Copper-Catalyzed Direct and Stereoselective Synthesis of Conjugated Enynes from α-Allenols

Article abstract of DOI:10.1002/adsc.201801211

A novel strategy for the stereoselective synthesis of conjugated enynes directly from α-allenols has been developed. The reaction proceeds with perfect E-selectivity and exhibits high functional group compatibility. This catalytic system can also be applied to the stereoselective synthesis of conjugated dienynes and enediynes. (Figure presented.).

Full text of DOI:10.1002/adsc.201801211

Title: Copper-Catalyzed Direct and Stereoselective Synthesis of
Conjugated Enynes from α-Allenols
Authors: Masahiro Sai and Seijiro Matsubara
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10.1002/adsc.201801211
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Copper-Catalyzed Direct and Stereoselective Synthesis of
Conjugated Enynes from -Allenols
Masahiro Saia,* and Seijiro Matsubarab
a
Research Foundation ITSUU Laboratory, C1232 Kanagawa Science Park R & D Building, 3-2-1 Sakado, Takatsu-ku,
Kawasaki, Kanagawa 213-0012, Japan
Phone: (+81)-44-819-4044; fax: (+81)-44-819-4483; e-mail: msai@itsuu.or.jp
Department of Material Chemistry, Graduate School of Engineering, Kyoto University, Kyoto-daigaku Katsura,
b
Nishikyo-ku, Kyoto 615-8510, Japan
Phone: (+81)-75-383-7130; fax: (+81)-75-383-2438; e-mail: matsubara.seijiro.2e@kyoto-u.ac.jp
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
Malacria, Lacôte, and Gandon reported the first
of conjugated enynes directly from -allenols has been catalytic Nazarov-type cyclization[6] of -allenols to
Abstract. A novel strategy for the stereoselective synthesis
developed.
The reaction proceeds with perfect E-
benzofulvenes using silver triflate, triflic acid, or
phosphomolybdic acid (Scheme 1, path c).[7] In our
previous study, we developed a similar Nazarov-type
cyclization for a broad range of substrates using
LiPF6 as the catalyst.[8b] In this study, enones were
also obtained via the attack of in situ-generated
lithium hydroxide at the allenic center of the cation
intermediate (Scheme 1, path d). On the basis of this
result, we envisioned that if the in situ-generated
metal hydroxide could be directed to selectively
abstract the terminal allenic proton instead of
attacking the allenic center, a new method for the
direct and stereoselective enyne synthesis would be
realized (Scheme 1, path e).[9,10] To the best of our
knowledge, there are only two previous reports on the
preparation of enynes directly from -allenols: in
2009, Lee et al. first reported the Lewis acid-
promoted transformation of an -allenol to an
selectivity and exhibits high functional group compatibility.
This catalytic system can also be applied to the
stereoselective synthesis of conjugated dienynes and
enediynes.
Keywords: -allenols; copper; enynes; dienynes;
enediynes
Conjugated enynes are important structures that serve
as key components of a wide range of biologically
active compounds, natural products, pharmaceuticals,
and functional materials.[1] The Sonogashira cross-
coupling of alkenyl halides with terminal alkynes is
the most widely employed method for the
construction of enyne scaffolds.[2,3] However, despite
its usefulness, stereocontrolled synthesis of
conjugated enynes by this method remains
challenging, largely because the transformation
proceeds in a stereospecific manner, necessitating the
preparation of stereochemically pure alkenyl halides
as starting materials. In addition, these reagents often
lose their stereospecificity during the coupling
reaction, resulting in a mixture of E and Z isomers.
Therefore, the development of a new strategy for
stereocontrolled enyne synthesis from simple starting
materials with high functional group tolerance is
highly desirable.
-Allenols react through the activation of their two
functional groups: the allene moiety and the hydroxy
group. Over recent decades, oxycyclization of -
allenols to 2,5-dihydrofurans via activation of the
allene moiety has been intensively studied (Scheme 1,
path a).[4] Furthermore, Ma et al. and Cho et al. have
independently reported the SN2’ reaction of -
allenols with metal halides to give 2-halo-1,3-
butadienes (Scheme 1, path b).[5] Moreover, in 2009,
enyne.[9a]
However, only one -allenol was
examined for the enyne synthesis, and considerable
amounts of enone byproduct were also generated.
Moreover, the reaction required stoichiometric
amounts of In(OTf)3 and BF3·Et2O or a high loading
of TMSOTf (20 mol%). In 2017, Lin et al. developed
a similar reaction with a broader substrate scope
using Sc(OTf)3 as the catalyst.[9b] However, the
yields were still moderate, and the reaction also
suffered from the formation of enone byproduct.
Accordingly, as part of the continuation of our work
on the Lewis acid-catalyzed transformation of
unsaturated alcohols,[8] we herein describe a novel
copper-catalyzed stereoselective enyne synthesis that
proceeds directly from -allenols.
1
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10.1002/adsc.201801211
Advanced Synthesis & Catalysis
Previous work
OH
nBu
Activation of the allene moiety
nBu
catalyst (10 mol%)
Ph
OH
O
toluene, 80 ˚C, 1 h
Ph
R1
OH
R2
M+
oxycyclization
path a
R1
R1
M+
R2
2,5-dihydrofurans
1
2
R2
Activation of the hydroxy group
O
Cl
O
Ph
R1
X
M
X
nBu
halide
migration
HO
R1
Ph
Me Ph
nBu
path b
nBu
nBu
MX
R2
R2
2-halo-1,3-butadienes
3
4
5
6
OH
R2
Nazarov-type
cyclization
Yield [%][b]
R2
M+
R2
R1
Entry Catalyst
2 (dr)[b]
16 (1.6:1) 17 33
77 <1
79 <1
71 <1
path c
1
0
3
4
5
0
10
19
22
0
0
0
0
0
6
0
0
0
0
0
0
35
0
R3
R3
1
2
3
4
5
6
7
8
LiPF6
AlCl3
InCl3
FeCl3
Sc(OTf)3
Y(OTf)3
AgOTf
Cu(OTf)2
CuOTf[c]
MOH
benzofulvenes
a-allenol
1
3
4
2
1
2
M+
R2
O
attack of
metal hydroxide
R1
R1
Me
path d
0
0
44 (1.8:1) 26 22
41 (1:1) 31 17
R2
enones
M–OH
32 22 (1.1:1)
1
5
9
5
12
16
This Work
0
0
83 (1.1:1)
63 (1.3:1)
OH
SiR'3
abstraction of
the allenic proton
SiR'3
R
9
7
M
SiR'3
R
[a]
Conditions: 1 (0.25 mmol) and catalyst (10 mol%) in
R
path e
–H2O
M–OH
[b]
1
toluene (1.5 mL) at 80 ˚C for 1 h.
Determined by H
H
H
[c]
stereodefined
conjugated enynes
NMR analysis of the unpurified reaction mixture.
CuOTf·1/2C6H6 complex was employed.
R = aryl, alkenyl, and alkynyl
Scheme 1. Lewis acid-catalyzed various transformations of
-allenols.
The effect of allenic substituents (R) on the
stereoselectivity was subsequently evaluated (Table
2). Perfect Z-selectivity was observed when the n-
butyl group was replaced by a tert-butyl group (7)
(entry 1), showing that the stereoselectivity of this
process is dominated by steric factors.[13] In view of
the synthetic utility and the further functionalization
of the product, silyl-containing substrates were
examined. Notably, the use of such substrates was
found to allow the exclusive formation of E isomers
(entries 2–4). TIPS-substituted -allenol 13a gave
the best result in terms of stereoselectivity and yield
(entry 4).
Our initial efforts were directed toward identifying
the appropriate catalyst and reaction conditions for
the transformation of -allenol 1[11] to conjugated
enyne 2 (Table 1). When LiPF6, an efficient catalyst
for the activation of the hydroxy group,[8b] was
employed, the desired enyne 2 was obtained in only
16% yield (entry 1). Metal chlorides such as AlCl3,
InCl3, and FeCl3 mainly afforded 2-chloro-1,3-
butadiene 5 via an SN2’-type attack of the chloride
anion on the allenic center (entries 2–4). Group 3
[9b]
metal triflates such as Sc(OTf)3
and Y(OTf)3
exhibited superior catalytic activities in this system,
albeit with the generation of considerable amounts of
benzofulvene 3 and enone 4 (entries 5 and 6). When
AgOTf was employed, 2,5-dihydrofuran 6 was
obtained as the major product with the formation of
enyne 2 in only 22% yield (entry 7). However, in this
case, the formation of byproducts 3 and 4 was largely
suppressed. Accordingly, the catalytic activities of
group 11 metal Lewis acids were further examined.
As a result, we found that Cu(OTf)2 was particularly
effective for this enyne synthesis and that the
competing side reactions were significantly inhibited
(entry 8).[12]
Table 2. The effect of the allenic substituents (R) on the
stereoselectivity.[a]
OH
R
R
Cu(OTf)2 (5 mol%)
Ph
toluene, 75 ˚C, 1 h
Ph
Entry
R
Yield [%][b]
dr[b]
1
2
3
tBu (7)
TMS (9)
TBS (11)
TIPS (13a)
78 (8)
Z only
E only
E only
E only
69 (10)
64 (12)
82[c] (14a)
4
Table 1. Catalyst screening.[a]
[a]
Conditions: -allenol (0.25 mmol) and Cu(OTf)2 (5
[b]
1
mol%) in toluene (1.5 mL) for 1 h.
NMR analysis of the unpurified reaction mixture.
Isolated yield (0.50 mmol scale).
Determined by H
[c]
2
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10.1002/adsc.201801211
Advanced Synthesis & Catalysis
[a]
The series of TIPS-substituted secondary -
Conditions: 13 (0.50 mmol) and Cu(OTf)2 (5 mol%) in
allenols 13 were converted to the corresponding
conjugated enynes 14 with complete E-selectivity
(Table 3). In all cases, none of the Z-isomers were
toluene (3 mL) for 1 h. Isolated yield is shown. [b] Run for
0.5 h.
1
detected by H NMR analysis of the crude reaction
mixtures. The reaction proceeded smoothly with
only 1 mol% catalyst loading when electron-rich
aromatic compounds were used (14b and 14c). -
Allenols containing electron-deficient aryl groups
gave the corresponding enynes (14d–14f) in
moderate to good yields.[14] Carbon–halogen bonds,
including the C–I bond, were well tolerated under the
Encouraged by these results, we attempted to apply
the new strategy to the stereoselective synthesis of
conjugated dienynes and enediynes (Scheme 2).
Conjugated dienynes are valuable precursors of
polysubstituted
benzene
derivatives
via
cycloaromatization.[16]
Furthermore, conjugated
enediynes cleave DNA by generating reactive
diradicals via the Bergman cyclization, thereby often
presenting potent antitumor activity.[17] -Allenols
15 having an aryl- or alkyl-substituted olefin were
found to be suitable for the reaction, providing the
corresponding E,E-dienynes as the sole products (16a
and 16b). The reaction of -allenol 17a bearing an
alkyne moiety was also examined. In this case, E-
18a was obtained as the major product (73% isolated
yield after column chromatography), while a small
amount of Z-18a was also observed (E/Z = 10:1).[18]
Similarly, the reaction of 17b showed high E-
selectively (E/Z = 12:1), and E-18b was isolated in
70% yield. The formation of Z-18 is likely due to the
linear geometry of the alkyne, which decreases the
steric repulsion between the alkyne moiety and the
TIPS group.
reaction
conditions
employed
(14g–14i),
demonstrating a significant synthetic advantage of the
current method over the cross-coupling method.
Steric encumbrance around the hydroxy functionality
has no deleterious effect on the yield (14k).
Heteroaromatic substrates can also be employed, and
enyne 14m was isolated in 91% yield.
The
stereochemistry of 14k was unambiguously
determined to be E via X-ray crystallography,[15] and
all of the enyne products were assigned by analogy.
Table 3. Substrate scope of the enyne synthesis.[a]
OH
TIPS
cat. Cu(OTf)2
toluene, 1 h
TIPS
Ar
Ar
13
E-14
TIPS
OH
TIPS
Cu(OTf)2 (1 mol%)
TIPS
TIPS
TIPS
toluene, 60 ˚C, 1 h
R1
R1
R1 = Ph (15a)
E,E-16a, 85%
E,E-16b, 69%
R1
=
nBu (15b)
MeO
TBSO
F
E-14b, 96%
(1 mol%, 60 ˚C)
E-14c, 92%
(1 mol%, 60 ˚C)
E-14d, 86%
(5 mol%, 85 ˚C)
TIPS
OH
TIPS
TIPS
TIPS
Cu(OTf)2 (2.5 mol%)
TIPS
toluene, 85 ˚C, 0.5 h
R2
R2
F3C
R2 = Ph (17a)
R2 nC5H11 (17b)
E-18a, 73% (E/Z = 10:1)
E-18b, 70% (E/Z = 12:1)
EtO2C
Cl
=
E-14e, 46%
(5 mol%, 85 ˚C)
E-14f, 51%
(5 mol%, 90 ˚C)
E-14g, 86%
(5 mol%, 85 ˚C)
Scheme 2. Stereoselective synthesis of conjugated
TIPS
TIPS
TIPS
dienynes and enediynes.
Finally, we investigated the mechanistic origin of
the E-selectivity of the reaction (Scheme 3). We
envisioned that the E-selectivity of this process is
likely due to the E/Z isomerization during the
reaction. To test this hypothesis, stereochemically
pure Z-10[19] was subjected to the same reaction
conditions as those presented in Table 2. As
anticipated, Z-10 was completely isomerized to E-10.
We also performed the isomerization of Z-18a under
copper catalysis, affording a 10:1 mixture of E- and
Z-18a, which was identical to the selectivity obtained
directly from 17a. Higher catalyst loading (5 mol%)
did not improve the E-selectivity further, again
resulting in an E/Z ratio of 10:1 (see the Supporting
Br
I
AcO
E-14h, 85%
E-14i, 86%
(6 mol%, 85 ˚C)
E-14j, 90%
(5 mol%, 85 ˚C)
(5 mol%, 75 ˚C)
TIPS
TIPS
TIPS
Me
S
Me
E-14k, 90%
E-14l, 87%
(5 mol%, 80 ˚C)[b]
E-14m, 91%
(1 mol%, 60 ˚C)
(5 mol%, 85 ˚C)
3
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10.1002/adsc.201801211
Advanced Synthesis & Catalysis
Information for details).
These results clearly
which are ubiquitous substructures in bioactive
compounds and functional materials.
indicate that E/Z-isomers were in equilibrium and that
the thermodynamically more stable E isomers were
predominantly formed. The isomerization did not
proceed in the absence of Cu(OTf)2. Thus, Cu(OTf)2
plays a key role in both enyne formation and E/Z
isomerization.
Experimental Section
General procedure: Cu(OTf)2 (9.0 mg, 0.025 mmol) was
charged in an oven-dried vial equipped with a stirring bar.
The vial was flushed with argon and sealed with a rubber
septum. To the vial was added a solution of -allenol
(0.50 mmol) in toluene (3 mL), and the resulting mixture
was stirred in a pre-heated oil bath (75 ˚C) for 1 h. The
reaction mixture was cooled to room temperature, diluted
with Et2O, filtered through a short pad of activated alumina,
and concentrated under reduced pressure. The residue was
purified by flash chromatography on silica gel to give the
corresponding enyne.
Ph
TMS
TMS
Cu(OTf)2 (5 mol%)
toluene, 75 ˚C, 1 h
Ph
E only, 88%
Z-10
Ph
TIPS
Cu(OTf)2 (2.5 mol%)
TIPS
Acknowledgements
toluene, 85 ˚C, 0.5 h
Ph
E/Z = 10:1
This work was supported by JSPS KAKENHI (grant numbers
15H05845 and 17K19120).
Z-18a
E/Z = 10:1 with 5 mol% of Cu(OTf)2
References
Scheme 3. Investigation of the isomerization of enynes
under copper catalysis.
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On the basis of these results, a plausible
mechanism is proposed, as shown in Scheme 4.
Initially, the C–O bond of the -allenol is cleaved by
Cu(OTf)2 to generate the cation intermediate A and
copper hydroxide species. Subsequent abstraction of
the terminal allenic proton by copper hydroxide
affords a conjugated enyne and regenerates Cu(OTf)2.
As demonstrated in Scheme 3, E/Z isomers of the
generated enyne are in equilibrium through the
coordination of Cu(OTf)2 to the alkyne moiety, and
thus the E/Z ratio is determined by the
thermodynamic stability of the products.
OH
enyne synthesis
E/Z isomerization
TIPS
R
TIPS
R
TIPS
[Cu]
R
Cu(OTf)2
–H2O
[Cu]
E-isomer
thermodynamically (TfO)Cu–OH
Cu(OTf)2
TIPS
more stable
H
HO
R
H
R
R
R
TIPS
[Cu]
TfO–
TIPS
TIPS
[Cu]
[2] For reviews on the synthesis of conjugated enynes by
Sonogashira reactions, see: a) K. Sonogashira in Metal-
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Cu(OTf)OH
R
Z-isomer
TfO–
[Cu] = Cu(OTf)2
TIPS
A
Scheme 4. A plausible mechanism.
In conclusion, we have developed a novel copper-
catalyzed stereoselective synthesis of functionalized
conjugated enyne directly from -allenols. This
method is also applicable to the stereoselective
synthesis of conjugated dienynes and enediynes,
[3] For other synthetic approaches such as Horner–
Wadsworth–Emmons reaction, dimerization of alkynes,
4
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10.1002/adsc.201801211
Advanced Synthesis & Catalysis
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high catalytic activity for the enyne formation, we
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allene moiety and the basicity of copper hydroxide may
play a key role for the success of the reaction.
[13] We also examined the reaction of the phenyl-
substituted -allenol, which resulted in low
diastereoselectivity (d.r. = 1.2:1).
[14] In the case of -allenols bearing strong electron-
1
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withdrawing groups, aldehydes are observed by H
NMR analysis. Thus, we assume that copper-catalyzed
retro-allenylation of -allenols competitively occurs,
leading to decreased yields of the enyne products. For
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50, 3294–3298.
[15] CCDC 1036920 contains the supplementary
crystallographic data for E-14k. These data can be
obtained free of charge from The Cambridge
Crystallographic
Data
Centre
via
www.ccdc.cam.ac.uk/data_request/cif.
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This article is protected by copyright. All rights reserved.

10.1002/adsc.201801211
Advanced Synthesis & Catalysis
COMMUNICATION
Copper-Catalyzed Direct and Stereoselective
Synthesis of Conjugated Enynes from -Allenols
direct and stereoselective
OH
TIPS
enyne formation
cat. Cu(OTf)2
TIPS
R
Adv. Synth. Catal. Year, Volume, Page – Page
R
conjugated enynes,
dienynes, and enediynes
R = aryl, alkenyl, and alkynyl
Masahiro Sai* and Seijiro Matsubara
6
This article is protected by copyright. All rights reserved.