Phosphine-catalyzed regioselective Michael addition to allenoates

Article abstract of DOI:10.1039/c5cc06197k

The first phosphine catalysed Michael addition of arylcyanoacetates to allenoates has been developed, and the β-selective products with a quaternary center were obtained in excellent yields. This unusual regioselectivity may open new opportunities to acce

Full text of DOI:10.1039/c5cc06197k

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DOI: 10.1039/C5CC06197K
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Phosphine‐catalyzed regioselective Michael addition to
allenoates
Cite this: DOI: 10.1039/x0xx00000x
Vasudeva Rao Gandi and Yixin Lua
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
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double bond in allenes, so‐called ‐umpolung addition. To the
The first phosphine catalysed Michael addition of arylcyanoacetates to
allenoates has been developed, and the ‐selective products with a best of our knowledge, there was only one report by Huang and
quaternary center were obtained in excellent yields. This unusual
regioselectivity may open new opportunities to access interesting
molecular structures.
workers, in which a phosphine was shown to catalyze aza‐
Michael addition of hydrazones to allenoates.8 Herein, we would
like to document the first phosphine‐catalyzed Michael additions
of carbon nucleophiles to allenoates.
Phosphine catalysis represents a powerful tool for constructing
C
C bonds.1 Most commonly, phosphines activate electron‐
deficient alkenes, alkynes and allenes by forming a zwitterionic
intermediate, which then further reacts with suitable
electrophiles to form new bonds.2 Among numerous phosphine‐
mediated reactions,
‐addition reactions have been well
investigated. The pioneering studies were independently
reported by the groups of Trost and Lu in the 1990s, in which
phosphine‐promoted
were successfully developed.3 Subsequently,
additions attracted much attention from synthetic community,
and many enantioselective ‐addition reactions have been
developed over the years.4 Recently, the Kwon group reported a
novel
’‐umpolung addition of ethyl‐2‐alkyl‐2,3‐butadienoate.5
Almost at the same time, Shi et al. also independently described
the synthesis of arylate derivatives via a
’‐umpolung addition.6
On the other hand, ‐addition (Michael) to activated allenes has

‐additions to allenoates or alkynoates
‐umpolung
Scheme 1 Various types of additions to activated allenes.


Table 1 Michael addition of ethyl phenylcyanoacetate 1a to
allenoate 2a catalyzed by phosphinesa


been explored only to a very limited extent (Scheme 1).
Brønsted base was shown to promote Michael addition to
activated allenes,7 which was easy to understand as the
,‐
Entry
Cat.
Solvent
Yield (%)b
/
c
double bond in the allene structures is more electron‐deficient
as compared with ‐double bond. However, Michael addition
1
2
3
4
PPh3
PPh3
PPh3
PPh3
CH2Cl2
CHCl3
THF
99
99
64
80
99/1
,
to activated allenes promoted by phosphines is a much more
challenging task; the attack of phosphonium zwitterion
intermediate generated from the phosphine to allenes will
eventually direct the nucleophile to less electron‐deficient
80/20
100/‐
78/22
MeOH
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selectivity was lost and
the above cases, the ‐ and
silica gel column chromatography.
‐adducts dominated (entries 68). In all
5
PPh3
CH3CN
ether
79
74
69
99
99
99
99
99
75
100/‐

‐ adducts were easily separable by
6
PPh3
73/27
99/1
99/1
66/33
99/1
76/24
72/28
99/1
99/1
99/1
99/1
99/1
99/1
99/1
100/‐
100/‐
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DOI: 10.1039/C5CC06197K
DMF
7
PPh3
By using the established synthetic protocol, we prepared a
number of ‐selective adducts by reacting the corresponding
DMSO
8
PPh3

Toluene
Acetone
Xylene
9
PPh3
cyanoacetates and allenoates in the presence of either PPh3 or
MePPh2 , and the desired quaternary carbon‐containing adducts
were obtained in high to quantitative yields (Figure 1). Extending
our current method to an asymmetric variant was unsuccessful.
10
11
12
13
14
15
16
17
18
19
20
PPh3
PPh3
Mesitylene
Dioxane
PPh3
Phosphine catalysts
adducts, however, no asymmetric induction was observed. On
the other hand, employment of yielded ‐addition products
4, 5 and 6 led to exclusive formation of ‐
PPh3
7

Dimethoxyethane 81
PPh3
with low enantioselectivity (Figure 2). More extensive work
needs to be carried out in the future for the development of a
phosphine‐catalyzed enantioselective
Dichloroethane
CH2Cl2
70
98
99
95
99
65
33
PPh3
‐selective addition
MePPh2
PCy3
reaction.
CH2Cl2
The mechanism for the formation of ‐selective products is
CH2Cl2
Me2PPh
P(tol)3
DBU
unclear, we propose that the steric hindrance of nucleophilic
anion makes common ‐addition unfavourable, accounting for
CH2Cl2

CH2Cl2
the formation of Michael adducts (Scheme 2).
CH2Cl2
21
a
DABCO
Table 2 Examination of different allene estersa
Reactions were performed with 1a (0.1 mmol), 2a (0.15 mmol)
and the catalyst (0.005 mmol) in the solvent specified (0.5 mL) at
b
c
room temperature. Isolated yield. Determined by 1H NMR
analysis of the crude mixture.
/
c
Entry
R
R1/R2
Yield (%)b
We chose ethyl phenylcyanoacetate 1a and allenoate 2a as
model compounds to start our investigation (Table 1). When the
reaction was performed in CH2Cl2 In the presence of PPh3, the ‐
addition took place almost exclusively, and the Michael product
was obtained quantitatively (entry 1). Solvents were
subsequently screened. While all the solvents favoured the
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
Et/Bn
99
92
96
98
84
98
95
94
89
99/1
Et/Et
75/25
66/33
90/10
90/10
‐/100
40/60
‐/100
‐/100
Et/t‐Bu
t‐Bu/Bn
t‐Bu/Et
formation of

‐addition product over
‐adduct, CH2Cl2 remained
CH2Ph t‐Bu/Bn
to be the best solvent for the reaction (entries 2

14). The effects
of different phosphines on the reaction were also examined, and
all the phosphines investigated showed similar activities to that
of PPh3 (entries 1518). Although DBU and DABCO led to the
formation of only Michael adducts, the chemical yields were less
satisfactory (entries 19 and 20).
t‐Bu/Et
t‐Bu/t‐Bu
Et/Bn
CH2Ph
CH2Ph
Me
9
a
Reactions were performed with 1 (0.1 mmol), 2 (0.15 mmol) and
b
PPh3 (0.005 mmol) in CH2Cl2 (0.5 mL) at room temperature.
With the above optimized reaction conditions established,
different allene esters were next utilized for the reaction (Table
2). When the ester moiety in phenylcyanoacetates was small,
Isolated yield. Determined by 1H NMR analysis of the crude
c
mixture.
e.g. ethyl group, the
along with different allene esters employed, with tert‐butyl ester
giving the best ‐selectivity (entries 1 3). By employing sterically
hindered tert‐butyl cyanoacetate, the high ‐selectivity was
constantly observed (entries and 5). When
‐selectivities of the products changed
In summary, we have developed the first phosphine‐
catalyzed
‐selective addition of arylcyanoacetates to 2,3‐


butadienoates. The desired Michael adducts with a quaternary
center were obtained in excellent yields. Currently, we are
investigating the origin of such regioselectivity. Meanwhile,

4
phenylcyanoacetate was replaced by benzylcyanoacetate,
‐
development of an asymmetric variant of such a ‐addition to
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We thank National University of Singapore (R‐143‐000‐599‐
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8
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Notes and references
a
Department of Chemistry, National University of Singapore, 3 Science
Drive 3, Republic of Singapore 117543.
Email: chmlyx@nus.edu.sg
†
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/c000000x/
1
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Res. 2001, 34, 535; (b) D. H. Valentine and J. H. Hillhouse,
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