Metal-free 1,5-regioselective azide-alkyne [3+2]-cycloaddition

Article abstract of DOI:10.1002/asia.201100404

[3+2]-cycloaddition reactions of aromatic azides and silylated alkynes in aqueous media yield 1,5-disubstituted-4-(trimethyl-silyl)-1H-1,2,3-triazoles. The formation of the 1,5-isomer is highly favored in this metal-free cycloaddition, which could be proven by 1D selective NOESY and X-ray investigations. Additionally, DFT calculations corroborate the outstanding favoritism regarding the 1,5-isomer. The described method provides a simple alternative protocol to metal-catalyzed "click chemistry" procedures, widening the scope for regioselective heavy-metal-free synthetic applications.

Full text of DOI:10.1002/asia.201100404

FULL PAPERS
DOI: 10.1002/asia.201100404
Metal-Free 1,5-Regioselective Azide–Alkyne [3+2]-Cycloaddition
Florian Kloss,[a, b] Uwe Kçhn,[a, b] Burkhard O. Jahn,[c] Martin D. Hager,[a, b]
Helmar Gçrls,[d] and Ulrich S. Schubert*[a, b]
On the occasion of the 10th anniversary of click chemistry
Abstract: ACHTUNGTRENNUNG[3+2]-cycloaddition reactions of aromatic azides and silylated alkynes in
aqueous media yield 1,5-disubstituted-4-(trimethyl-silyl)-1H-1,2,3-triazoles. The
formation of the 1,5-isomer is highly favored in this metal-free cycloaddition,
which could be proven by 1D selective NOESY and X-ray investigations. Addi-
tionally, DFT calculations corroborate the outstanding favoritism regarding the
1,5-isomer. The described method provides a simple alternative protocol to metal-
catalyzed “click chemistry” procedures, widening the scope for regioselective
heavy-metal-free synthetic applications.
Keywords: alkynes · azides · click
chemistry · cycloaddition · regiose-
lectivity
Introduction
iant (CuAAC) yields regiospecifically 1,4-disubstituted
1,2,3-triazoles under mild conditions. On the contrary, ruthe-
nium catalysis has been developed providing the comple-
mentary 1,5-disubstituted triazoles (RuAAC).[3] However,
conditions required for RuAAC are often harsh compared
to those for copper catalysis. Therefore, more recent investi-
gations have increasingly focused on new methods to yield,
efficiently, 1,5-disubstituted 1,2,3-triazoles under mild condi-
tions.[4] Regrettably, there are only very few reports avail-
able that provide 1,5-regioselective azide–alkyne cycloaddi-
tion protocols under heavy-metal-free conditions.[5] The in-
creased interest in 1,2,3-triazoles is based on their molecular
properties, for example, biological activity[6] or the ability
for metal coordination.[7] Moreover, the dipolar cycloaddi-
tion of azides and alkynes provides a wide scope and fideli-
ty. In this context, in addition to the apparent metal-cata-
lyzed techniques, efficient metal-free cycloadditions have
also been developed successfully.[8] The most prominent ex-
ample, the “strain promoted” 1,3-dipolar cycloaddition
(SPAAC) of highly reactive cyclooctynes with azides, allows
a fast and efficient functionalization of, for example, biologi-
cal samples.[9] However, this method features only very lim-
ited regioselectivity.[10] In addition, owing to the complexity
of the required substrates, this method is rarely appropriate
to straightforward synthetic applications. To overcome the
problem of low regioselectivities observed in the majority of
thermal azide–alkyne cycloadditions,[11] regiodirecting meth-
ods with substituted unstrained alkynes, using electronic as
well as steric effects, can be targeted.[2d,12] For instance, tri-
methylsilyl (TMS)-acetylenes as dipolarophiles in azide–
The classical thermal Huisgen [3+2]-cycloaddition[1] be-
tween azides and alkynes, formerly of not much value in
synthetic applications owing to poor regioselectivity, experi-
enced a renaissance after the findings of Tornøe and Sharp-
less, and their respective co-workers, as a prominent exam-
ple for a “click”-concept reaction.[2] This CuI-catalyzed var-
[a] F. Kloss,+ Dr. U. Kçhn, Dr. M. D. Hager, Prof. Dr. U. S. Schubert
Laboratory of Organic and Macromolecular Chemistry (IOMC)
Friedrich-Schiller-University Jena
Humboldtstr. 10, 07743 Jena (Germany)
Fax : (+49)3641-9482-02
E-mail: ulrich.schubert@uni-jena.de
[b] F. Kloss,+ Dr. U. Kçhn, Dr. M. D. Hager, Prof. Dr. U. S. Schubert
Jena Center for Soft Matter (JCSM)
Humboldtstr. 10, 07743 Jena (Germany)
[c] Dr. B. O. Jahn
Department of Biochemistry and Organic Chemistry, Box 576,
Uppsala University, 751 23 Uppsala (Sweden)
[d] Dr. H. Gçrls
Laboratory of Inorganic and Analytical Chemistry
Friedrich-Schiller-University Jena
Lessingstraße 8, 07743 Jena (Germany)
[+]
[+]
Current address:
Leibniz Institute for Natural Product Research and Infection Biology
(HKI)
Dept. of Biomolecular Chemistry
Beutenbergstr. 11a, 07745 Jena (Germany)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201100404.
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Chem. Asian J. 2011, 6, 2816 – 2824

alkyne cycloadditions have been applied.[13] Notably, the
TMS-group can lead to a high selectivity considering 4-
TMS-triazoles. Initially, a combination of steric interactions
and electronic effects, which lead to an increase of the elec-
trophilicity of the b-carbon of alkynes, was assumed.[14]
However, the regiocontrolling parameters of the TMS group
have not been confirmed in detail up to now. Even more im-
portantly, silylated triazoles have been recognized as valua-
ble building blocks in cross-coupling reactions.[15]
through Sonogashira cross-coupling reactions. While the tri-
methylsilyl group is a standard protecting group in classical
alkynyl coupling protocols, this method directly provides the
desired precursors without additional expense. In order to
avoid metal contaminations from the used catalyst, which
may subsequently catalyze dipolar cycloadditions, all alkyne
derivates were distilled prior to use. As a matter of course,
terminal alkynes were converted to the corresponding trime-
thylsilyl compounds by nucleophilic substitution with trime-
thylchlorosilane under basic conditions (see Supporting In-
formation).
Aromatic azides were also synthesized by a metal-free
procedure. In the first step, aniline derivatives were convert-
ed to diazonium salts using a standard protocol.[18] Subse-
quently, the resulting diazonium salts were treated with
aqueous solutions of sodium azide and sodium acetate. The
resulting azide compounds 1a–f were isolated in good to
very good yields (see Supporting Information).
Here, a systematic investigation of cycloadditions of sub-
stituted TMS-acetylenes with azides is reported (Scheme 1).
It is noteworthy that using water as a solvent/dispersant for
The initial studies were focused on the thermal 1,3-dipolar
cycloaddition between p-tolyl azide 1a and phenylacetylene
3a, an example well-known for being unselective
(Scheme 2).[11] Expectedly, the reaction of p-tolyl azide 1a
Scheme 1. Schematic representation of synthetic pathways to 1,5-disubsti-
tuted-4-trimethylsilyl-1,2,3-triazoles by metal-free 1,3-dipolar cycloaddi-
tion.
Scheme 2. Schematic representation of the azide–alkyne [3+2] cycloaddi-
tion of 1a and 3a. a) H2O, 85 8C, 22 h, 85%, 25a/25b=49:51.
dipolar cycloadditions entails economic advantages, is easy
to handle (e.g., simplified purification), and is known to
have an influence on the reactivity as well as the regioselec-
tivity of cycloadditions.[16]
and phenylacetylene 3a in the presence of water resulted in
the desired triazole compounds (later referred to as 25a,b,
see Table 2). In contrast to the observations of Wang and
co-workers,[19] both isomers were found in an almost 1:1
ratio in the crude product.
Results and Discussion
In the context of the trimethylsilyl regiodirected azide–
alkyne cycloaddition approach, the required trimethylsilyl-
acetylene derivatives[17] were synthesized by a simple route
These results were used as the starting point to privilege
one regioisomer by the use of trimethylsilylacetylene deri-
vates (see Table 1). Intriguingly, the reaction of 1a with un-
substituted trimethylsilylacetylene 2a afforded the 4-silylat-
ed isomer 4a in good yield and excellent regioselectivity.[20]
In analogy, the conversion of 2-(trimethylsilyl)-phenyl-acety-
lene 2c as dipolarophile and p-tolyl azide 1a gave the 1,5-
disubstituted 4-(trimethylsilyl)triazole 5 in high 1,5-regiose-
lectivity (97%).
In order to stress the regiodirecting influence of the TMS
group, we next installed a sterically hindered substituent R2
at the alkyne compounds. If the steric effect of the trime-
thylsilyl-group is the dominant factor, the 1,5-regioselectivity
should decrease with an increase of the steric demand of
this substituent. Therefore, mesityl-2-(trimethylsilyl)-acety-
lene 2b was synthesized through Sonogashira reaction with
mesityliodide. Surprisingly, the 1,3-dipolar cycloaddition be-
tween 2b and 1a also provided the 1,5-isomer (6a) with an
even greater 1,5-regioselectivity (99%). It seems that the
Abstract in German:
ACHTUNGTRNE[NUNG 3+2]-Cycloadditionen zwischen
Aziden und silylierten Alkinen fꢁhren in wꢂssrigen Lçsungs-
mitteln zu 1,5-disubstituierten 4-(Trimethylsilyl)-1H-1,2,3-
triazoles. In dieser schwermetallfreien Cycloadditions-var-
iante ist die Bildung des 1,5-Regioisomers besonders bevor-
zugt. Dies konnte durch selektive NOESY-Experimente
(1D) und Einkristall-Rçntgendiffraktometrie bestꢂtigt
werden. Weiterhin wurde die herausragende 1,5-Regioselek-
tivitꢂt durch DFT-Berechnungen unterstꢁtzt. Die hier be
schriebene Methode stellt eine einfache Alternative zu
metall-katalysierten “Click-Chemie”—Synthesewegen dar—
eine 1,5-regioselektive [3+2]-Cycloaddition fꢁr schwerme-
tallfreie Syntheseanwendungen.
Chem. Asian J. 2011, 6, 2816 – 2824
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U. S. Schubert et al.
FULL PAPERS
Table 1. Schematic representation and selected details of the discussed
azide-alkyne 1,3-dipolar [3+2] cycloadditions.
The inductive effect of the methyl group has no influence
on the regioselectivity.
In all cases, single crystal X-ray diffractometry or NMR
spectroscopy has been utilized to determine the regiochem-
istry of the silylated triazoles.
Regrettably, the heteronuclear long-range coupling of car-
bons and hydrogens between R1 and R2 could not be ob-
served using the HMBC experiment owing to their large dis-
tance. Therefore, NOESY experiments were performed to
determine the substitution pattern of the triazoles. The re-
giochemistry of the major isomer was confirmed by the
characteristic NOE correlation. In this context, 1D selective
NOESY experiments could be accomplished. Exemplarily, a
1D selective NOESY spectrum is shown for compound 6a
in Figure 1. Excitation of the CH protons in the p-tolyl
Triazole R1 R2 T [8C]
t [h]
Yield [%][b] Ratio a/b [%][h] ([i])
4
5
6
1a 2a
1a 2c
1a 2b
85
5
80
>95 a[a] (>99 a)[k]
>95 a (97 a)
>95 a (99 a)
>93 a[e] (> 99 a)
>95 a (99 a)
95 a (97 a)
85/110 15+16[c] 86
85/110 22+3[c] 60
7
8
1b 2b 120
1a 2d 110
46
21
64
84
85
9
1a 2e
1a 2 f
85/110 22+20
85
10
11
12
13
14
15
16
17
18
19
20
21
22
23
25
70
41
16
17
30
8.5
17
17
20
22
28
42
18
64
>94 a[e] (>99 a)
ꢀ94 a[d] (99 a)
>91 a[d] (97 a)
ꢀ90 a[d] (96 a)
>95 a (> 99 a)[k]
>91 a[e] (98 a)
n.d. (97 a)
1a 2g 85[m]
31[f]
86
1a 2h
85
1a 2i 110
1c 2b 110
1d 2b 110
1e 2b 110
1c 2j
1d 2j 110
1e 2j 85
1c 2k 110
1e 2k 85
81
78
61
26[f]
74
85
ꢀ94 a (> 99 a)[k]
28[f]
92
87 a[g] (97 a)
87 a (91 a)
39[f]
59[f]
66
ꢀ93 a (98 a)
n.d. (90 a)
1b 2k 110
1 f 2l 100
ꢀ92 a (98 a)
>95 a (>99 a)[k]
91
[a] No byproduct was observed in 1H NMR. [b] Yields of unpurified
products. [c] First period at 858C, second period at 1108C. [d] Regioselec-
tivity is expected to be higher, signal in the 1H NMR spectrum shows par-
ticipation of an additional impurity. [e] Interference with desilylated com-
pound cannot be completely ruled out. [f] Yield of isolated product.
[g] Desilylated product. [h] 1H NMR quantified. [i] GC-MS/FID quanti-
fied. [k] No byproduct was observed in GC-MS/FID chromatogram.
[m] Run in DMSO; n.d.: not determined.
Figure 1. 1D selective NOESY spectrum (bottom) and 1H NMR spec-
trum (top) for triazole 6a.
steric bulkiness of the mesityl group has no significant influ-
ence on the 1,5-regioselectivity of the triazole ring forma-
tion. In addition, the azide 1a was changed to 1-adamantyla-
zide 1b in order to induce higher steric constraints. Even so,
the reaction between 1b and mesityl-2-(trimethylsilyl)-acet-
ylene 2b afforded the corresponding triazole derivate 7 in
moderate yield, but still with very high 1,5-regioselectivity
(>99%). These first attempts illustrated a remarkable influ-
ence of the TMS group in alkynes with respect to the regio-
selectivity of these kinds of 1,3-dipolar cycloaddition reac-
tions. It seems that the TMS group clearly favors the 4-posi-
tion in the 1,4,5-trisubstituted triazole derivates to a great
extent, independent of the steric bulkiness of substituents.
A possible electronic influence of the TMS moiety on the
regioselectivity in 1,3-dipolar cycloadditions, however, re-
quires a more detailed study using p-tolyl azide 1a and dif-
ferent substituted ethynyltrimethylsilanes. Starting with
o-tolyl substituted trimethylsilylacetylene 2d, the triazole 8a
was obtained with high 1,5-regioselectivity (99%). Com-
pared to the triazole 6a, the NMR and GC results showed
that no significant change in the regioselectivity occurred.
group resulted in a NOE of the o-methyl protons in the me-
sityl group, indicating that the 1,5-isomer was formed. Nota-
bly, selective NOE experiments provide a high performance
in terms of time efficiency.
In order to gain a deeper understanding of the electronic
influence of the TMS group on the regioselectivity, a stron-
ger electron-releasing group with marginal steric hindrance
was installed at the trimethylsilylacetylene unit.
Thus, triazole 9a was synthesized by the reaction of
p-tolyl azide 1a with (p-anisylethynyl)trimethylsilane 2e. In
comparison to 6a, a similar ratio of regioselectivity was
measured (97%). Consequently, an aromatic group that
contains ring substituents with a strong electron releasing
effect has no decreasing influence on the regioselectivity. As
a consequence, the electronic influence of electron-with-
drawing groups in the trimethylsilylacetylene unit on the re-
gioselectivity was investigated. Thus, triazole 11a was
formed between 2-(trimethylsilylethynyl)pyridine 2g and
1a. This reaction was carried out in DMSO owing to the
side reactions observed in water such as TMS cleavage. This
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Metal-Free 1,5-Regioselective Azide–Alkyne [3+2]-Cycloaddition
effect can be explained by the basicity of the pyridine
moiety. However, the reaction proceeded much slower in
DMSO than in water, but still afforded the 1,5-regioisomer
(99%) of 11 highly selectively. Using substituted TMS-ace-
tylenes providing stronger electron-withdrawing groups,
such as ester (2h) or pentafluorphenyl (2i), a slight decrease
of the regioselectivity was observed. Treatment of the TMS-
acetylene derivates 2h and 2i with 1a yielded triazoles 12a
1b as dipoles have been performed, providing similar results
with respect to the regiodirecting behavior (triazoles 20–22).
These results confirmed the assumption that the preference
of the 1,5-substitution pattern is slightly decreased by using
an electron-withdrawing group in the TMS-acetylene. The
preference regarding 1,5-disubstituted triazoles is increasing-
ly disfavored by introducing a sterically demanding group in
the azide, for example, a mesityl group. Surprisingly, the
adamantyl substituent shows a much weaker effect than me-
sityl. Additionally, it appears that azides bearing electron-
withdrawing moieties slightly disfavor the 1,5-regioprefer-
ence between trimethylsilylalkynes and azides (see triazoles
13, 15, or 18). By contrast, azides attached to electron-re-
leasing groups favor 1,5-regioselectivity, exclusively (see tri-
azole 14 and 17).
These investigations have shown that the developed
method represents a powerful and versatile tool for the effi-
cient synthesis of 1,5-disubstituted-4-silylated-1H-1,2,3-tri
azoles in high to excellent 1,5-regioselectivity. Additionally,
the applicability of this potent 1,3-dipolar cycloaddition type
was extended to a TMS-acetylene derivative functionalized
with a benzylic alcohol group inspired by this study. Exem-
plarily, the triazole 23a bearing three different functionali-
ties (benzylic alcohol, bromine, and trimethylsilyl) for po-
tential further modifications could be obtained in high yield
and with excellent 1,5-regioselectivity (>99%) (see Sup-
porting Information). Single-crystal X-ray analysis con-
firmed the assumed 1,5 substitution pattern; the ORTEP
drawing of 23a is shown in Figure 2.
and 13a with
a regioselectivity of over 90% of the
1,5-isomer, respectively. It should be noted that the effect of
electron-withdrawing groups is small, but cannot be neglect-
ed.
In order to delve deeper into the electronic influence of
the substituents R1 and R2 on the triazolesꢃ substitution
preference, 1,3-dipolar cycloadditions were investigated by
using different substituted azides. For this purpose, the
scope of the developed protocol was further extended to the
synthesis of the 1,4,5-trisubstituted triazoles 14, 15, and 16
by using mesityl-2-(trimethylsilyl)acetylene 2b as dipolaro-
phile. The attempted reaction between 2b and 3,4,5-trime-
thoxy-phenylazide 1c (strong electron-releasing group) af-
forded the triazole 14a with excellent regioselectivity. Not
even traces of the regioisomer could be detected by the ap-
plied techniques (GC-MS/FID). It should be mentioned that
the formation of 14a represents the most selective reaction
1
in the present study. Also H NMR spectroscopy indicated
that no further product was formed.
A related protocol which involves 2b and mesityl azide
1e resulted in the expected triazole 16a, which was isolated
in low yield, but a high regioselectivity (97%) could be ob-
served. Moreover, the azide derivate 1d, bearing a penta-
fluorophenyl moiety, was reacted with 2b to afford the tria-
zole 15a in a ratio of regioselectivity of 98% of the 1,5-
isomer. These results show that the 1,5-regioselectivity did
not decrease significantly by introducing electron-withdraw-
ing groups as the azide substituents.
Based on these findings we focused on the use of TMS-
acetylenes with electron-withdrawing groups in reactions
with different azides. Therefore, trimethyl((p-nitrophenyl)-
ethynyl)silane 2j was applied. The reaction of 2j with 3,4,5-
trimethoxy-phenylazide 1c yielded the corresponding tria-
zole 17a with very high 1,5-regioselectivity. No byproduct
could be detected in the GC chromatogram. By contrast,
the treatment of 2j with perfluorophenylazide 1d resulted
in the formation of 18a with 97% 1,5-regioselectivity. Re-
garding this case, it should be pointed out that both re-
gioisomers were obtained in the desilylated form. A more
remarkable decrease in the 1,5-regioselectivity was found in
the reaction between 2j and mesitylazide 1e with a value of
91% (triazole 19a). The chosen examples show that the in-
troduced electron-withdrawing group in the TMS-acetylene
decreases the 1,5-regioselectivity. This effect is increased by
introducing an electron-withdrawing group (triazole 18a) or
a sterically demanding group (triazole 19a) in the azide. In
analogy to the approach involving alkyne 2j, 1,3-dipolar cy-
cloadditions between trimethyl((p-trifluoro-methyl-phenyl)-
ethynyl)-silane 2k as dipolarophile and azides 1c, 1e, and
Figure 2. ORTEP diagram of 23a.
In order to provide concrete evidence about the influence
of the TMS group on the regioselectiviy in the 1,3-dipolar
cycloadditions studied, reactions without the TMS-group
have been performed (see Table 2).
According to earlier reports, water is expected to effect
changes in the regioselectivity of thermal azide–alkyne cy-
cloadditions.[19] However, our first findings are partially non-
Chem. Asian J. 2011, 6, 2816 – 2824
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U. S. Schubert et al.
FULL PAPERS
Table 2. Schematic representation and selected details of the discussed
azide-alkyne 1,3-dipolar [3+2] cycloadditions.
the triazole ring exclusively. In contrast, the mesityl-group
has a strong preference to the 5-position as described above.
Additionally, an electron-releasing substituent in azide or
acetylene also supports a regiopreference towards the 1,5-
substitution pattern in the triazole ring. In a related ap-
proach, these findings have been confirmed by a 1,3-dipolar
cycloaddition between azide and an acetylene, both contain-
ing an electron-withdrawing group. As supposed, the treat-
ment of ethyl propiolate 3h and pentafluorophenyl azide 1d
afforded the triazoles 30 with an excess of the 1,4-isomer.
Compared to the formation of triazoles 26, no significant
difference in the ratio of 1,4-selectivity was observed. It
seems that in the case of unsilylated acetylene derivates, an
increase in the ratio of 1,4-selectivity is achieved by the use
of electron-withdrawing groups in the acetylene derivates.
An electron-withdrawing group attached to the azide does
not seem to have a substantial additional influence on the
1,4-regioselectivity (see triazoles 30).
Surprisingly, during the investigation of the trimethylsilyl-
regiodirected azide–alkyne cycloaddition, the TMS group of
the generated 1,4,5-substitutetd triazoles 4–23 and of the re-
spective alkynes are very stable under the applied hydrolytic
conditions (see Table 1). Finally, in order to demonstrate
that the cleavage of the TMS group of the synthesized 1,4,5-
substituted triazoles 4–23 is feasible, the reaction between
3,4,5-trimethoxy-phenylazide 1c and (mesitylethynyl)trime-
thylsilane 2b was used.
[b]
Triazole R1 R2 T [8C] t [h] Yield [%][a] Ratio a/b [%][c]
( )
24
25
26
27
28
29
30
1g 3a
1a 3a
1a 3h
1a 3b 110
1c 3b 110
1c 3a 110
85
85
85
26
25
4.5
25
24
24
5
82
90
87
79
84
93
92
47 (49)
42 (51)
22 (22)
86 (n.d.)
94 (97)
66 (67)
22 (23)
1d 3h
85
[a] Yields of unpurified products. [b] GC-MS/FID quantified.
[c] 1H NMR quantified; n.d.: not determined.
compliant with this postulation. Using p-tolylazide 1a or
phenylazide 1g as azide, the reactions yielded approximately
1:1 mixtures of the triazoles 24 and 25, respectively. By con-
trast, the reaction between 1a and ethyl propiolate 3h re-
sulted in a preference of the 1,4-isomer of the triazole deri-
vate 26. The obtained regioisomeric ratio is 78:22 and is
comparable to the result reported by Wang and co-work-
ers.[19] In order to demonstrate that the use of sterically de-
manding groups with only a moderate electron-releasing
character is expected to direct the cycloaddition towards
1,4-substituted triazoles, the re-
Corresponding to earlier reports, TMS modified triazoles
can be desilylated by using potassium fluoride and catalytic
amounts of tetrabutylammonium fluoride (TBAF) in metha-
nolic solution (Scheme 3).[22] The attempted desilylation re-
action between mesitylacety-
lene 3b and 1a was explored.
Surprisingly, the conversion af-
forded the triazole 27, notably
in
high
1,5-regioselectivity
(86%). In a related reaction,
treatment of 3b with 3,4,5-tri-
methoxyphenylazide 1c afford-
ed the triazole 28 in an even
higher
1,5-regioselectivity
(97%). Both the azide and the
alkyne substituent are supposed
to favor the 1,5-position in tria-
Scheme 3. Schematic representation of the one pot desilylation of 14a to 28a.
zoles 28, and this tendency was
further proven by the reaction
between the azide derivate 1c and phenylacetylene 3a. The
regioselectivity decreased significantly to 67%, however,
still an excess of the 1,5-regioisomer was noted. This result
illustrated that despite the steric demand of the mesityl
moiety, a strong electronic preference for 1,5-disubstitution
is present. On the basis of these observations, the excellent
1,5-regioselectivity in the formation of triazole 14a is com-
prehensible. All three substituents have a convergent influ-
ence on the regioselectivity, whereas the trimethylsilyl group
has the most powerful effect, substituting the 4-position in
action of the silylated triazole 14a was carried out in one
pot, forming the desilylated 1,5-disubsituted triazole 28a in
good yield (see Supporting Information).
Furthermore, DFT calculations were performed in order
to gain deeper insights regarding the regiodirecting role of
the trimethylsilyl group in 1,3-dipolar cycloadditions of
azides and alkynes.[9,23] Recently, Houk and co-workers re-
ported that the energy to distort 1,3-dipoles and dipolaro-
philes to their transition state geometries is related to the
activation energies of these kinds of 1,3-dipolar cycloaddi-
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Metal-Free 1,5-Regioselective Azide–Alkyne [3+2]-Cycloaddition
tion.[24] In addition, Houk has also shown by DFT calcula-
tions that the mechanism of 1,3-dipolar cycloadditions of
phenyl azide and cyclooctyne derivates are concerted and
nearly synchronous. This observation is supported by the
performed calculations. The DFT calculations of 6a,b reveal
that the activation barrier of the 1,5-substituted 4-(trime-
thylsilyl) triazole 6a(ts) is 23.2 kJmolꢁ1 lower compared to
1,4-regioisomeric transition state 6b(ts) and, therefore, con-
sistent with the synthetic observations. The activation ener-
gies for both transition states (179.1 kJmolꢁ1 for 6b(ts) and
155.9 kJmolꢁ1 for 6a(ts); see Figure 3 and Table 3) are very
high owing to the distortion energies (Table 4) of the azides
and of acetylene compounds based on their relaxed starting
geometries. The N-N-N dipole angles of the azide reactant
distort to 134.78 (6a(ts)) and 135.48 (6b(ts)), starting from a
relaxed azide angle of 173.38. The Si-C-C angle of the sily-
lated acetylene is deformed from nearly 1808 to 145.88
(6a(ts)) and 151.78 (6b(ts)) (Figure 3 and Supporting Infor-
mation).
Compared to Houkꢃs investigations, the azide N-N-N
angles of about 1358 provide a hint for a late transition state
of the corresponding 1,3-dipolar cycloaddition with silylated
acetylene compounds.
Additionally, an analogous study was performed for the
cycloaddition exhibiting the highest (triazole 14) and a
lower (triazole 13) experimentally found 1,5-regioisomeric
ratio. As expected, in both cases the 1,5-regiosiomeric fa-
voritism was confirmed repeatedly (Table 3). In contrast to
the synthetic experiment, the DFT-calculation of triazole 13
does reflect a marginal influence of an electron-withdrawing
group in silylated acetylene derivates. For the consideration
of water as solvent, solvent corrections were performed
both by using the conductor-like polarizable continuum
model C-PCM[25] and Truhlar and co-workersꢃ SMD[26] solva-
tion model, which is based on the quantum mechanical
charge density of the solute molecule. However, solvent cor-
rections for water with both models at B3LYP/6-311++G-
Figure 3. B3LYP/6-311++GACTHNUTRGNEUG(N 2d,2p) calculated transition state structures
of 6a(ts) and 6b(ts) (see also Supporting Information).
Table 3. Calculated free energies (in kJmolꢁ1) and predicted regioiso-
meric ratios of selected azide-alkyne 1,3-dipolar [3+2] cycloadditions.
AHCTUNGTREG(NNNU 2d,2p) level provided similar results compared to the gas-
phase regioisomeric preference. Here, the computed stabili-
ty of the triazole isomers depends on the model used. Nev-
ertheless, the DDG values are not significantly different.
While the practical results showed that the silyl group has a
dominant influence on the regioselectivity, it was decided to
use a related DFT-model and solvent corrections of 1,3-di-
polar cycloadditions with selected unsilylated acetylenes (tri-
azoles 25, 26, and 28). In the gas phase, the differences in
the transition state energies are found to be less compared
to the cycloaddition reactions with silylated acetylenes. For
example, the activation energy of 26b(ts) is computed to be
3.7 kJmolꢁ1 lower than that for 26a(ts). Evidently, these low
energy differences in the activation barrier diminish the
preference of regioselectivity. The gas phase findings of the
calculated regioselectivities are in good agreement with the
practical results, favoring the 1,4-addition for the triazole 26
and the 1,5-addition for the triazole 28. Notwithstanding, in
the case of triazole 25, the examination of both transition
states predicts a change of the regioselectivity. The calcula-
tions of solvent energy corrections of the studied triazoles in
water are nearly equivalent (Table 3) compared to the gas
phase.
Moreover, the activation barriers for these 1,3-dipolar cy-
cloadditions were analyzed by using the distortion/interac-
tion reactivity model for 1,3-dipolar cycloadditions devel-
oped by Houk and co-workers.[24] The distortion energy
(DEd°) corresponds to the energy required for deforming
the 1,3-dipole and the dipolarophiles into their transition
state geometries, while the energy of interaction (DEi°) is
derived from electrostatic and frontier orbital interactions
(activation energy DE° =DEd°+ DEi°). A comparison of
Gas phase
SMD solvation C-PCM solva-
model
tion model
R1 R2 Isomer
DG° DG
DG° DG
DG° DG
a (100)[a] 155.9 ꢁ90.9 155.2 ꢁ104.9 154.1
ꢁ98.1
ꢁ97.5
6
1a 2b
b (0)[a]
179.1 ꢁ86.7 180.3 ꢁ113.1 184.0
a (99)[a] 153.1 ꢁ108.5 161.7 ꢁ121.8 159.4 ꢁ112.5
13 1a 2i
14 1c 2b
25 1a 3a
26 1a 3h
28 1c 3b
b (1)[a]
169.4 ꢁ107.5 172.3 ꢁ127.0 173.6 ꢁ115.9
a (100)[a] 155.4 ꢁ85.2 154.6 ꢁ107.8 156.8 ꢁ100.3
b (0)[a]
180.7 ꢁ87.2 181.3 ꢁ106.3 183.4
ꢁ98.9
a (90)[a] 145.6 ꢁ156.5 149.1 ꢁ176.3 151.6 ꢁ163.2
b (10)[a] 152.6 ꢁ171.7 155.4 ꢁ185.8 156.7 ꢁ178.4
a (24)[a] 140.9 ꢁ178.7 141.3 ꢁ189.7 145.8 ꢁ182.6
b (76)[a] 137.2 ꢁ192.8 138.8 ꢁ208.7 138.9 ꢁ199.6
a (96)[a] 145.9 ꢁ141.5 144.5 ꢁ159.9 145.5 ꢁ150.4
b (4)[a]
156.3 ꢁ149.4 163.0 ꢁ164.5 159.8 ꢁ157.8
[a] Predicted product ratio based on DFT calculations.
Table 4. Distortion energies, energies of interaction and activation ener-
gies (in kJmolꢁ1) for selected triazoles calculated at B3LYP/6-311++G-
ACHTUNGTRENNUNG
°
°
DEd
(alkyne)
DEd° (total) DE° DEi°
G
ACHTUNGTRENNUNG
a
b
a
b
a
b
a
b
a
b
a
b
92.0
89.6
84.6
83.0
88.8
90.1
79.8
78.0
75.3
70.8
80.9
81.0
34.3
53.1
35.9
53.1
35.1
52.2
34.5
38.7
33.7
31.6
33.2
36.5
126.3
142.7
120.4
136.1
123.9
142.3
114.3
116.7
109.1
102.4
114.1
117.5
100.5 ꢁ25.8
125.2 ꢁ17.5
99.6 ꢁ20.8
115.1 ꢁ21.0
100.5 ꢁ23.4
125.3 ꢁ17.0
96.0 ꢁ18.3
101.1 ꢁ15.6
88.3 ꢁ20.8
84.6 ꢁ17.8
93.9 ꢁ20.3
105.2 ꢁ12.3
6
1a 2b
13 1a 2i
14 1c 2b
25 1a 3a
26 1a 3h
28 1c 3b
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U. S. Schubert et al.
FULL PAPERS
the distortion energies of the azides and acetylene com-
pounds provides information about their reactivity
(Table 4). The distortion energies for triazoles 6a,b are com-
puted to be 142.7 kJmolꢁ1 (6b(ts)) and 126.3 kJmolꢁ1
(6a(ts)), respectively, indicating an enhanced reactivity to
form the 1,5-isomer. The decreased distortion energy is fur-
ther reflected by a larger azide angle in the transition state
geometry of 6b(ts) (135.48) compared to 6a(ts) (134.78)
(Figure 3). As expected, the 1,5-isomer 6a(ts) shows an ad-
ditional increase of the stabilizing interaction energy
(ꢁ25.8 kJmolꢁ1) in comparison to the 1,4-isomer 6b(ts)
(ꢁ17.5 kJmolꢁ1).
and alkynes are commonly known as being unselective in
regio-orientation.[27] Water was used by default as dispersant
in azide–alkyne cycloaddition because of its promising prop-
erties for cycloadditions[28] and for economic reasons. As a
result, an efficient and highly regioselective metal-free syn-
thesis route for substituted 1,2,3-triazoles by using a thermal
dipolar cycloaddition reaction between readily and inexpen-
sively accessible trimethylsilylacetylenes and azides in aque-
ous media was developed.
The results illustrate a high regiopreference induced by
the trimethylsilyl moiety, with additional support for this
tendency achieved through electron-releasing alkyne sub-
stituents. A comparable trend was observed with regard to
the azide substituent. In contrast, electron withdrawing
alkyne/azide substituents effect a marginal, but detectable
decrease in regioselectivities.
In order to support these findings more sensitively, addi-
tional studies using the corresponding unsilylated terminal
alkynes were examined. While the previous tendencies were
confirmed, the regiodirective influence of the azide substitu-
ent turned out to be less potent than that of the alkyne sub-
stituent.
Accordingly, the highest 1,5-regiopreferences can be ex-
pected by using a TMS-alkyne and an azide, both attached
to electron-releasing groups (see triazole 14a). Additionally,
the controlled TMS-cleavage of hydrolytically very stable si-
lylated triazoles has been demonstrated.
DFT-calculations on selected reactions were performed to
understand the influence of TMS-substituted acetylenes on
the predominate regioselectivity. The calculated activation
barriers showed that the differences between the regioiso-
meric paths are significant. The silylated acetylenes prefer
1,5-regiochemistry in the gas phase and, according to solva-
tion models, the relative stabilities of the products barely
differ. Extended calculations using the distortion/interaction
model also confirmed the 1,5-regiochemistry. The total dis-
tortion energies to acquire the transition state geometries
are lower compared to the 1,4-isomers and predict a higher
reactivity to form the 1,5-regioisomer.
Finally, the trimethylsilyl induced 1,5-regioselective azide–
alkyne cycloaddition has been shown to be a simple and
powerful synthetic tool which provides convenient access to
1,5-disubstituted-4-(un-)silylated 1H-1,2,3-triazoles in high
regioselectivities and good yields. Our protocol comple-
ments modern regioselective metal catalyzed azide–alkyne
cycloaddition strategies and, thus, sets the stage for a variety
of synthetic applications.
The distortion energies for the silylated triazoles 13 and
14 are very close to those for 6. In both cases, the formation
of the 1,5-isomer is preferred, which is predominantly re-
flected by lower total distortion energies. For example, the
distortion energy of 14a(ts) is 18.4 kJmolꢁ1 lower than that
of the 1,4-isomer 14b(ts). The results obtained from the dis-
tortion/interaction model for the silylated triazoles 6, 13,
and 14 are also in good agreement with the experimental
data. Analogously, the differences in the total distortion en-
ergies of the unsilylated triazoles (25, 26, and 28) are less
compared to the respective energies of the silylated tria-
zoles, reflecting the dominant role of the silyl group in this
kind of dipolar cycloaddition. The total distortion energy of
25a(ts) is only 2.4 kJmolꢁ1 lower than that of 25b(ts). The
favoritism regarding both regioisomers is similar and, owing
to the uncertainties in the accuracy of the DFT functional
used, nearly equal. Also, this finding is in agreement with
the experimental results. Changing the phenyl moiety in the
acetylene compound 3a to an ester functionality, an in-
creased participation of the 1,4-isomer was experimentally
found (triazole 26). The difference in the total distortion en-
ergies of 26b(ts) and 26a(ts) is calculated to be 6.7 kJmolꢁ1,
indicating a stronger preference of the 1,4-isomer compared
to 25. This result is in good accordance with the experiment.
Finally, in order to elucidate the preference of the 1,5-regio-
isomer in the case of 1,3-dipolar cycloaddition of unsilylated
acetylenes, the reaction between 3,4,5-trimethoxyphenyla-
zide 1c and mesitylacetylene 3b was considered. The calcu-
lated distortion energies for 28a(ts) and 28b(ts) indicate
only a slight preference of the 1,5-regioisomer. However, a
difference of the energies of interaction of 8.0 kJ provides
additional support for the high 1,5-regioisomeric privilege.
Conclusions
Simple and practical methods for the 1,5-regioselective
azide–alkyne [3+2]-cycloaddition without heavy metal catal-
ysis are rarely known in literature. The intent of this work
was to focus on the use of substituted trimethylsilylacety-
lenes in order to induce regioselectivity. Inspired by the
work of Hlasta and co-workers,[14] a fundamental investiga-
tion considering the performance of regioselective azide–
alkyne cycloadditions by support of trimethylsilyl groups
was targeted, since thermal dipolar cycloadditions of azides
Experimental Section
General Methods
All reagents (e.g., 1b, 2a, 2c–f, 2k, 3a, 3h) were obtained from commer-
cial suppliers and used without additional purification unless stated other-
wise. Dry THF was obtained by a PS-MD-4-EN solvent purification
system (Innovative Technologies Inc.). Diisopropylamine and triethyla-
mine were dried over potassium hydroxide and were freshly distilled
before use. Water was deionized by a Seralsoft SW 300 device with a Ser-
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Metal-Free 1,5-Regioselective Azide–Alkyne [3+2]-Cycloaddition
aDest SD2000 combined ion exchanger and used without further treat-
ment. Tetrakis(triphenylphosphine)palladium(0)[29] was obtained accord-
ing to literature procedures. Chromatographic separations were executed
on silica gel (Kieselgel 60, 40–63 mm, Merck KGaA). Reaction progress
was tracked by thin layer chromatography (TLC) (silica gel on aluminum
sheets 20ꢄ20 cm with fluorescent dye (254 nm), Merck KGaA) or GC-
MS. Regioselectivities were quantified by 1H NMR spectroscopy of the
dried crude products after qualitative analysis (GC-MS, TLC) and sup-
ported by GC-MS/FID measurements (ratio of peak areas). Yields were
not optimized.
used as solvent in respect of the experimental paragon. NBO analysis
was achieved by using the Gaussian included NBO program.[39] The rela-
tive rate constants of competitive reactions are described by Eyring tran-
sition-state theory ([Eq. (1)].[40]
DGꢂ ꢁ DGꢂ2
k1=k2 ¼ eꢁ
1
ð1Þ
RT
The steady-state approximation results in Equations (2)–(3) derived from
processes shown in Scheme 4. The product formation is deduced exem-
plary from 6a,b.
Instrumentation
All 1D (1H, 13C, and selective NOESY experiments) and 2D NMR
(1H-1H COSY, HSQC, NOESY, HMBC) have been recorded in deuterat-
ed solvents (euriso-top) on a Bruker AVANCE 250, 300 or 400 MHz in-
strument. The chemical shifts are reported in ppm relative to the solvent
residual peak (d (CHCl3)=7.26 ppm, d (CHDCl2/CH2Cl2)=5.32 ppm).
Gas-chromatographic monitoring of the reaction progress was executed
on a Shimadzu GC2010 equipped with ATAS GL-series OPTIC3 multi-
purpose injector and coupled with a Shimadzu GCMS-QP 2010S electron
impact (EI) quadrupole mass spectrometer. Regioisomeric ratios were
determined with a Thermo Trace GC simultaneously providing an FID
(flame ionization detector) and a PolarisQ EI - ion trap mass spectrome-
ter. Elemental analyses were obtained on a vario EL III Elementaranaly-
sator (Analysensysteme GmbH Hanau). Melting points of solids were
studied with a NAGEMA PHMK 05 hotplate microscope. Infrared spec-
tra were recorded on a Bio-Rad FTS 25 or on a Nicolet Avatar 320 FT-
IR by using the attenuated total reflectance (ATR) technique.
Scheme 4. Schematic representation of the equilibrium.
k1½1 aꢃ½2 bꢃ ¼ ðkꢁ1þk2Þ½6 aðtsÞꢃ
k3½1 aꢃ½2 bꢃ ¼ ðkꢁ3þk4Þ½6 bðtsÞꢃ
ð2Þ
ð3Þ
Based on Equations (2)–(3), the formula of formation ratio on the exam-
ple of the products 6a and 6b is given in Equation (4). All the rate con-
stants were computed directly from Gibbs free energies according to
Equation (1).
½6 aꢃ=½6 bꢃ ¼ k1k2ðkꢁ3þk4Þ=k3k4ðkꢁ1þk2Þ
ð4Þ
Crystal Structure Determination
General Procedure for the Preparation of 1,2,3-Triazoles in Water[19]
The intensity data for the compounds were collected on a Nonius Kappa
CCD diffractometer, using graphite monochromated Mo-Ka irradiation.
Data were corrected for Lorentz and polarization effects, but not for ab-
sorption effects.[30,31] The structures were solved by direct methods
(SHELXS[33]) and refined by full-matrix least squares techniques against
A mixture of azide (1.0 eq.) and alkyne (1.0 eq.) was filled into a glass
vessel for microwave applications (Biotage, 5 mL), equipped with a mag-
netic stirrer bar. Water was added to the solution (approximately 3 mL
for 1 mmol of the azide, for more details, see Supporting Information)
and the vial was closed with a crimp cap. The mixture was allowed to
warm up by using a fitting aluminum heat exchanger on a magnetic stir-
rer equipped with a contact thermostat (80–1208C). The resulting emul-
sion was stirred at the highest setting for several hours (see Supporting
Information) and monitored by GC-MS. The vessel was cooled down to
room temperature. The water was removed directly with a rotary evapo-
rator. Subsequently, the residue was dried in fine vacuum and used with-
out further purification for 1H NMR spectroscopy and GC-MS/FID
measurements to determine the ratio of the regioisomers. The remaining
part was treated as described in the detailed substance information (Sup-
porting Information).
2
Fo (SHELXS-97[33]). The absolute configuration of 11a could be deter-
mined. The hydrogen atom for the hydroxy group of 23a was located by
difference Fourier synthesis and refined isotropically. All other hydrogen
atoms were included at calculated positions with fixed thermal parame-
ters. All non-hydrogen atoms were refined anisotropically.[33] Crystallo-
graphic data as well as structure solution and refinement details are sum-
marized in Table S1 (Supporting Information). XP (SIEMENS Analytical
X-ray Instruments, Inc.) was used for structure representations.
CCDC 817830 (8a), 817831 (9a), 817832 (11a), 817833 (13a), 817834
(14a) contains the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cambridge Crystal-
lographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/asia.201100404 containing preparation, sub-
stance characterization, NMR data, DFT results. Crystallographic data
(excluding structure factors) has been deposited with the Cambridge
Crystallographic Data Centre as supplementary publications (see Sup-
porting Information).
Computational Methods
Full geometry optimizations without symmetry constraints were carried
out with the GAUSSIAN09[34] program package. All geometry optimiza-
tions reported herein were performed by using the well-established
hybrid B3LYP[35] density functional method in combination with the
6–311++GACHTUNGTRENNUNG
(2d,2p)[36] basis set, which includes diffuse functions[37] on all
atoms as well as 2 sets of d functions on heavy atoms supplemented by 2
sets of p functions on hydrogens.[38] All calculated stationary points were
characterized as minima or transition structures on the potential hyper-
surface, according to the number of imaginary modes, by applying a
second-order derivative calculation (vibrational analysis) at the same
level of theory as that at which the optimization was performed. Vibra-
tional analysis was also initiated to derive the ZPEs and thermochemical
corrections for the enthalpies and free energies. All energies related to
standard thermodynamics are given as enthalpies, however, kinetic de-
scriptions of reaction paths are given as relative Gibbs free energies in
relation to separated reactants. Solvent corrections were performed both
by using the conductor-like polarizable continuum model C-PCM[25a] and
Truhlar and co-workersꢃ SMD[26] solvation model, which is based on the
quantum mechanical charge density of the solute molecule. Water was
Acknowledgements
Financial support of this work by the Dutch Polymer Institute (DPI), the
Thꢀringer Kultusministerium and the Fonds der Chemischen Industrie is
kindly acknowledged.
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Received: April 23, 2011
Published online: August 31, 2011
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