Iron-catalyzed C-O bond activation for the synthesis of propargyl-1,2,3-triazoles and 1,1-bis-triazoles

Article abstract of DOI:10.1021/ol101082v

(Equation Presented). The FeCl₃-catalyzed triazole propargylation was developed. This transformation was suitable for a large scope of substituted propargyl alcohols, giving the corresponding propargyl triazoles in excellent yields (up to 96%). Further derivatization produced the 1,1-bis-triazoles in excellent yields and regioselectivity, which could be applied as potential transition metal ligands or new reagents.

Full text of DOI:10.1021/ol101082v

ORGANIC
LETTERS
2010
Vol. 12, No. 15
3308-3311
Iron-Catalyzed C-O Bond Activation for
the Synthesis of
Propargyl-1,2,3-triazoles and
1,1-Bis-triazoles
Wuming Yan,† Qiaoyi Wang,† Yunfeng Chen,‡ Jeffrey L. Petersen,† and
Xiaodong Shi*,†
C. Eugene Bennett Department of Chemistry, West Virginia UniVersity, Morgantown,
West Virginia 26506, and School of Chemical Engineering and Pharmacy,
Wuhan Institute of Technology, 430074, People’s Republic of China
xiaodong.shi@mail.wVu.edu
Received May 11, 2010
ABSTRACT
The FeCl3-catalyzed triazole propargylation was developed. This transformation was suitable for a large scope of substituted propargyl alcohols,
giving the corresponding propargyl triazoles in excellent yields (up to 96%). Further derivatization produced the 1,1-bis-triazoles in excellent
yields and regioselectivity, which could be applied as potential transition metal ligands or new reagents.
Since the discovery of “click chemistry” at the beginning of
this century,1 1,2,3-triazoles have become one of the most
important heterocycles in medicinal,2 material,3 and
biological4 research. Comparing with the application as a
highly efficient linkage strategy that dominated the early
stage of 1,2,3-triazole research, recent efforts have been
aimed at the investigation of the chemical and biological
properties of this unique heterocycle.5 Significant progress
† West Virginia University.
(3) (a) Li, H. M.; Cheng, F. O.; Duft, A. M.; Adronov, A. J. Am. Chem.
Soc. 2005, 127, 14518–14524. (b) Rozkiewicz, D. I.; Janczewski, D.;
Verboom, W.; Ravoo, B. J.; Reinhoudt, D. N. Angew. Chem., Int. Ed. 2006,
45, 5292–5296. (c) Wyszogrodzka, M.; Haag, R. Chem.sEur. J. 2008, 14,
9202–9214. (d) Gadzikwa, T.; Farha, O. K.; Malliakas, C. D.; Kanatzidis,
M. G.; Hupp, J. T.; Nguyen, S. T. J. Am. Chem. Soc. 2009, 131, 13613–
13615. (e) Golas, P. L.; Matyjaszewski, K. Chem. Soc. ReV. 2010, 39, 1338–
1354.
‡ Wuhan Institute of Technology.
(1) (a) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B.
Angew. Chem., Int. Ed. 2002, 41, 2596–2599. (b) Kolb, H. C.; Finn, M. G.;
Sharpless, K. B. Angew. Chem., Int. Ed. 2001, 40, 2004–2021. (c) Moses,
J. E.; Moorhouse, A. D. Chem. Soc. ReV. 2007, 36, 1249–1262. (d) Wu,
P.; Fokin, V. V. Aldrichim. Acta 2007, 40, 7–17.
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1285. (b) Colombo, M.; Peretto, I. Drug DiscoVery Today 2008, 13, 677–
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J. G.; Reeve, M. M. Org. Process Res. DeV. 2010, 14, 152–158. (d)
Moumne, R.; Larue, V.; Seijo, B.; Lecourt, T.; Micouin, L.; Tisne, C. Org.
Biomol. Chem. 2010, 8, 1154–1159.
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10.1021/ol101082v  2010 American Chemical Society
Published on Web 07/09/2010

occurred in applying triazole building blocks as either
bioactive components in drug discovery or special func-
tional groups in new materials synthesis.6 Recently, several
interesting studies that utilized 1,2,3-triazoles as ligands
in transition metal catalysis have been reported.7,8 The
fast growing research applications of this heterocycle neces-
sitate the development of effective methods for the prepara-
tion of diverse 1,2,3-triazole derivatives. Herein, we report
the successful use of Fe(III)-catalyzed C-O bond activation
as an efficient strategy in post-triazole propargylation and
its application for the preparation of asymmetric N-C type
1,1-bis-triazole compounds.
bis-triazole compounds could be summarized as three
different classes: N-N type,12 C-C type,13 and N-C type
(Scheme 1).
Scheme 1. Three Different Types of Bis-triazole Compounds
Our interest in studying 1,2,3-triazole compounds was
initiated by the recent success of Lewis base-catalyzed
nitroalkene activation.9 With this method, various 4,5-
disubstituted NH-triazoles were prepared in good yields.10
Moreover, the post-triazole N-2 functionalization was de-
veloped,11 where alkylation, arylation, and vinylation of
1,2,3-triazoles have been successfully achieved with good
yields and regioselectivity.
During the last two years, our group has been working
on the investigation of 1,2,3-triazole derivatives as ligands
in transition metal catalysis.8 These triazole compounds
have shown significant influence on the metal catalyst
reactivity by serving as effective nitrogen σ-donor. To
further extend our studies of triazole-metal coordination,
we aimed at the bis-triazole compounds as potential
interesting bidentate ligands to coordinate with transition
metal cations. Considering the substitution pattern, the
While the N-N and C-C type bis-triazoles have been
successfully synthesized from either post-triazole al-
kylation11a or click chemistry (Scheme 1, A and B), the
N-C type bis-triazoles have not been reported. These
unsymmetrical N-C type bis-triazoles, especially the 1,1-
bis-triazoles, are particularly interesting because of the
presence of the stereocenter. A brief synthetic design of
this type of compounds is shown in Scheme 1C, where
the two triazole moieties are introduced by click chemistry
and post-triazole propargylation sequentially. Although the
retrosynthesis design looked straightforward, the actual
preparation was much more challenging than we expected
(Vide infra), especially the post-triazole propargylation.
(5) (a) Chemama, M.; Fonvielle, M.; Arthur, M.; Valery, J. M.; Etheve-
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In general, the propargylation could be challenging since
the nucleophiles would potentially attack the propargyl
position as well as the triple bonds, to give corresponding
allene intermediates that further convert into other prod-
ucts (such as Meyer-Schuster rearrangement).14,15 There-
fore, the performance of this transformation usually depends
on the nature of the substrates (i.e., the stability of leaving
groups and steric hindrance of alkynes). With simple
propargyl bromide 2a, effective triazole propargylation could
be achieved in excellent yields (Scheme 2A). However, the
direct substitution failed to work for substituted alkynes. For
example, reaction between triazole 1a and propargyl acetate
2b gave no reaction with Cs2CO3 as the base. Treating the
substrates under harsher conditions (DMSO and strong base)
led to the formation of complex reaction mixtures with no
desired propargyl triazole 3b observed (Scheme 2B). More-
over, attempts in converting propargyl alcohol 4a into
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.
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Lett. 2008, 10, 5389–5392. (c) Duan, H.; Yan, W.; Sengupta, S.; Shi, X.
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Y. Inorg. Chem. 2009, 48, 1449–1468.
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Nishibayashi, Y.; Shinoda, A.; Miyake, Y.; Matsuzawa, H.; Sato, M. Angew.
Chem., Int. Ed. 2006, 45, 4835–4839. (b) Zhan, Z. P.; Yu, J. L.; Liu, H. J.;
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Org. Lett., Vol. 12, No. 15, 2010
3309

was an effective catalyst in promoting this transformation
and gave the desired product 3b in good yield (entry 1).
Further screening revealed MeCN as the optimal solvent
(entries 14-20) and effective conversion was accomplished
even with decreased catalyst loading (entries 23 and 24).
With this optimal condition in hand, different triazoles and
propargyl alcohols were evaluated to investigate the reaction
substrate scope. The results are shown in Figure 1.
Scheme 2. Challenges in Triazole Propargylation
propargyl tolsylate or halide also failed, which was likely
caused by the undesired side reactions associated with
propargyl carbon cations.
We therefore deduced that one practical synthesis of
propargyl triazoles could likely occur from the effective C-O
bond activation of a propargyl alcohol (Scheme 2C). A series
of different commonly used Lewis acid catalysts were then
investigated in promoting the propargylation of triazole 1a
and propargyl alcohol 4a. The results are summarized in
Table 1. Although significant decomposition of 4a occurred
with most of the Lewis acid catalysts, we observed that FeCl3
Table 1. Catalyst Screeninga
loading
(%)
temp time convn yield
catalyst
1 FeCl3
solvn (°C) (h) (%)b (%)c N1:N2c
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
10
5
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
THF
60
60
60
60
60
60
60
60
60
60
60
60
60
60
17
17
17
17
17
17
17
17
17
17
17
17
17
7
100
57
90
<5
<5
<5
49
65
<5
<5
<5
<5
<5
35
9
70
40
44
<5
<5
<5
85
50
93
90
82
8:1
2 Cu(OAc)2
3 CuI
22
4 PdCl2
13
5 RuCl3
69
1.1:1
2:1
6 IrCl3
96
7 Co(OAc)2
8 LaCl3
28
21
9 CeCl3
30
10 Ti(O-iPr)4
11 AlCl3
12 TfOH
13 H3PO4
14 FeCl3
15 FeCl3
16 FeCl3
17 FeCl3
18 FeCl3
19 FeCl3
20 FeCl3
21 FeCl3
22 FeCl3
23 FeCl3
24 FeCl3
52
26
Figure 1. Reaction substrate scope. Yields were determined by
100
73
1.5:1
1:1
NMR with 1,3,5-trimethoxybenzene as internal standard, and ratios
determined by NMR of crude reaction mixtures. The N-2 3f
structure was confirmed by X-ray crystallography.
90
100
60
6:1
Toluene 60
7
2:1
MeOH
MeNO2
DMF
60
60
60
60
60
rt
90
90
90
7
7:1
7
90
7
<5
DMSO
MeCN
MeCN
MeCN
MeCN
MeCN
7
<5
7
91
10:1
9:1
11:1
10:1
9:1
(15) For examples of the Meyer-Schuster reaction, see: (a) Georgy,
M.; Boucard, V.; Campagne, J. M. J. Am. Chem. Soc. 2005, 127, 14180–
14181. (b) Engel, D. A.; Dudley, G. B. Org. Lett. 2006, 8, 4027–4029. (c)
Sun, C. X.; Lin, X. C.; Weinreb, S. M. J. Org. Chem. 2006, 71, 3159–
3166. (d) Trost, B. M.; Chung, C. K. J. Am. Chem. Soc. 2006, 128, 10358–
10359. (e) Matsuzawa, H.; Miyake, Y.; Nishibayashi, Y. Angew. Chem.,
Int. Ed. 2007, 46, 6488–6491. (f) Sugawara, Y.; Yamada, W.; Yoshida, S.;
Ikeno, T.; Yamada, T. J. Am. Chem. Soc. 2007, 129, 12902–12903. (g)
Dai, L. Z.; Shi, M. Chem.sEur. J. 2008, 14, 7011–7018. (h) Bandini, M.;
Eichholzer, A. Angew. Chem., Int. Ed. 2009, 48, 9533–9537. (i) Wang, D.;
Ye, X.; Shi, X. Org. Lett. 2010, 12, 2088–2091.
12
5
62
100
100
90
10
12
a Standard reaction condition: 1 equiv of propargyl alcohols, 1.2 equiv
of triazoles, and 0.2 equiv of catalyst were mixed in corresponding solvents.
b Conversions were determined based on the consumption of 4a. c Yields
determined by NMR with 1,3,5-trimethoxybenzene as internal standard, and
ratios determined by NMR of crude reaction mixtures.
3310
Org. Lett., Vol. 12, No. 15, 2010

As shown in Figure 1, this Fe(III)-catalyzed propargylation
was suitable for various different propargyl alcohols, which
further enriched the available methods for effective post-
triazole functionalization. Similar to our previously reported
strategy,11a the regioselectivity of 1,2,3-triazole strongly
depends on the nature of triazole substrates. For example,
the benzotriazole gave N-1 substitutions and dominant N-2
isomers were obtained when keto-modified 4,5-disubstituted
triazoles were applied (i.e., 3c, 3g). Meanwhile, the C-4
phenyl triazole gave a mixture of both N-1 and N-2 isomers
with roughly 4:1 ratio, favoring the N-2 isomer.
the reactions between TMS-alkynes and corresponding azides
gave the desired bis-triazoles (5a-h) without the TMS
deprotection step in excellent yields under standard “click
chemistry” condition (Figure 2).16
The substituted groups on the propargyl position were
critical for this transformation. The reaction generally worked
well with aromatic substituted propargyl alcohols, except
substrates with strong electron withdrawing groups (the
p-nitrobenzene gave no reaction). No reactions were observed
with aliphatic substituted propargyl alcohols. Impressively,
the reaction proceeded smoothly with vinyl-substituted
substrate (such as 3r), giving the corresponding triazole
substituted enynes in excellent yields. Notably, Nazarov
cyclization products were not observed in these reactions,
which highlighted the rather mild conditions of the reported
method.
Excellent yields were generally received for internal
alkynes with different substituted groups, including alkyl,
aryl, TMS, and cyclopropyl. The reaction was also suitable
for terminal alkyne and gave the corresponding propargyl
triazoles in good yields based on NMR (Scheme 3).
Figure 2. Synthesis of unsymmetrical N-C type bis-triazoles.
Isolated yields for all cases. Condition: 0.05 equiv of CuSO4, 0.1
equiv of sodium ascorbate, t-BuOH-H2O (1:1), rt, 12 h. Structure
5g was confirmed by X-ray crystallography.
In conclusion, a highly efficient FeCl3-catalyzed post-
triazole propargylation was developed, giving the desired
propargyl triazole in excellent yields. Application of this
strategy led to the synthesis of unsymmetrical 1,1-bis-
triazoles. This study not only gave another efficient post-
triazole functionalization strategy for the preparation of
diverse triazole analogues, but also provided entry to a new
class of bis-triazole compounds as bidentate ligands. Ap-
plication of these bis-triazole ligands in transition metal
coordination is currently under development in our group.
Scheme 3
.
Unexpected Decomposition of Terminal Alkyne
Substrates
Surprisingly, these substrates were not stable upon concen-
tration and gave complex reaction mixtures. This interesting
transformation is currently under investigation.
The unexpected decomposition of terminal alkyne 3t raised
serious concerns regarding the designated click chemistry
for the introduction of the second triazole rings. Fortunately,
Acknowledgment. We thank the NSF (CHE-0844602),
DOE (DE-FC26-04NT42136), and ACS-PRF-47843-G1 for
financial support.
Note Added after ASAP Publication. Some yields were
missing from Figure 2 in the version published ASAP July
9, 2010; the correct version reposted on July 13, 2010.
(16) (a) Thibault, R. J.; Takizawa, K.; Lowenheilm, P.; Helms, B.;
Mynar, J. L.; Frechet, J. M. J.; Hawker, C. J. J. Am. Chem. Soc. 2006, 128,
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Wu, Y. L.; Schweizer, W. B.; Diederich, F. Org. Lett. 2008, 10, 3347–
3350. (e) Schweinfurth, D.; Hardcastle, K. I.; Bunz, U. H. F. Chem.
Commun. 2008, 2203–2205. (f) Ozcubukcu, S.; Ozkal, E.; Jimeno, C.;
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Supporting Information Available: Experimental details
and spectrographic data. This material is available free of
charge via the Internet at http://pubs.acs.org.
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