Catalytic asymmetric allenylation of malonates with the generation of central chirality

Article abstract of DOI:10.1002/anie.201204346

Water plays an important role in a palladium-catalyzed allenylation of diethyl malonate with 2,3-allenyl acetates to yield centrally chiral allenyl malonates bearing synthetically useful functional groups (see scheme). The products were formed with 92-96 %ee in the presence of a bulky, electron-rich biphenyl ligand at room temperature. Copyright

Full text of DOI:10.1002/anie.201204346

Angewandte
Chemie
DOI: 10.1002/anie.201204346
Asymmetric Catalysis
Catalytic Asymmetric Allenylation of Malonates with the Generation
of Central Chirality**
Qiankun Li, Chunling Fu, and Shengming Ma*
It is well-known that biomolecules exist mostly as single
enantiomers. Since different enantiomers show different
biological activities, asymmetric synthesis has always been
of high interest. There is no universal approach to optically
active compounds. Recent developments in the chemistry of
allenes,[1] such as transition-metal-catalyzed reactions and
radical, electrophilic, and nucleophilic addition reactions,
may offer new efficient approaches, provided that optically
active starting allene compounds are readily available. The
malonate unit has been used as a tether for the synthesis of
many complex molecules.[2] Thus, enantioselective
approaches to 2-allenyl malonates are highly desirable. In
pioneering studies on the palladium-catalyzed asymmetric
construction of axially chiral allenyl malonates,[3] the remark-
similar propadienyl and R groups is challenging [Scheme 1,
Eq. (2)]. Herein, we describe the first example of such
a reaction: a highly enantioselective synthesis of diethyl 2-
(2,3-alkadienyl)malonates at room temperature.
In a comprehensive screening of ligands L1–L9 (see
Figure S1 in the Supporting Information) for the reaction of
2,3-allenyl acetate 1a and dimethyl malonate (2a) in diethyl
ether, the biphenyl ligand L5 (Scheme 2) was promising (see
Table S1 in the Supporting Information, entry 5 versus
entries 1–4). Subsequent fine-tuning of the structure of the
biphenyl ligand led to the identification of ligand (R)-L9 as
the most efficient (Table 1, entry 1). To our surprise, when
commercial K2CO3 was baked in a Muffle furnace at 3808C
for 6 h and then used in the reaction, the yield determined by
NMR spectroscopy dropped to 29%; 1a was present at the
end of the reaction in 42% yield (as determined by NMR
spectroscopy; Table 1, entry 2). Thus, we explored the effect
of the amount of water present on the yield (Table S2,
entries 2–5) and found 1 equivalent of water to be optimal. At
a lower reaction temperature, the enantioselectivity was
= =
ably different linear RCH C CH group and the hydrogen
atom were differentiated [Scheme 1, Eq. (1)]. However, the
synthesis of optically active 2-(2,3-alkadienyl)malonates with
central chirality in the allene chain from racemic 2,3-
alkadienyl precursors through differentiation of the relatively
Table 1: Effect of water and fine-tuning of substrate 2 to improve the yield
and enantioselectivity.[a]
Scheme 1. Transition-metal-catalyzed asymmetric allenylation. Tf=tri-
fluoromethanesulfonyl.
Entry
R
H2O
[equiv]
T [8C]/
t [h]
Yield
[%][c]
ee [%][d]
1[e]
2[f]
3
Me (2a)
Me (2a)
Me (2a)
Et (2c)
0
0
1
1
1
35/16
35/16
20/16
20/24
20/24
93
29
94
80
84
89 (3a-Me)
87 (3a-Me)
90 (3a-Me)
94 (3a)
[*] Q. Li, Prof. Dr. C. Fu, Prof. Dr. S. Ma
Laboratory of Molecular Recognition and Synthesis
Department of Chemistry, Zhejiang University
Hangzhou 310027, Zhejiang (P. R. China)
E-mail: masm@mail.sioc.ac.cn
4
5[g–i]
Et (2c)
94 (3a)
[**] Financial support from the National Basic Research Program of
China (2011CB808700) and the National Natural Science Founda-
tion of China (21232006) is greatly appreciated. We thank the
referees for their suggestions on the reorganization of some of the
material in this manuscript, Prof. F. Xiao, Prof. X. Meng, and Q. Wu
for their kind help with the SEM study, and J. Ye in this research
group for reproducing the preparation of (S)-3e in Table 2 as well as
(S)-3l and (S)-3n in Table 3. S.M. is a Qiu Shi Adjunct Professor at
Zhejiang University.
[a] Reaction conditions: 1a (0.4 or 0.5 mmol), 2 (2.0 equiv), [{Pd(allyl)-
Cl}2] (2.5 mol%), (R)-L9 (7.5 mol%), K2CO3 (2.0 equiv), Et2O (4 or
5 mL). [b] Commercial K2CO3 was used after it had been baked in
a Muffle furnace at 3808C for 6 h. [c] The yield was determined by NMR
spectroscopy. [d] The ee value was determined by HPLC analysis on
a chiral phase. [e] Commercial K2CO3 was used as obtained. [f] The
starting allene 1a was present in 42% yield at the end of the reaction, as
determined by NMR spectroscopy. [g] The K2CO3 used in this reaction
was bought from Alfa Aesar and used after it had been baked in a Muffle
furnace at 3808C for 6 h. [h] [{Pd(p-cinnamyl)Cl}2] was used instead of
[{Pd(allyl)Cl}2]. [i] (R)-L9: 6.0 mol%.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201204346.
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11783

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Angewandte
Communications
slightly higher (Table 1, entry 3). Interestingly, when dibenzyl
malonate was used instead of dimethyl malonate, the ee value
dropped to 82%. Further investigations showed that the
reaction of diethyl malonate afforded 3a with 94% ee
(Table 1, entry 4; for details, see Tables S1 and S2 in the
Supporting Information)! To establish a set of internationally
reproducible standard reaction conditions, we used anhy-
drous K2CO3 bought from Alfa Aesar and dried in a Muffle
furnace for 6 h for further study; this material afforded a very
similar result. [{Pd(p-cinnamyl)Cl}2] was then used instead of
[{Pd(allyl)Cl}2] as the metal catalyst for the sake of straight-
forward purification of the product through the removal of
the catalyst-derived allylic malonate. Under these optimized
conditions, 6.0 mol% of (R)-L9 is enough for this trans-
formation (Table 1, entry 5). The nature of the leaving group
and the carbon nucleophile are also important for the
enantioselectivity: the best results were observed with the
allenyl acetate and diethyl malonate (Tables S3 and S4).
We studied the effects of solvents and bases in an attempt
to improve the enantioselectivity and found Et2O and K2CO3
to be the most suitable (Table S5, entries 1–9). The reaction at
108C gave the product with a higher ee value, but the reaction
time was much longer (Table S5, entry 10). Thus, we defined
the reaction conditions in entry 5 of Table 1 as optimal for
further study.
As expected, the reaction of 1a with 2c in the presence of
(S)-L9 as the ligand under the optimized conditions afforded
the enantiomer (R)-3a in good yield with high enantioselec-
tivity [Eq. (3)].
The reaction is sensitive to the steric bulkiness of the R
group: reactions of substrates with a phenyl or isopropyl R
group are extremely slow at room temperature. However,
ꢀ
many synthetically useful functional groups, such as halide,
ꢀ
ꢀ
CN, OH, OAc, alkenyl, and alkynyl groups may be
comfortably accommodated to afford the products with 92–
96% ee (Table 3).
Table 3: Asymmetric allenylation with 2,3-allenyl acetates bearing syn-
thetically useful functionalities.[a]
We next explored the scope of the asymmetric allenyla-
tion of diethyl malonate with allenyl acetates under our
optimized conditions (Table 2). The reaction is very general:
when the length of the carbon chain of the R group was
increased from ethyl to n-nonyl, the products were formed
with very similar high ee values (93–95%; Table 2, entries 1–
9). In particular, even an ethyl or propyl R group was
recognized with remarkable enantioselectivity, although the
size difference between the propadienyl group and the R
group was so small. We also investigated the reaction of 1d on
a 1 g scale under the optimized conditions and isolated (S)-3d
in 76% yield with 95% ee (Table 2, entry 4).
Entry
1
n
FG
t [h]
Yield [%][c]
ee [%][d]
1[e]
2
3
4
5
6
1i
1j
1k
1l
1m
1n
5
8
3
5
5
3
Cl
26
37
36
33
24
47
72
71
83
84
84
72
94 (3i)
93 (3j)
95 (3k)
96 (3l)
96 (3m)
92 (3n)
vinyl
CN
OH
OAc
[a] Reaction conditions: 1 (0.5 mmol), 2c (2.0 equiv), [{Pd(p-cinna-
myl)Cl}2] (2.5 mol%), (R)-L9 (6.0 mol%), K2CO3 (2.0 equiv), H2O
(1.0 equiv), Et2O (5 mL), 208C. [b] K2CO3 bought from Alfa Aesar was
used after it had been baked in a Muffle furnace at 3808C for 6 h. [c] Yield
of the isolated product. [d] The ee value was determined by HPLC
analysis on a chiral phase. [e] The reaction was conducted with
[{Pd(allyl)Cl}2] as the metal catalyst instead of [{Pd(p-cinnamyl)Cl}2].
TMS=trimethylsilyl.
Table 2: Asymmetric allenylic alkylation of 2,3-allenyl acetates.[a]
The absolute configurations of the products were assigned
tentatively on the basis of an X-ray single-crystal diffraction
study of (1R,9R,10R)-5d[4] (Figure S2), which was formed
from (S)-3d according to our previously reported procedure[5]
[Eq. (4); MS = molecular sieves, Ts = p-toluenesulfonyl].
Entry
R
t [h]
Yield [%][c]
ee [%][d]
1
2
3
Et (1b)
nPr (1c)
nBu (1d)
nBu (1d)
n-C5H11 (1e)
n-C6H13 (1a)
n-C7H15 (1 f)
n-C8H17 (1g)
n-C9H19 (1h)
24
23
24
24
24
24
26
27
26
75
76
77
76
78
81
78
75
75
93 (3b)
93 (3c)
95 (3d)
95 (3d)
95 (3e)
94 (3a)
93 (3 f)
93 (3g)
93 (3h)
4[e]
5
6
7
8
9
[a] Reaction conditions: 1 (0.5 mmol), 2c (2.0 equiv), [{Pd(p-cinna-
myl)Cl}2] (2.5 mol%), (R)-L9 (6.0 mol%), K2CO3 (2.0 equiv), H2O
(1.0 equiv), Et2O (5 mL), 208C. [b] K2CO3 bought from Alfa Aesar was
used after it had been baked in a Muffle furnace at 3808C for 6 h. [c] Yield
of the isolated product. [d] The ee value was determined by HPLC
analysis on a chiral phase. [e] The reaction was conducted on a 1 g scale.
To gain an understanding of the factors dictating the
enantioselectivity observed with ligand L9, we carried out
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a number of control experiments with commercially available
ligands (Scheme 2, Table 4).
Scheme 2. Ligands used in control experiments to unveil the role of
each unit in ligand L9.
Figure 1. SEM of the ground anhydrous K2CO3 suspended in Et2O in
the absence (left) and presence of H2O (1 equiv; right). Scale bar:
200 mm.
The enantioselectivities and catalytic activities observed
with the Ph2P-substituted ligands L5 and L6 were very
similar; the reaction proceeded (albeit at a very slow rate)
with higher enantioselectivity with another Ph2P-substituted
ligand, L10, most probably because of the presence of the two
five-membered rings. As expected, the more electron-rich
nature of the phosphorus atoms in L11 as a result of the
electron-donating Ar group greatly improved the activity of
the particle size of K2CO3 in Et2O upon the addition of water
(1 equiv) with stirring (Figure 1, right) is much smaller than
that of anhydrous K2CO3 (Figure 1, left; for detailed infor-
mation, see the Supporting Information).
ꢀ
the oxidative addition to cleave the C O bond in the allene
In conclusion, we have developed a highly enantioselec-
tive protocol for the asymmetric allenylation of diethyl
malonate with racemic 2,3-allenyl acetates. Owing to the
excellent generality of the reaction, its functional-group
tolerance, the mild reaction conditions, the ready availability
of all starting chemicals,[6] and the synthetic potential of the
chiral products, this reaction will be of high interest for
organic, materials, and medicinal chemists. We are pursuing
further studies in this area, in particular the construction of
both axial and central chirality in allenyl malonates.
1a (Table 4, entry 4). Thus, we conclude that in L9, the 4,4’-
bibenzo[d][1,3]dioxole unit together with the bulky C6H2(m-
tBu)2(p-OMe) group are responsible for the high enantiose-
lectivity, and the electron-rich nature of the phosphorus
atoms leads to the high catalytic activity.
Table 4: Investigation into the factors dictating the enantioselectivity.[a]
Entry
Ligand
Recovery
Yield [%][d]
ee [%][e]
of 1a [%][c]
Experimental Section
1
2
3
4
5
(R)-L5
(R)-L6
(R)-L10
(R)-L11
(R)-L9
22
20
66
0
51
59
9
83
81
48
54
67
67
94
Typical procedure: [{Pd(p-cinnamyl)Cl}2] (6.4 mg, 0.0125 mmol), (R)-
DTBM-segphos (L9; 35.5 mg, 0.03 mmol), 1b (70.5 mg, 0.5 mmol),
and Et2O (2.5 mL) were added sequentially to a Schlenk tube
containing ground anhydrous K2CO3 (138.1 mg, 1.0 mmol) under
nitrogen. Then 2c (160.0 mg, 1.0 mmol), Et2O (2.5 mL), and H2O
(9 mL, 0.5 mmol) were added sequentially with stirring, and the
Schlenk tube was equipped with a reflux condenser to avoid loss of
the solvent. The reaction was complete after the mixture had been
stirred at 208C for 24 h, as monitored by TLC (eluent: petroleum
ether/ethyl acetate (20:1)). After filtration through a short pad of
silica gel with Et2O (50 mL) and the evaporation of volatile
components of the mixture, purification by chromatography on
silica gel afforded (S)-3b (90.2 mg, 75%, 93% ee, eluent: n-hexane/
ethyl acetate (50:1)) as a liquid. HPLC conditions: Chiralpak PA-2
column, eluent: n-hexane/iPrOH (97:3), rate: 0.5 mLminꢀ1; l =
0
[a] Reaction conditions: 1a (0.5 mmol), 2c (2.0 equiv), [{Pd(p-cinna-
myl)Cl}2] (2.5 mol%), chiral ligand (6.0 mol%), K2CO3 (2.0 equiv), H2O
(1.0 equiv), Et2O (5 mL), 208C, 24 h. [b] K2CO3 bought from Alfa Aesar
was used after it had been baked in a Muffle furnace at 3808C for 6 h.
[c] The quantity of 1a was determined by NMR spectroscopy by analysis
of the crude product with mesitylene as an internal standard. [d] Yield of
the isolated product. [e] The ee value was determined by HPLC analysis
on a chiral phase.
20
220 nm; tR = 14.6 min (major), 15.7 min (minor). ½aꢁD ¼ + 18.1 (c =
1
=
0.99, CHCl3); H NMR (300 MHz, CDCl3): d = 5.17–5.01 (m, 1H,
To explain the effect of water, we reasoned that the
solubility of K2CO3 in water makes the two-phase reaction
a three-phase reaction and increases the efficiency of
deprotonation to generate the malonate anion, since it was
noted that the enantioselectivity is almost the same in the
absence of water: the difference lies in the yield [Eq. (5)]. In
fact, it was observed by SEM studies (Hitachi SU 1510) that
=
CH), 4.75–4.61 (m, 2H, CH2), 4.25–4.07 (m, 4H, 2 ꢀ CH2), 3.35 (d,
J = 8.7 Hz, 1H, CH), 2.79–2.63 (m, 1H, CH), 1.60–1.15 (m, 8H, CH2
and 2 ꢀ CH3), 0.90 ppm (t, J = 7.4 Hz, 3H, CH3); 13C NMR (75 MHz,
CDCl3): d = 208.4, 168.3, 168.1, 90.3, 75.6, 61.2, 61.1, 56.6, 40.3, 25.5,
~
14.0, 11.4 ppm; IR (neat): n = 2979, 2937, 2872, 1958, 1751, 1732, 1464,
1369, 1258, 1177, 1097, 1035 cmꢀ1; MS (EI): m/z (%): 240 (M+, 36.71),
79 (100); HRMS calcd for C13H20O4 (M+): 240.1362; found: 240.1369.
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Received: June 5, 2012
Revised: August 26, 2012
Published online: October 10, 2012
Keywords: allenes · asymmetric allenylation · central chirality ·
.
malonates · palladium
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