work-up would
explain the detection of anilines in the reaction crudes.
Competitive TS21,5-Ph would produce aldimine 8da, a more
unstable product that would completely hydrolyse into aniline
and an aliphatic aldehyde, which in turn is likely to oligomer-
ise under the reaction conditions. The overall reactions are
now strongly exoenergic.
Table 10 Calculated values of ΔG‡353 for TS2a
b
Method
ΔG‡353
ΔΔG353
TS21,5-H
TS21,5-Ph
TS21,4a
30.1
30.2
21.8
20.9
−53.0
−49.4
−42.4 (−13.9)c
−61.3
TS21,4b
a At the B3LYP+GD3BJ/6-311++G(d,p) level, relative to 3da or 3da′ in
kcal mol−1 b Overall reaction free energies. c Energy of intermediate bi-
.
radical. Full FAIR data is available via a data repository at DOI:
10.14469/hpc/4326.
Fig. 4 Computed properties along an intrinsic reaction coordinate (IRC) for (a) energy profile for TS21,5-H, (b) dipole moment response for TS21,5-H
,
(c) energy profile for TS21,4-b and (d) dipole moment response for TS21,4-b
.
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Two diastereomeric transition states (TS21,4a and TS21,4b
)
and the alkene and might also be dynamically controlled.
were located for the loss of dinitrogen from 1,4-disubstituted Further studies on DES applications and dynamic calculations
triazoline 3da′. The activation free energies are now low are underway in our laboratories.
enough to explain the absence of reactant 3da′ in the reaction
products (Table 10). The IRC for TS21,4a revealed the formation
of a singlet dipolar biradical followed by a relatively low energy
Experimental section
General procedure for the dipolar cycloadditions
(e.g. ΔG‡353trans = 2.6 kcal mol−1) for electrocyclic ring closure to
the corresponding aziridines cis-4da and trans-4da. In contrast,
Azide (1.0 equiv.) and alkene (2.0 equiv.) were stirred in deep
eutectic solvent (choline chloride/urea = 1 : 2; 0.5 M) at 80 °C
for 16 h, unless stated otherwise. The reaction mixture was
cooled down to room temperature, diluted with water (2 mL
per mmol of azide) and pentane/Et2O (3 : 1; 1 mL per mmol of
azide) and stored at −18 °C overnight. If triazoline precipitated
overnight, this was triturated at room temperature, collected
by filtration, washed three times with ice cold pentane/Et2O
and recrystallised from boiling ethanol if necessary.
Occasionally, the washings and/or filtrate from this recrystalli-
sation were further purified by column chromatography as
described next, either to improve the triazoline recovery, or to
isolate the corresponding aziridine. If no solid precipitated at
−18 °C, the mixture was extracted with EtOAc, the combined
organic phases were washed with water and brine, dried over
MgSO4, filtered, concentrated under reduced pressure and pur-
ified by column chromatography on basified silica (eluent: pet-
roleum ether/EtOAc 0 → 25% gradient basified with 2% v/v
NEt3 unless stated otherwise; reaction crude was dry-loaded
onto stationary phase). Occasionally, the product recovered
after column chromatography required washing with ice-cold
pentane/Et2O (1 : 1).
TS21,4b was found to evolve into imine 8da upon a migration
of a hydrogen atom (Fig. 4), which would be expected to easily
hydrolyse into the corresponding aniline. The transition state
again has transient cationic character (Fig. 4c) as revealed by
the dipole moment response along the IRC.
Overall, our calculations are in good agreement with the
experimental results. A thermal dipolar cycloaddition step
leads to the formation of two regioisomeric triazolines.
Whereas the 1,5-disubstituted triazoline 3da would be kineti-
cally relatively stable at the reaction temperature and render
only small quantities of imine by-products at most, the 1,4-di-
substituted regioisomer 3da′ readily reacts to form either the
corresponding aziridine or imines with dinitrogen evolution.
We have experimentally shown that the product distribution is
also highly dependent on the aryl alkene and azide substi-
tutions. This is consistent with the insight revealed by the cal-
culations for nitrogen extrusion in particular, which show sig-
nificant dipolar/ionic character localised in the region of the
transition state for this step. It has indeed been established
that variation in the substituents may indeed induce dramatic
changes in reaction mechanisms.50 A full study of the influ-
ence of such substituents upon the reactions described here
will be reported separately.
3aa: Following the general procedure from 1-azido-4-
trifluoromethylbenzene (5.00 g, 26.7 mmol) and styrene
(6.18 mL, 53.4 mmol), the title compound was isolated as a
white solid (3.68 g after recrystallisation, 0.82 g after column:
58% overall). From this reaction, aziridine 4aa was also iso-
lated as a white solid (1.28 g, 18%) after column chromato-
graphy and recrystallisation from pentane at −18 °C.
Conclusions
A range of di- and tri-substituted Δ2-1,2,3-triazolines have been
prepared and fully characterised. The studied azide–alkene
cycloadditions in DES typically led to mixtures of 1,2,3-triazo-
lines and aziridines, although the overall product distributions
were largely influenced by the alkene substitution. The
benefits of DES in this context are twofold. First, the DES
employed herein is non-flammable and it is composed of two
safe and inexpensive components, urea and choline chloride.
Secondly, much cleaner reaction crudes were obtained in DES
when compared to standard organic solvents, and typically
3aa: Single crystals for X-ray diffraction were grown from Et2O,
several grams of the desired triazolines could then be isolated CCDC 1843142;† Mp 88.0–90.0 °C; Rf = 0.49 (petroleum ether/
analytically pure after a simple recrystallisation step. EtOAc = 80 : 20); IR: νmax 1612 (m), 1523 (m), 1502 (m), 1458,
Furthermore, a mechanism for the reaction between aro- 1431, 1365 (m), 1316 (m), 1193, 1153 (m), 1111 (s), 1067 (s),
matic azides and olefins to yield triazolines and/or aziridines 1010 (m), 990 (m), 963 (m), 926 (m), 841 (m), 820 (s), 751 (s),
1
has been proposed. All our calculations have shown that this 698 (s) cm−1; H NMR (CDCl3, 400 MHz) δ 7.45 (d, J = 8.5 Hz,
interesting process can proceed through two divergent path- 2H, H2), 7.35–7.24 (m, 5H, HAr), 7.15 (d, J = 8.5 Hz, 2H, H3),
ways, cycloaddition followed by simple loss of dinitrogen to a 4.94 (dd, J = 12.5; 8.0 Hz, 1H, H6), 4.88 (dd, J = 17.5; 12.5 Hz,
biradical intermediate and then cyclization to the corres- 1H, H5), 4.37 (dd, J = 17.5; 8.0 Hz, 1H, H5); 13C NMR (CDCl3,
ponding aziridines or loss of dinitrogen together with conco- 101 MHz): δ 142.9 (C4), 139.5 (C7), 129.5 (C9), 128.4 (C10), 126.5
mitant group migration to form imines. The process seems to (q, J = 3 Hz, C2), 125.9 (C8), 124.3 (q, J = 269 Hz, C11), 124.0 (q,
be highly dependent on the nature of both the starting azide J = 33 Hz, C1), 114.4 (C3), 76.1 (C5), 57.4 (C6); 19F NMR (CDCl3,
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377 MHz): δ −61.9 (s); HRMS (ES+) calculated for C15H13N3F3
292.1062, found 292.1058 ([M + H]+); elemental analysis calcu-
lated for C15H12N3F3: C, 61.85; H, 4.15; N, 14.43, found: C,
61.95; H, 4.27; N, 14.27.
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4aa: Single crystals for X-ray diffraction were grown from Et2O,
CCDC 1843144;† Mp 85.0–87.0 °C; Rf = 0.83 (petroleum ether/
EtOAc = 80 : 20); IR: νmax 3053, 1614 (m), 1516, 1464, 1418,
1389, 1327 (s), 1279 (s), 1185, 1163 (m), 1127 (m), 1101 (s),
1076 (m), 1065 (s), 1010 (m), 981 (m), 914, 867, 843 (s), 790,
767 (m), 758 (s), 714 (s), 698 (s) cm−1 1H NMR (CDCl3,
;
400 MHz) δ 7.50 (d, J = 8.5 Hz, 2H, H2), 7.38–7.36 (m, 4H, HAr),
7.34–7.29 (m, 1H, HAr), 7.11 (d, J = 8.5 Hz, 2H, H3), 3.16 (dd,
J = 6.5; 3.5 Hz, 1H, H6), 2.49 (dd, J = 6.5; 1.0 Hz, 1H, H5), 2.47
(dd, J = 3.5; 1.0 Hz, 1H, H5); 13C NMR (CDCl3, 101 MHz)
δ 157.6 (C4), 138.6 (C7), 128.6 (C9), 127.7 (C10), 126.3 (q, J =
3 Hz, C2), 126.2 (C8), 124.6 (q, J = 32 Hz, C1), 124.4 (q, J =
269 Hz, C11), 120.7 (C3), 41.7 (C6), 37.7 (C5); 19F NMR (CDCl3,
377 MHz): δ −61.8 (s); HRMS (ES+) calculated for C15H13NF3
264.1000, found 264.0988 ([M + H]+); elemental analysis calcu-
lated for C15H12NF3: C, 68.44; H, 4.59; N, 5.32, found: C, 68.39;
H, 4.69; N, 5.29.
Conflicts of interest
9 B. Wei-Qiang and S. Chiba, Org. Lett., 2009, 11, 729–732.
10 S. Xie, S. A. Lopez, O. Ramström, M. Yan and K. N. Houk,
J. Am. Chem. Soc., 2015, 137, 2958–2966.
There are no conflict to declare.
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This research was financially supported by Imperial College
London and the EPSRC (DTP studentship to F. S. and EP/
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the Spanish government for a grant in the 2017 Salvador de
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