Iron-catalyzed ene-type propargylation of diarylethylenes with propargyl alcohols

Article abstract of DOI:10.1039/c1ob06456h

The diarylalkenyl propargylic complex framework has been found in many natural products and medicinal regents. Herein, we have disclosed an unprecedented FeCl₃ catalyzed ene-type reaction of propargylic alcohols with 1,1-diaryl alkenes which en

Full text of DOI:10.1039/c1ob06456h

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Iron-catalyzed ene-type propargylation of diarylethylenes with propargyl
alcohols†
Shiyong Peng, Lei Wang and Jian Wang*
Received 25th August 2011, Accepted 20th September 2011
DOI: 10.1039/c1ob06456h
The diarylalkenyl propargylic complex framework has been
found in many natural products and medicinal regents.
Herein, we have disclosed an unprecedented FeCl3 catalyzed
ene-type reaction of propargylic alcohols with 1,1-diaryl
alkenes which enabled us to furnish a diarylalkenyl propar-
gylic complex framework in moderate to high chemical yields
(up to 98%).
a variant of these catalytic transformations was developed by
using ruthenium complexes.6b–f In 2004, Toste and co-workers
developed a mild rhenium-catalyzed propargylation of electron-
rich arenes.7 Although an example of iron-catalyzed nucleophilic
substitution of propargylic alcohols was disclosed by Zhan group
in 2006,8 diarylethylene-type nucleophiles were not included in
this contribution. More recently, Yoshimatsu et al. developed
a scandium-catalyzed propargylation.9 Besides arenes and het-
eroarenes, allylsilane and vinyl silyl ethers were also used as nucle-
ophiles in this transformation. While the methods described above
used a-arylated propargylic alcohols as highly reactive alkylation
reagents, all the above reports of the arylation of a-substituted
propargyl groups are based on the Friedel–Crafts reaction. Herein,
we document a FeCl3-catalyzed ene-type substituted alkylation
reaction of propargyl alcohols bearing not only a terminal group
but also a internal alkyne group (eqn (2)). To the best of our
knowledge, this is the first report of an ene-type reaction triggered
propargylation of 1,1-diarylethylene with propargyl alcohol.
Introduction
Iron as one of the most abundant metals on the earth and
has attracted much attention in modern catalysis because of its
unique reactivity towards carbon–carbon and carbon–heteroatom
bond formation. Owing to its inexpensive and environmental
benign characteristics, considerable effort has focused on iron
catalysis which resulted in a series of novel iron-catalyzed organic
transformations.1
The propargylic moiety is a widely distributed structure in
medicinal and organic chemistry due to the high synthetic value
of the alkyne functionality. The electron-rich triple bond, in com-
bination with the fairly acidic features of the terminal acetylenic
hydrogen atom, makes it a versatile entity for further chemical
transformation.2 This makes propargylic moieties suitable pre-
cursors for the synthesis of highly substituted 1,1-diarylalkanes.
In addition, various natural products, fine chemicals and phar-
maceuticals containing propargylic subunits as components of
their structures have been reported.3 Consequently, efficient routes
to this important scaffold are constantly needed. One attractive
method is the Brønsted acid catalyzed propargylation.4 Another
efficient way for making this propargylic moiety is the direct
propargylation of arenes or heteroarenes with propargyl alcohols
via metal catalyzed Friedel–Crafts (F–C) reactions (eqn (1)).
Since the discovery by Nicolas in 1987,5 the propargylation
of aromatic systems have attracted much attention. In 2002,
Uemura and coworkers discovered that a stoichiometric amount
of Ru-allenylidene reacted with 2-methylfuran leading to the
rapid formation of 5-propargylated 2-methylfuran.6a Subsequently
(1)
(2)
Results and discussion
We began our investigation by examining the FeCl3 catalyzed two-
component reaction of alkenes and 1-phenyl-2-propyn-1-ol. The
initial experiment results showed that the use of a catalytic amount
of anhydrous FeCl3 (10 mol%) could not enable a reaction between
styrene and 1-phenyl-2-propyn-1-ol (Scheme 1, 48 h, no reaction).
Meanwhile, we also tested the reaction activity of trans-stilbene
and cyclopentene. The results showed that a sluggish reaction
or no reaction happened in 48 h (Scheme 1, <5% yield or 0%
yield, respectively). Surprisingly, if 1,1-diphenylethylene was used
Department of Chemistry, National University of Singapore, 3 Science Drive
3, Singapore, 117543. E-mail: chmwangj@nus.edu.sg; Fax: +65 6779 1691;
Tel: +65 6516 1760
† Electronic supplementary information (ESI) available. CCDC reference
numbers 821919. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c1ob06456h
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Table 1 Investigation of catalystsa
Entry
Catalyst
Yield (%)b
1
2
3
FeCl3
74
77
56
FeCl3·6H2O
FeBr3
c
4
5
6
7
8
9
10
11
12
13
14
15
16
17
Fe2(SO4)3·H2O
Fe(acac)3
Fe(NO3)3·9H2O
FeCl2
—
—
52
15
—
c
c
FeBr2
c
Fe(OAc)2
Fe(BF4)2·6H2O
FeSO4·7H20
Fe(ClO4)2·H2O
FeS
CuCl2
CuCl
—
51
c
—
24
—
—
—
—
18
c
c
c
c
AgOAc
Zn(OTf)2
Scheme 1 Investigation of the ene-type reaction.
a Reaction conditions: 1,1-diphenylethylene 1a (0.24 mmol, 1.2 equiv.),
1-phenylprop-2-yn-1-ol 2a (0.2 mmol, 1.0 equiv.), 10 mol% catalyst,
80 ◦C, MeCN (1.0 mL), 2 h. b Yield of isolated product after column
chromatography. c <10% yield.
to replace the above alkenes, the reaction went smoothly and
efficiently (Scheme 1, 2 h, 74% yield). However, when we tried
to use a strong electron-withdrawing group (Cl) or a electron-
donating group (Me) to replace the phenyl group (Scheme 1,
1,1-dichloroethylene and 2-methylpropene), no desired compound
was achieved (Scheme 1, no reaction, respectively). We deduced
that the phenyl group played a critical role in stabilizing the carbon
cation after the ene-type reaction.
Table 2 Optimization of other parametersa
Having this finding in hand, we started to optimize the reaction
parameters of this ene-type substitution reaction. During our
investigation of the metal salt (10 mol%) catalyzed reaction of 1,1-
diphenylethylene 1a with 1-phenylprop-2-yn-1-ol 2a in CH3CN
(1 mL) at 80 ◦C for 2 h, FeCl3·6H2O was discovered to be the
most efficient catalyst and promoted the highest yield of 3a with
77% (Table 1, entry 2). Subsequently, we examined other reaction
parameters by varying temperature and solvent inorder to improve
the reaction efficiency. The results are summarized in Table 2.
In general, higher reaction yields were obtained with less polar
solvents (Table 2, entries 7–9, 54–70%). No reaction happened
when highly polar solvents were used as reaction media (Table 2,
entries 12 and 13). In addition, oxygen-containing solvents were
also not suitable for reaction media in this process (Table 2, entries
10 and 11, <10% yield, respectively). We deduced that oxygen-
containing solvents, such as THF and 1,4-dioxane, coordinated
with the iron catalyst resulting in the loss of iron catalytic activity.
Lower temperature did not favor this process and caused the loss
of reaction yields to some degree (Table 2, entries 4 and 5, 60
◦C and 25 ◦C, 70% and 58%, respectively). Surprisingly, a higher
temperature did not give an improved result (Table 2, entry 3, 100
◦C, 2 h, 80% yield).
Entrya
T/◦C
Solvent
Yield (%)b
1
2
3
4
5
6
7
8
9
10
11
12
13
80
80
100
60
25
80
80
80
80
80
80
80
80
DCE
74
77
80
70
58
29
62
70
54
CH3CN
CH3CN
CH3CN
CH3CN
Toluene
EtOAc
CH3NO2
PhCF3
1,4-Dioxane
THF
c
—
—
—
c
c
MeOH
DMSO
c
—
a Unless specified, see the Experimental section for reaction conditions.
b Yield of isolated product after column chromatography. c <10% yield.
naphthalene ring, and heterocyclic thiophene ring provided the
desired complexes 3a–w in moderate to high yields (Table 3, 3a–r,
44–90% yield). In addition, this process tolerated an R2 group as
well as the R1 group (Table 3, 3t–w, 44–81% yield). It is noteworthy
that alkenyl group could be applied to the R1 position (Table 3,
3s, 70% yield).
Extension of substrate scope was examined using various
symmetric and asymmetric 1,1-diphenylethylenes 2b–d (Table 4).
Moderate to excellent yields were obtained within 11 h (Table 4,
57–98%). Notably, asymmetric 1,1-diphenylethylene provided a
With the optimized conditions in hand, we decided to explore
the scope of this ene-type substitution reaction. The substrate
scope of FeCl3·6H2O catalyzed process of 1,1-diphenylethylene
1a with propargylic alcohol 2 is shown in Table 3. A wide
range of propargylic alcohol bearing an electron-donating group
or electron-withdrawing group at the R1 position, as well as
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Table 3 Scope of propargylic alcohols
Scheme 2 Proposed catalytic cycle.
Conclusions
In summary, we have documented here a Fe-catalyzed reaction of
propargylic alcohols with 1,1-diaryl alkenes. The propargylation
of propargylic alcohols with 1,1-diaryl alkenes in the presence
of FeCl3·6H2O enabled us to trigger an ene-type substitution
process to furnish a diarylalkenyl propargylic complex framework
in moderate to high chemical yields (43–98%). Studies directed
to clarify the functionalities of these compounds as well as the
extension of this strategy to other substrates is currently underway.
Table 4 Scope of diarylethylenes
Acknowledgements
We gratefully acknowledge the National University of Singa-
pore and Singapore Ministry of Education for financial sup-
port of this work (Academic Research Grants: R143000408133,
R143000408733, R143000443112 and R143000480112).
Notes and references
1 For recent reviews, see: (a) B. Plietker, Iron Catalysis in Organic
Synthesis, Wiley-VCH, Weinheim, 2008; (b) C. Bolm, J. Legros, J. L.
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good yield (Table 4, 3d¢, 75%), but with poor regioselectivity (Z/E
~ 1 : 1). In addition, heterocyclic ring functionalized propargylic
alcohol 2 also reacted with 1,1-diphenylethylenes and afforded the
desired product in moderate yield (Table 4, 3b¢ and 3c¢).
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Our postulated reaction pathways are summarized in Scheme
2. In the initial step, FeCl3 triggers the dehydroxylation of propar-
gylic alcohol 2a to form the intermediary propargyl cation A which
is in equilibrium with the corresponding sp2-hybridized allenylium
cation B. The subsequent ene-type nucleophilic addition of 1,1-
diphenylethylene 1a to allenylium cation B leads to an intermediate
C. Finally, intermediate C undergoes a dehydrogenation step to
offer a diarylalkenyl propargylic complex 3a. The configuration
of the new products was determined by analogy with the X-ray
crystal structure of a suitable single crystal (Table 4, product 3p)
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