Direct catalytic asymmetric conjugate addition of terminal alkynes to α,β-unsaturated thioamides

Article abstract of DOI:10.1021/ja105141x

Direct catalytic asymmetric conjugate addition of terminal alkynes to α,β-unsaturated thioamides under proton transfer conditions is described. Soft Lewis acid/hard Bronsted base cooperative catalysis is crucial for simultaneous activation of terminal alkynes and thioamides, affording the β-alkynylthioamides in a highly enantioselective manner. Control experiments suggested that the intermediate copper thioamide enolate can work as Bronsted base to drive the catalytic cycle via proton transfer. The divergent transformation of the thioamide functionality highlights the synthetic utility of the alkynylation products.

Full text of DOI:10.1021/ja105141x

Published on Web 07/14/2010
Direct Catalytic Asymmetric Conjugate Addition of Terminal Alkynes to
r,ꢀ-Unsaturated Thioamides
Ryo Yazaki,†,‡ Naoya Kumagai,*,† and Masakatsu Shibasaki*,†
Institute of Microbial Chemistry, Tokyo, 3-14-23 Kamiosaki, Shinagawa-ku, Tokyo 141-0021, Japan, and Graduate
School of Pharmaceutical Sciences, The UniVersity of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Received June 12, 2010; E-mail: nkumagai@bikaken.or.jp; mshibasa@bikaken.or.jp
Table 1. Initial Screeninga
Abstract: Direct catalytic asymmetric conjugate addition of ter-
minal alkynes to R,ꢀ-unsaturated thioamides under proton transfer
conditions is described. Soft Lewis acid/hard Brønsted base
cooperative catalysis is crucial for simultaneous activation of
terminal alkynes and thioamides, affording the ꢀ-alkynylthioam-
ides in a highly enantioselective manner. Control experiments
suggested that the intermediate copper thioamide enolate can
work as Brønsted base to drive the catalytic cycle via proton
transfer. The divergent transformation of the thioamide functional-
ity highlights the synthetic utility of the alkynylation products.
entry
ligand
(S)-tol-BINAP
(R)-DTBM-Segphos
4
x
time (h) yield (%)b ee (%)
1
2
3
4
5
(S)-4a
(R)-4b
5
5
5
5
2
2
12
12
12
24
24
24
30
88
88
81
43
86
0
89
93
94
94
94
(R)-3,5-tBu-4-MeO-MeOBIPHEP (R)-4c
(R)-3,5-iPr-4-Me2N-MeOBIPHEP (R)-4d
(R)-3,5-iPr-4-Me2N-MeOBIPHEP (R)-4d
(R)-3,5-iPr-4-Me2N-MeOBIPHEP (R)-4d
c
6
Catalytic enantioselective conjugate addition of active carbon
nucleophiles generated in situ via proton transfer is an attractive
protocol for C-C bond-forming reactions1 in terms of atom and
step economy.2 Direct use of readily available terminal alkynes as
pronucleophiles in this class of reaction offers an efficient approach
affording chiral building blocks that are amenable to diverse
transformations. Despite the prospects for synthetic utility, catalytic
generation of metal alkynylides coupled with a subsequent enan-
tioselective conjugate addition has been limited because of the low
nucleophilicity of transition-metal alkynylides.3,4 Pioneering work
on copper-catalyzed enantioselective conjugate addition of terminal
alkynes employing highly reactive olefins and compensating for
the inherent low nucleophilicity of Cu alkynylides was reported
by Carreira.5 Subsequently, Hayashi6 and Fillion7 showed that
rhodium catalysis is effective for enantioselective conjugate addition
to enones and enals. However, conjugate addition to R,ꢀ-unsaturated
carboxylate derivatives remains uncovered because of their attenu-
ated electrophilicity. Herein, we describe the direct asymmetric
conjugate addition of alkynes to R,ꢀ-unsaturated thioamides pos-
sessing the same oxidation state as carboxylic acid derivatives,
catalyzed by soft Lewis acid/hard Brønsted base/hard Lewis base
cooperative catalysis8 reinforced by a chiral counteranion (eq 1).9
b
a 1a/2a ) 0.2 mmol/0.4 mmol. Determined using H NMR analysis
1
with 2-methoxynaphthalene as an internal standard. c Using 4 mol % 5.
electrophiles that would have enhanced electrophilicity upon
activation in proximity to a soft metal alkynylide through a
soft-soft interaction.11
An initial attempt to carry out a reaction using R,ꢀ-unsaturated
thioamide 1a and phenylacetylene (2a), conducted in THF at 50
°C with a 5 mol % loading of the soft Lewis acid/hard Brønsted
base catalyst prepared from [Cu(CH3CN)4]PF6, (S)-tol-BINAP, and
Li(OC6H4-p-OMe), delivered the desired adduct 3aa, albeit in a
low yield with no enantioselection (Table 1, entry 1). After
evaluation of several chiral bisphosphine ligands (entries 2-4),
MeO-BIPHEP (R)-4d was identified as a ligand producing a high
yield and enantioselectivity (entry 4). The combined use of
bisphosphine oxide 5 as a hard Lewis base that coordinates to
lithium through a hard-hard interaction enhances the Brønsted
basicity of Li(OC6H4-p-OMe), allowing for the completion of the
reaction using 2 mol % catalyst without a detrimental effect on the
enantioselectivity (entry 6).8d
Table 2 outlines the scope of the reaction under the optimized
reaction conditions. The use of n-hexane instead of THF increased
both the yield and the enantioselectivity with as little as 1 mol %
catalyst, presumably because the formation of an intimate Cu
alkynylide/thioamide association was enhanced in the nonpolar
reaction medium (entry 1). The direct asymmetric addition of 2a
to a range of ꢀ-aryl-R,ꢀ-unsaturated thioamides (1b-f) proceeded
smoothly with 1 mol % catalyst to afford the corresponding products
3ba-fa with high enantioselectivity (entries 3-7). The catalyst
loading could be reduced to 0.25 mol % to afford 3fa while
maintaining a high enantioselectivity (entry 8). A catalyst loading
of 5 mol % was required in order to ensure a satisfactory yield of
We envisioned that simultaneous activation of both the terminal
alkyne and the electrophile would hold promise for overcoming
any low reactivity to engage the enantioselective coupling under
proton transfer conditions. Soft metal alkynylides can be catalyti-
cally generated using a soft Lewis acid/hard Brønsted base
cooperative catalytic system.10 In this context, we focused on the
employment of soft Lewis basic R,ꢀ-unsaturated thioamides as
† Institute of Microbial Chemistry, Tokyo.
‡ The University of Tokyo.
9
10.1021/ja105141x  2010 American Chemical Society
J. AM. CHEM. SOC. 2010, 132, 10275–10277 10275

C O M M U N I C A T I O N S
Table 2. Substrate Scopea
Table 3. Chiral Counteranion Catalysisa
temp
yield ee
entry
R1
1
R2
2
x
(°C) product (%)b (%)
1
2
3
4
Ph
Ph
1a Ph
1a Ph
1b Ph
1c Ph
2a
2a 0.5
1
50
50
50
50
80
80
50
3aa
3aa
3ba
3ca
3da
3ea
3fa
98 98
72 98
97 98
74 97
77 95
81 94
98 97
83 97
97 80
63 92
58 96
o-Me-C6H4
p-Me-C6H4
m-OMe-C6H4 1d Ph
2a
2a
2a
2a
2a
1
1
1
1
1
c
5
6
c
entry
R1
1
R2
2
6
product yield (%)b ee (%)
p-OMe-C6H4 1e Ph
1c
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
Ph
Ph
1a nC5H11
1a nC5H11
1a nC5H11
1a cC3H5
1a cC6H11
2c
2c
2c
2d
2e
-
S
R
S
S
S
S
S
3ac
3ac
3ac
3ad
3ae
3af
3ag
3gc
90
90
0
88
63
63
72
43
82
89
ND
83
91
87
90
69
7
8
9
p-Br-C6H4
p-Br-C6H4
Me
1f Ph
1f Ph
1g Ph
1h Ph
2a 0.25 50
2a
2a
3fa
5
5
1
50
50
50
3ga
3ha
3ab
10 iPr
11 Ph
1a 1-cyclohexenyl 2b
1a (CH3)2CHCH2 2f
a 1/2 ) 0.2 mmol/0.4 mmol, 24 h. b Isolated yield. c n-Heptane was
used as the solvent instead of n-hexane.
1a PhCH2CH2
2g
2c
Me 1g nC5H11
Scheme 1. Chemoselective Activation of Thioamide
a 1/2 ) 0.2 mmol/0.4 mmol, 24 h. b Isolated yield. c The catalytic
system was identical to those described in Table 2 ([Cu(CH3CN)4]PF6/
(R)-4b/Li(OC6H4-p-OMe), 5 mol %; phosphine oxide 5, 10 mol %).
Scheme 2. Control Experiments
ꢀ-alkyl-R,ꢀ-unsaturated thioamides 1g and 1h (entries 9 and 10).
The conjugated enyne 2b was also applicable to this catalysis,
affording the desired product 3ab in high enantioselectivity, albeit
with a moderate yield (entry 11).
In a competition experiment with 1 equiv of chalcone, which
has a higher electrophilicity than R,ꢀ-unsaturated thioamide 1a, the
conjugate addition proceeded with 1a exclusively while the chalcone
remained unchanged, highlighting the highly chemoselective nature
of the present catalytic system, which exploits the soft-soft
interaction (Scheme 1).
Saturated aliphatic terminal alkynes afforded moderate enanti-
oselectivity, even after ligand screening12 (as exemplified in Table
3, entry 1), prompting us to implement an additional stereocon-
trolling element in the catalyst. We endowed the copper counter-
anion with chirality using mesitylcopper13 and chiral phosphoric
acid14,15 (S)-6 as the copper source, generating a catalyst armed
with a chiral bulky phosphate anion in proximity to the Cu cation.
Chiral phosphate was also expected to act as a hard Lewis base
(similar to 5) to enhance the reaction rate. Indeed, the developed
soft Lewis acid/hard Brønsted base/chiral counteranion catalyst
improved the enantioselectivity to 89% ee (entry 2). Intriguingly,
the use of antipode (R)-6 terminated the catalysis (entry 3),
suggesting that the phosphate anion is closely involved at the
transition state.16 High enantioselectivity was observed in the series
of aliphatic alkynes 2d-g (entries 4-7). The yield and enantiose-
lectivity remained moderate in the reaction with ꢀ-alkyl thioamide
1g (entry 8).
tylcopper13 and p-methoxyphenol was not an efficient catalyst in
the addition of allylic cyanides to ketoimines and ketones,8d the
present reaction proceeded smoothly with Cu(OC6H4-p-OMe) to
afford a reaction outcome comparable to that obtained using
Li(OC6H4-p-OMe) (Scheme 2b vs Table 1, entry 4). Furthermore,
using both copper phenylacetylide and (R)-4d at 5 mol % exhibited
efficient catalytic performance, providing 3aa in 92% yield with
95% ee, which suggests that the Cu thioamide enolate formed by
the addition of the alkyne directly deprotonates the terminal proton
of the alkyne as a Brønsted base, liberating the product with
concomitant regeneration of the copper alkynylide that engaged in
the enantioselective addition to 1a (Scheme 2c). These control
experiments indicate that the use of a soft Lewis basic nucleophile/
electrophile substrate set allows for an exceedingly efficient proton
A series of control experiments was performed to probe the
reaction mechanism. Neither a soft Lewis acid copper nor a
Brønsted base lithium aryloxide independently promoted the desired
reaction, verifying the crucial cooperative nature of the soft Lewis
acid and hard Brønsted base (Scheme 2a). In contrast to our previous
observation that Li-free Cu(OC6H4-p-OMe) prepared from mesi-
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C O M M U N I C A T I O N S
transfer in which the reaction intermediate pendant on the soft
Lewis acid works as a Brønsted base for the next catalytic cycle
(Figure 1).
The transient thioamide enolate was shown to function as a Brønsted
base that drives the efficient proton transfer. The divergent
transformation of the thioamide functionality contributes to the
synthetic application of the present catalysis. Further effort will be
dedicated to the implementation of other soft Lewis basic substrate
sets.
Acknowledgment. This work was financially supported by a
Grant-in-Aid for Scientific Research (S) and the Sumitomo Founda-
tion. R.Y. thanks JSPS for a predoctoral fellowship. Dr. M. Shiro
at the Rigaku Corporation is gratefully acknowledged for X-ray
crystallographic analysis of 3aa and the Cu/(R)-4b/(S)-6 complex.
Supporting Information Available: Experimental procedures,
characterization of new compounds, and crystallographic data (CIF).
This material is available free of charge via the Internet at http://
pubs.acs.org.
Figure 1. Plausible catalytic cycle with (R)-4d/Cu alkynylide catalyst.
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Scheme 3. Transformation of the Producta
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diastereomers > 98:2, 97% ee.
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In summary, we have developed a direct catalytic asymmetric
conjugate addition of terminal alkynes to R,ꢀ-unsaturated thioam-
ides under proton transfer conditions, allowing efficient access to
optically active ꢀ-alkynyl carboxylate derivatives. Simultaneous
activation of soft Lewis basic thioamides and terminal alkynes via
a soft-soft interaction enables high chemoselectivity and efficient
catalytic turnover. The combined use of chiral counteranions
improved the enantioselectivity in the reaction with alkyl acetylenes.
JA105141X
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