Phase-Transfer-Catalyzed olefin isomerization/α-Alkylation of α-Alkynylcrotonates as a route for 1,4-Enynes

Article abstract of DOI:10.1002/adsc.201000179

The phase-transfer-catalyzed alkylation of a-alkynylcrotonates was developed as a means to provide 1,4-enynes deconjugated by an all-carbon quaternary center. Extension to the asymmetric version using the chiral phase-transfer catalyst (S)-3 provided the alkylated compounds with up to 87% ee.

Full text of DOI:10.1002/adsc.201000179

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DOI: 10.1002/adsc.201000179
Phase-Transfer-Catalyzed Olefin Isomerization/a-Alkylation of
a-Alkynylcrotonates as a Route for 1,4-Enynes
Takuya Hashimoto,a Kazuki Sakata,a and Keiji Maruokaa,*
a
Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo, Kyoto, 606-8502, Japan
Fax : (+81)-75-753-4041; e-mail: maruoka@kuchem.kyoto-u.ac.jp
Received: March 8, 2010; Published online: June 30, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000179.
Abstract: The phase-transfer-catalyzed alkylation of
a-alkynylcrotonates was developed as a means to
provide 1,4-enynes deconjugated by an all-carbon
quaternary center. Extension to the asymmetric ver-
sion using the chiral phase-transfer catalyst (S)-3
provided the alkylated compounds with up to 87%
ee.
carbon quaternary center bearing an acetylene moiety
which is hardly accessible by other means.[3]
As an extension of this method, we became inter-
ested in implementation of the base-mediated olefin
isomerization/a-alkylation of a-alkynylcrotonates,
generating 1,4-enynes with an all-carbon quaternary
center as a linch-pin [Scheme 1, Eq. (2)].[4] It is antici-
pated that incorporation of a vinyl moiety to the
product would increase the synthetic value of this
process, given its unrivaled diversity of synthetic
transformations and functional orthogonality with al-
kynes, as well as a myriad of reactions utilizing 1,n-
enynes as substrates.[5]
Keywords: acetylenes; alkylation; asymmetric syn-
thesis; enynes; phase-transfer catalysis
Although the olefin isomerization/alkylation reac-
Construction of the asymmetric all-carbon quaternary tions of a-alkylcrotonoyl esters are well known in the
center has widely attracted the attention of synthetic literature,[6] they normally required the use of strong
community as it could only be achieved by relying on base under an inert atmosphere. In contrast, the reac-
À
the use of an enantioselective C C bond-forming pro- tion system developed herein can be accomplished
cess.[1] Among the variety of protocols developed to under operationally simple phase-transfer catalytic
date, phase-transfer-catalyzed asymmetric functionali- conditions owing to the electron-withdrawing proper-
zation has been increasingly accepted as one promis- ty of the a-alkynyl group which facilitates the enolate
ing tool for this purpose.[2] In this context, we recently formation.
introduced the phase-transfer-catalyzed enantioselec-
The scarcity of the methodologies to access 1,4-
tive alkylation of a-alkynyl esters [Scheme 1, Eq. (1)] enynes connected by an all-carbon quaternary center
as a novel means to generate an asymmetric all- in the literature,[7,8] despite their synthetic potential,
initially prompted us to establish the reliability of our
synthetic plan in the synthesis of racemic materials 2
using a-silylethynylcrotonate (1, R1 =TBS) as sub-
strate (Table 1). After brief screening of the base and
solvent, we settled on the use of cyclopentyl methyl
ether (CPME) as solvent and powdered KOH as base
to promote the process.
The olefin isomerization/alkylation of a-silylethyn-
AHCTUNGTREGyNNNU lcrotonate and benzylic bromides could be facilitated
irrespective of the substituent on the benzene ring
(Table 1, entries 1–4). In the case of sterically de-
manding alkyl bromides like 2-chlorobenzyl bromide
(entry 3), a small amount of the g-alkylated com-
pound was observed. Use of allyl and propargyl bro-
mides offered a facile access to a densely functional-
Scheme 1. Phase-transfer-catalyzed olefin isomerisation/a-al-
kylation sequence.
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Takuya Hashimoto et al.
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Table 1. Synthesis of racemic 1,4-enynes.[a]
Scheme 2. Phase-transfer-catalyzed alkylation of the hexa-
2,4-dienoate.
Entry R1
R2X
Time [h] Yield [%][b]
1
2
3
4
5
6
TBS BnBr
6
24
8
85
94
72
91
89
88
57
53
92
56
3-MeC6H4CH2Br
1,4-enynes in moderate yields (entries 7 and 8). The
reaction system was then applied to other a-alkynyl-
crotonates bearing a different functionality at the
acetylene terminus. Whereas the a-phenylethynylcrot-
onate could be utilized uneventfully (entry 9), use of
the substrate bearing an alkyl moiety was found to be
sluggish. Accordingly, cesium hydroxide was used as a
stronger base to give the 1,4-enyne in a reasonable
yield (entry 10).
In addition, the established reaction conditions
could be extended to the alkylation of the hexa-2,4-
dienoate by use of a large excess of potassium hy-
droxide to give the product with a diene moiety
(Scheme 2).[9]
2-ClC6H4CH2Br
4-MeOC6H4CH2Br
H2C=CHCH2Br
6
22
12
22
41
11
12
ꢀ
HC CCH2Br
7[c]
8[c]
9
MeI
EtI
Ph
BnBr
10[d]
n-Bu BnBr
[a]
Reactions were performed with a-alkynylcrotonate
(0.10 mmol) and alkyl halide (0.12 mmol) in the presence
of 20 mol% Bu4NBr (0.02 mmol) and powdered KOH
(0.25 mmol).
[b]
[c]
Isolated yield.
Performed with 5 equiv. of alkyl halide (0.50 mmol) and
10 equiv. of powdered KOH (1.0 mmol).
Performed with CsOH·H2O (1.0 mmol).
As the viability of our synthetic plan for the prepa-
ration of 1,4-enynes connected by an all-carbon qua-
ternary center was validated, we then moved our at-
tention to implement the asymmetric version of this
[d]
ized dienyne and endiyne (entries 5 and 6). Methyla- reaction using chiral quaternary ammonium salt as
tion and ethylation could be achieved as well by using catalyst (Table 2). In the initial investigation, the bi-
excess amounts of the corresponding alkyl iodides naphthyl-modified phase-transfer catalyst (S)-3 was
(5 equiv.) and powdered KOH (10 equiv.), giving the selected as an appropriate catalyst in consideration of
Table 2. Screening of the reaction conditions.
Entry
R1
Base
Solvent
Temp./time [8C/h]
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
TBS
TPS
TMS
Ph
KOH
KOH
KOH
KOH
KOH
KOH
CsOH·H2O
CsOH·H2O
CPME
CPME
CPME
CPME
toluene
toluene
toluene
toluene
0/20
0/33
0/32
0/48
70
70
66
93
53
trace
97
20
29
42
81
82
-
0/48
À20/48
0/21
82
87
À20/24
89
[a]
Reactions were performed with a-alkynylcrotonate (0.10 mmol) and benzyl bromide (0.12 mmol) in the presence of
2 mol% (S)-3 (0.002 mmol) and powdered KOH (0.25 mmol) or CsOH·H2O (0.50 mmol).
Isolated yield.
Determined by chiral HPLC.
[b]
[c]
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Phase-Transfer-Catalyzed Olefin Isomerization/a-Alkylation of a-Alkynylcrotonates
Table 3. Phase-transfer catalyzed asymmetric olefin isomerisation/a-alkylation.[a]
Entry
R1
Ph
R2
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
9
Bn
89
80
85
78
82
91
67
69
83
87
82
80
76
87
64
75
83
58
3-MeC6H4CH2
2-ClC6H4CH2
4-MeOC6H4CH2
H2C=C
AHCTNUGTERN(GNNU CH3)2C=CHCH2
HC CCH2
Bn
Bn
ACHTUGNRTNE(NUNG CH3)CH2
ꢀ
4-ClC6H4
4-MeOC6H4
[a]
Reactions were performed with a-alkynylcrotonate (0.10 mmol) and alkyl halide (0.12 mmol) in the presence of 2 mol%
(S)-3 (0.002 mmol) and powdered CsOH·H2O (0.50 mmol).
Isolated yield.
Determined by chiral HPLC.
[b]
[c]
our previous study, and the reaction was carried out ee (entry 8). In contrast, use of the substrate with an
under otherwise identical reaction conditions as electron-donating group led to a significant drop of
above. Use of a-silylethynylcrotonates led to disap- the ee value (entry 9).
pointingly low enantioselectivities, irrespective of the
In conclusion, we developed herein the operational-
substituents of the silyl group (entries 1–3). On the ly simple procedure for the synthesis of 1,4-enynes
other hand, use of a-phenylethynylcrotonate was linked by an all-carbon quaternary center. Investiga-
found to be promising, giving the alkylated compound tions toward the asymmetric variant led to the obser-
with 81% ee (entry 4). Optimization of the reaction vation that a-arylethynylcrotonates could be utilized
conditions revealed a slight increase of the enantiose- to give 1,4-enynes with a promising level of enantiose-
lectivity by use of toluene as solvent (entry 5) and a lectivities.
significant decrease of the reaction rate when con-
ducted at À208C (entry 6). As the use of cesium hy-
droxide successfully increased the reaction rate with- Experimental Section
out deteriorating the enantioselectivity (entry 7), the
reaction was then carried out at À208C using cesium Representative Procedure for Asymmetric Alkylation
hydroxide. As such, the ee could be further improved of a-Alkynylcrotonate (Table 3, entry 1)
to 87% ee (entry 8).[10] Although some other catalysts
were also screened under these reaction conditions,
To a test tube equipped with the magnetic stir bar were
added the catalyst (S)-3 (0.002 mmol, 1.5 mg), toluene
none of them exceeded the result attained by use of
(0.50 mL),
tert-butyl
2-(phenylethynyl)but-2-enoate
(S)-3.[11]
(0.10 mmol, 24.2 mg) and benzyl bromide (0.12 mmol,
14.3 mL). After cooling the mixture to À208C, CsOH·H2O
(0.50 mmol, 93.3 mg) was added in one portion. The reac-
tion was stirred vigorously at the same temperature for 24 h
and quenched with saturated aqueous NH4Cl. The organic
layer was extracted with hexane, dried over Na2SO4 and
concentrated under vacuum. The residue was purified by
column chromatography on silica gel (eluting with hexane/
CH2Cl2/Et2O=200:20:3) to give the alkylated compound as
a colorless oil; yield: 29.7 mg (89%).
With the optimized conditions in hand, we investi-
gated the scope of this asymmetric transformation
using a-arylethynylcrotonates and alkyl halides
(Table 3). As for the benzylic bromides, the reaction
provided the alkylated compounds consistently with
nearly 80% ee (entries 2–4). On the other hand, the
enantioselectivities varied considerably when allylic
bromides were used. Whereas the alkylation with
methallyl bromide resulted in good enantioselectivity,
use of prenyl bromide furnished the alkylated com-
pound with 64% ee (entries 5 and 6). Propargylation
could be also accomplished with modest selectivity
(entry 7). Attachment of an electron-withdrawing
group at the aryl moiety of the alkyne terminus was
Acknowledgements
This work was partially supported by a Grant-in-Aid for Sci-
tolerated, giving the product in 69% yield with 83% entific Research from the MEXT, Japan.
Adv. Synth. Catal. 2010, 352, 1653 – 1656
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Takuya Hashimoto et al.
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