Synthesis of allene triazole through iron catalyzed regioselective addition to propargyl alcohols

Article abstract of DOI:10.1039/c2cc17522c

Allene triazole derivatives were successfully synthesized for the first time through iron catalyzed regioselective triazole addition to tertiary propargyl alcohols. The reaction proceeds under mild conditions, giving the desired allene-triazoles in good to excellent yields (up to 96%). The resulting allene-triazoles were confirmed by X-ray crystallography and indicated improved stability.

Full text of DOI:10.1039/c2cc17522c

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COMMUNICATION
Synthesis of allene triazole through iron catalyzed regioselective
addition to propargyl alcoholsw
Wuming Yan, Xiaohan Ye, Keith Weise, Jeffrey L. Petersen and Xiaodong Shi*
Received 1st December 2011, Accepted 15th February 2012
DOI: 10.1039/c2cc17522c
Allene triazole derivatives were successfully synthesized for the
first time through iron catalyzed regioselective triazole addition
to tertiary propargyl alcohols. The reaction proceeds under mild
conditions, giving the desired allene-triazoles in good to excellent
yields (up to 96%). The resulting allene-triazoles were confirmed
by X-ray crystallography and indicated improved stability.
The 1,2,3-triazole was one very important class of heterocycles in
chemistry research during the last decade1 due to their wide
Scheme 2 Proposed approaches for triazole-allene synthesis.
applications in material science,2 biological research3 and medicinal
chemistry.4 The resultant interest has led to the development of
Based on the literature reported strategies, two common
approaches were proposed for the allene-triazole synthesis
(Scheme 2).
effective methods for the synthesis of functional triazoles. By
utilizing the nucleophilicity provided by the nitrogen lone-pair
electrons, several strategies have been used to introduce functional
groups on the nitrogen of the triazole ring, including alkylation,5
arylation,6 vinylation,7 propargylation8 etc. Herein, we report, for
the first time, the successful synthesis of allene triazoles through
iron catalyzed regioselective triazole addition to the propargyl
alcohol. This work provides an effective strategy for the synthesis
of allene triazoles to fill the ‘‘missing piece’’ of triazole function-
alizations (Scheme 1). Moreover, the observed improved stability
of a triazole-modified allene, compared with other simple
allenes, suggests that these derivatives may be employed as
ligand backbones for catalyst design.9
As shown in Scheme 2A, because propargyl triazoles could be
readily prepared,8 one plausible synthesis of allene-triazole might
be from the deprotonation at the propargyl position, followed by
the treatment with H+ or other electrophiles. However, as shown
in Scheme 3A, while treating the propargyl triazole 1a with
n-BuLi followed by quenching with either water or NBS, a
complex reaction mixture was obtained with no allene products
observed. We then focused on the second strategy, the triazole
addition to propargyl alcohol derivatives. Unfortunately, the
reaction between 2a and a triazole anion gave no product even
after the reaction mixture was refluxed for 10 h (Scheme 3B).
These results suggested that the synthesis of an allene-triazole
was indeed a great challenge using conventional methods.
Considering our previous success in the synthesis of propargyl
triazoles through iron-catalyzed C–O bond activation, we decided
to apply this process for the preparation of allene triazoles.
As shown in Scheme 4, the di-substituted propargyl alcohols
will be used with the hope to increase the steric hindrance
at the propargyl position to direct the triazole to the
alkyne based on our understanding of C–O bond activation.
Although the di-substitution limited the reaction substrate scope,
Although allene is a basic building block in organic chemistry,
the available strategies for allene synthesis are rather limited.10
Scheme 1 Triazole allenation: a missing methodology.
C. Eugene Bennett Department of Chemistry,
West Virginia University, Morgantown, WV 26506, USA.
E-mail: Xiaodong.Shi@mail.wvu.edu; Fax: +1-304-293-4904;
Tel: +1-304-293-3435 x6438
w Electronic supplementary information (ESI) available: Experimental
details, X-ray measurement and 1H NMR, 13C NMR for all com-
pounds. CCDC 851290–851294. For ESI and crystallographic data in
CIF or other electronic format see DOI: 10.1039/c2cc17522c
Scheme 3
c
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Chem. Commun., 2012, 48, 3521–3523 3521

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Scheme 4 Iron-catalyzed C–O bond activation.
the success of this strategy will lead to the first synthesis of
the allene triazole and opens the door for further development.
To test this idea, the propargyl alcohol 3a was reacted with
benzotriazole under various conditions.
As indicated in Table 1, with FeCl3 as catalyst, the allene
triazole 4a was successfully prepared with 57% NMR yield,
though a significant amount of propargylation product 5a was
received (entry 1). The structure of 4a was characterized by
X-ray crystallography. To further improve the regio-selectivity
(4a : 5a), different metal catalysts were investigated (entries 2–15).
Of the metal catalysts studied, FeCl3 was by far the best choice.
The screening of solvents (entries 16–25) revealed that
1,2-dichloroethane (DCE) was the optimal solvent, giving the
desired allene triazole 4a in excellent yield (90% isolated yield,
4a : 5a > 20 : 1). Interestingly, the ratio between 4a and 5a is
Table 1 Catalyst screeninga
Fig. 1 Reaction substrate scope.a
dependent on the reaction temperature, where poorer
selectivity was obtained while conducting the reaction at
rt (entry 26).
With the optimal conditions, a series of different propargyl
alcohols were investigated to explore the reaction substrate
scope. The results are summarized in Fig. 1.
Loading
Catalyst (%)
Temp./ Time/ Conv.c Yieldd
Sol.b
1C
h
(%)
(%)
4a : 5ad
As shown in Fig. 1, the alkyne terminal R3 position tolerated
TMS, n-Bu, t-Bu, vinyl and cyclopropanyl groups. Surprisingly,
the bulky t-Bu group gave 4e in 91% yield, though longer reaction
time (12 h) was needed. No enyne decomposition (4f, 4r) or
cyclopropane ring opening (4d, 4s) products were observed.
The substrates could also be extended to phenol substituted
propargyl alcohols to afford products (4j, 4k) in good yields. The
phenyl substituted alkyne gave the corresponding hydration
product instead of the formation of desired allene. The terminal
alkynes (R3 = H) gave a complex reaction mixture under the
optimal conditions. This limitation could be easily overcome by
the readily TMS deprotection (vide infra).
1
2
3
4
5
6
7
8
9
FeCl3 10
Cu(OAc)2 10
MeCN 60
MeCN 60
MeCN 60
MeCN 60
MeCN 60
MeCN 60
MeCN 60
MeCN 60
MeCN 60
MeCN 60
MeCN 60
MeCN 60
MeCN 60
MeCN 60
MeCN 60
Acetone 60
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
86
o5
o5
30
82
85
57
o5
o5
o5
36
3 : 1
—
—
—
1 : 1
1 : 2
—
—
—
2 : 1
1 : 5
2 : 1
1 : 1
1 : 1
—
2 : 1
2 : 1
—
CuI
10
10
10
10
PdCl2
RuCl3
IrCl3
25
Fe(acac)3 10
o5
o5
o5
o5
42
7
10
LaCl3
CeCl3
10
10
19
25
10 Bi(OTf)3 10
71
63
75
69
11 AlCl3
12 TfOH
13 SnCl2
14 FeCl2
15 LiCl
16 FeCl3
17 FeCl3
18 FeCl3
19 FeCl3
20 FeCl3
21 FeCl3
22 FeCl3
23 FeCl3
24 FeCl3
25 FeCl3
26 FeCl3
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
29
20
50
o5
o5
Various substitutions on the propargyl position have also
been investigated. The di-alkyl substituted propargyl alcohols
were unreactive enough even at higher temperature for longer
time (60 1C, 24 h). The fact that aryl–alkyl substituted groups gave
no allene triazole product was likely caused by the elimination of
propargyl alcohols. For the electron-rich aryl substitution, higher
yields were observed while the substrate was treated at room
temperature (4g–4k). Heterocycles, such as thiophene (4l), were
suitable for this reaction. Substituted groups on triazole indicated
little influence on the reaction (4m–4s), likely due to the excellent
overall nucleophilicity of the NH-triazole. Impressively, the
alkyne-substituted propargyl alcohol was also suitable for this
reaction, giving the conjugated alkyne–allene triazole 4t in
good yield. The nitro-substituted propargyl alcohol did not
work due to strong electron-withdrawing groups on the
83
73
32
42
THF
60
Toluene 60
MeOH 60
MeNO2 60
DMSO 60
DMF 60
CHCl3 60
EtOAc 60
30
71
78
o5
o5
80
78
100
50
o5
o5
60
o5
o5
40
—
4 : 1
—
—
3 : 1
4 : 1
>20 : 1
8 : 1
56
DCE
DCE
60
rt
90e
40
a
Standard reaction condition: 1 equiv. propargyl alcohol (0.25 mmol),
1.3 equiv. triazole (0.325 mmol), 0.1 equiv. catalyst (0.025 mmol) and
b
2 mL solvent. DCE: 1,2-dichloroethane, EtOAc: ethyl acetate.
c
Conversions were determined based on the consumption of propargyl
d
alcohol. NMR yields of 4a with 1,3,5-trimethoxybenzene as internal
e
standard. Isolated yield.
c
3522 Chem. Commun., 2012, 48, 3521–3523
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such as ligand development and material construction, which
are currently under investigation.
We thank the support from NSF (CHE-0844602).
Notes and references
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Fig. 2 Extending the substrate scope with propargyl acetate.a,b
Scheme 5 TMS-deprotection and X-ray crystal structures.
benzene ring. Interestingly, although the triazole ring was a
highly electron-deficient aromatic ring, allene bis-triazole 4u was
obtained in modest yield under the standard conditions, suggesting
the potential coordination of triazole–Fe in the activation of a
propargyl C–O bond. To further extend the substrate group of
the electron-deficient ring, propargyl acetates 6 were prepared
to react with triazoles. The desired allene triazoles (4v–4z) with
electron-withdrawing group substitutions were received in
good to excellent yields as shown in Fig. 2.
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significantly higher stability than the regular allene. For
example, upon treating allene 4a with 2 equivalents of TfOH
in wet DCM at room temperature, no allene decomposition
(even the TMS deprotection) was observed after 12 hours
based on the recovered yield of 4a (97%). The TMS group
could be readily removed by treatment with base as shown in
Scheme 5.
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of the allene-triazoles, but also revealed the detailed configu-
ration. Among all five allene-triazole crystal structures (4a, 4g,
4u, 4y and 7a), excellent conjugations between a triazole ring
and the allene p-bond were observed, even with bulky TMS
groups on the same carbon center. This extended conjugation
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Herein, we report the first synthesis of allene-substituted
1,2,3-triazole derivatives. With the improved allene stability,
the allene-triazoles are expected to exhibit potential new reactivity
that may lead to interesting chemical and physical properties,
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 3521–3523 3523