1,2,3-Triazole: Unique ligand in promoting iron-catalyzed propargyl alcohol dehydration

Article abstract of DOI:10.1021/ol300778e

A 1,2,3-traizole-promoted iron(III)-catalyzed propargyl alcohol dehydration was developed for the synthesis of conjugated enynes. The desired conjugated enynes were prepared in good to excellent yields (up to 95%) with a large substrate scope and excellen

Full text of DOI:10.1021/ol300778e

ORGANIC
LETTERS
2012
Vol. 14, No. 9
2358–2361
1,2,3-Triazole: Unique Ligand in
Promoting Iron-Catalyzed Propargyl
Alcohol Dehydration
Wuming Yan, Xiaohan Ye, Novruz G. Akhmedov, Jeffrey L. Petersen, and
Xiaodong Shi*
C. Eugene Bennett Department of Chemistry, West Virginia University, Morgantown,
West Virginia 26506, United States
xiaodong.shi@mail.wvu.edu
Received March 26, 2012
ABSTRACT
A 1,2,3-traizole-promoted iron(III)-catalyzed propargyl alcohol dehydration was developed for the synthesis of conjugated enynes. The desired
conjugated enynes were prepared in good to excellent yields (up to 95%) with a large substrate scope and excellent stereoselectivity
(only Z-isomers).
Ligands play a crucial role in transition-metal catalysis.
Besides determining the spatial arrangement (asymmetric
synthesis) at the metal center, ligands often influence the
Scheme 1
electronic environment, thus adjusting metal reactivity.1
The great successes of alkyneꢀazide cycloaddition (click
chemistry) made 1,2,3-triazole one of the most important
heterocycles in chemical,2 biological,3 and material research.4
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lone-pair electrons) and π receptor (highly electron-
deficient aromatic ring) makes triazoles potentially unique
ligands in altering metal cation reactivity (Scheme 1).
Herein, we report the iron-catalyzed propargyl alcohol
dehydration for the synthesis of conjugated enyne on
gram-scale. In this investigation, 1,2,3-triazoles were re-
vealed as the only ligands effectively promoting this
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r
10.1021/ol300778e
Published on Web 04/23/2012
2012 American Chemical Society

important and challenging transformation (gave up to
95% yields). Other tested N-heterocycles, including the
1,2,4-triazole, tetrazole, and pyridine, all gave poor results
(<15%) even with similar binding patterns, which high-
lighted the unique role of 1,2,3-triazole ligands in iron
catalysis.
influences the iron cation reactivity, we studied the pro-
pargyl alcohol dehydration for the preparation of conju-
gated enynes (Scheme 2).
Conjugated enynes and enediynes are basic building
blocks in biology,13 material science,14 and fine chemical
synthesis.15 However, there are few available methods for
effective preparation of this synthon. Although special
methods (such as cyclopropane ring-opening) have been
reported for specific substrates,16 the Pd/Cu-catalyzed
vinyl halide/alkyne coupling17 remains the primary avail-
able method, which suffered from limited substrate scope
and was considered less practical for large-scale enyne
preparation. The catalytic propargyl alcohol dehydration
should be one atom-economic and practical approach for
conjugated enyne synthesis. However, this transformation
is challenging and problematic.
Scheme 2. Conjugated Enyne Synthesis: Important but Chal-
lenging Process
In the past several years, our group has been working on
new methods for the preparation of various triazole
derivatives6 and their applications in coordination chem-
istry to form new catalysts/reagents. These efforts led to
the discoveries of triazoleꢀAu7 and triazoleꢀRh catalysts8
and triazoleꢀborane reagent9 with interesting new reactiv-
ities. These encouraging results initiated our interest in
evaluating the influence of 1,2,3-triazole ligands in iron-
based catalysis.
Homogeneousiron catalysisisbecomingmoreattractive
due to the economic benefit (much lower cost compared
with noble metals) and low toxicity.10 Although the iron-
containing catalysts (enzyme) have been long known,11
small organic molecule coordinated iron catalysts are much
less developed.12 One interesting property of iron catalyst is
the dual reactivity, where Fenþ could either serve as Lewis
acid (electron pair receptors) or as redox center through
single electron process. To evaluate how 1,2,3-triazole
Table 1. Direct Propargyl Alcohol Dehydration: A Challenging
Transformationa
entry
catalyst
temp (°C)
convb (%)
yieldc (%)
1
2
TfOH
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
rt
90
10
90
22
80
23
26
78
75
30
52
26
71
30
95
59
32
30
<5
21
<5
15
<5
<5
22
20
<5
<5
<5
9
AlCl3
3
Bi(OTf)3
NiCl3
4
5
In(OTf)3
CeCl3
6
7
LaCl3
8
RuCl3
9
IrCl3
10
11
12
13
14
15
16
17
PdCl2
Cu(OAc)2
Co(OAc)3
Ti(Oi-Pr)4
FeCl2
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<5
29
12
11
FeCl3
Fe(acac)3
FeCl3
a General reaction conditions: 1a (0.25 mmol, 1.0 equiv) and Lewis
acid catalyst (10 mol %) in MeCN (5 mL). b Conversions were deter-
mined on the basis of the consumption of propargyl alcohol. c NMR
yields of 2a with 1,3,5-trimethoxybenzene as internal standard.
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Org. Lett., Vol. 14, No. 9, 2012
2359

As shown in Table 1, the commonly used Lewis acids
gave poor yields of enyne 2a; even most of the propargyl
alcohol 1a were consumed. Therefore, to fill this “missing
methodology”, new catalysts need to be developed either
by providing proper acidicity (only activating the CꢀO
bond without formation of “pure” carbocation) or by
going through an alternative reaction path (such as radical)
to avoid the undesired decomposition. On the basis of our
recent success in developing new triazoleꢀmetal catalysts,
we postulated that triazole ligands might provide the needed
reactivity for this simple but important transformation.
enyne 2a in good yields. Screening the triazole ligands
revealed even better reactivity of chelating ligands, giving
enyne in excellent yields. Interestingly, other heteroaro-
matic ligands, including pyridine, imidazole, tetrazole, and
1,2,4-triazoles, could not provide this chemoselectivity at
all, even with very similar binding patterns, which demon-
strates the unique properties of 1,2,3-triazoles as ligands in
adjusting iron cation reactivity.
The bidentate ligands gave improved reactivity. Increas-
ing the ligand loading revealeda 2:1 (ligand/Fe) ratio as the
optimal condition, which was consistent with the Fe3þ
octahedral coordination (six coordination sites, requiring
open coordination sites for OH binding in the transition
state). Solvent screening revealed acetonitrile as the opti-
mal solvent (see details in the Supporting Information).
Attempts to obtain the ironꢀtriazole complex crystal
structure have been unsuccessful to this point. Neverthe-
less, addition of readily available 1,2,3-triazole to FeCl3
provided a practical and efficient catalyst system, which
gave the critical chemoselectivity for the CꢀO bond acti-
vation. To the best of our knowledge, this is the first
catalytic system reported that can effectively promote this
transformation.18 Various functional propargyl alcohols
were prepared to investigate the reaction substrate scope.
The results are summarized in Figure 2.
Figure 1. Screening of ligands. (a) General reaction conditions:
1a (0.25 mmol, 1.0 equiv), ligands (10 mol %), and Lewis acid
catalyst (10 mol %) in MeCN (5 mL). (b) Conversions were
determined on the basis of the consumption of propargyl
alcohol. (c) NMR yields of 2a with 1,3,5-trimethoxybenzene
as internal standard.
To test our hypothesis, various triazoleꢀFeCl3 mixtures
were employed as the catalysts to react with 1a. To ensure
consistency, all reactions were conducted under identical
conditions, and the reaction mixtures were measured after
7 h (Figure 1). To our surprise, the simple addition of
N-methylbenzotriazole L1 to FeCl3 significantly decreased
the undesired decomposition of 1a, giving the desired
Figure 2. Substrate scope. (a) General reaction conditions: 1a
(0.25 mmol, 1.0 equiv), ligands L10 (20 mol %) and Lewis acid
catalyst (10 mol %) in MeCN (5 mL). (b) Isolated yields.
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874–922. (c) Chinchilla, R.; Najera, C. Chem. Soc. Rev. 2011, 40, 5084–
5121.
(18) The Ru(II)-based catalyst has been used for propargyl alcohol
´
dehydration but only limited to terminal alkyne:Cadierno, V.; Garcıa-
Garrido, S. E.; Gimeno, J. Adv. Synth. Catal. 2006, 348, 101–110.
ꢀ
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Org. Lett., Vol. 14, No. 9, 2012

As indicated in Figure 2, both terminal alkyne (2r) and
internal alkyne were suitable for this reaction, giving the
desired enynes in excellent isolated yields. The alkyne
terminal can tolerate various substituted groups, including
alkyl (2a, 2b), aryl (2e), TMS (2c), cyclopropanyl (2g), and
even vinyl groups (2d). The propargyl position tolerates an
aromatic ring with either electron-donating (2j, 2k) or
electron-withdrawing (2s to 2u) groups. Elimination to
the alkenes showed excellent stereoselectivity, with only
one double bond isomer observed, which were unambigu-
ously characterized by X-ray crystal structure (2n). The
formation cyclohexenyl enyne 2i indicated a slower reac-
tion rate caused by the lower reactivity of the CꢀO bond.
However, the starting propargyl alcohol could be fully
recovered, indicating the excellent chemoselectivity of the
1,2,3-triazole/Fe catalysts. Enynes with 1,2-disubsitututed
alkenes could not be formed because of the low reactivity
of the CꢀO bond. Raising the reaction temperature caused
the decomposition of propargyl alcohols. However, the
highly reactive 1,4-enediynes could be easily synthesized
with this method (Figure 3), which highlighted the benefits
of the milder reaction condition.19
Figure 4. Mechanistic investigations.
Comsidering that both Lewis acid catalyzed cyclopro-
pane opening22 and radical initiated ring-opening23 were
plausible, mixtures of NH-triazole and radical trapper
1,4-cyclohexyldiene (CHD) were used to investigate the
mechanism.
As shown in Figure 4, reaction of 3a gave the chloro
enyne 4a as the only isolated product (25% yield). With the
addition of NH-triazole, enyne 4c was obtained (75%
yield, confirmed by X-ray). Addition of radical trapper
CHD did not lead to the formation of H-quenched enyne
2b. Instead, the chloro enyne 4a was the only enyne
product isolated. These results strongly suggested the
carbocation ring-opening pathway instead of radical me-
chanism, which is consistent with our hypothesis that
1,2,3-triazole ligands provided the required electronic
effect in adjusting Lewis acidity of Fe3þ to achieve the
needed chemoselectivity for this transformation.
In conclusion, 1,2,3-triazoles were identified as unique
ligands for iron-mediated catalysis. The challenging cata-
lytic dehydration of propargyl alcohols to conjugated
enynes was successfully achieved. The fact that 1,2,3-
triazoles were the only heterocycles “working” among
the tested ligands illustrated their ability in adjusting iron
cation reactivity, thereby providing the foundation for
further development of new iron-catalyzed transformations.
Figure 3. Synthesis of 1,4-enediynes. (a) General reaction con-
ditions: identical as above. (b) Isolated yields.
Substrates 2nꢀu illustrated good functional group toler-
ability of this method. The COOH or ester-substituted
enyne could be readily prepared through this approach.
Treating 2s, 2t, and 2u with NBS resulted in either 6-endo
or 5-exo cyclization, giving the bromoallenes or lactone in
excellent yields and diastereoselectivity.20 Notably, large-
scale (10 g) reaction has been performed, and 2a was
prepared with 82% isolated yield.
Acknowledgment. We thank the NSF (CHE-0844602)
for the financial support.
To investigate the reaction mechanism of this triazole-
ligand coordinated Fe3þ cation catalyst,21 the cyclopro-
pane-substituted propargyl alcohols (3a, 3b) were pre-
pared and treated with FeCl3 under various conditions.
Supporting Information Available. Experimental de-
tails, spectrographic data, and X-ray crystal structures
and CIF files. This material is available free of charge via
the Internet at http://pubs.acs.org.
(19) The alkenyl group activated propargyl alcohols have also been
investigated. However, complex reaction mixtures were observed with
no clear products isolated. This is likely caused by plausible decomposi-
tion or polymerization of the corresponding dienes.
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The authors declare no competing financial interest.
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