Catalytic use of Strontium hexamethyldisilazide in the asymmetric Michael addition of malonate to chalcone derivatives

Article abstract of DOI:10.1246/cl.2009.296

Strontium hexamethyldisilazide, combined with a chiral bis(sulfonamide) ligand, was found to be very effective for the catalytic asymmetric Michael addition of malonate to chalcone derivatives. Copyright

Full text of DOI:10.1246/cl.2009.296

296
Chemistry Letters Vol.38, No.3 (2009)
Catalytic Use of Strontium Hexamethyldisilazide in the Asymmetric Michael Addition
of Malonate to Chalcone Derivatives
Shu¯ Kobayashi,Ã Miyuki Yamaguchi, Magno Agostinho, and Uwe Schneider
Department of Chemistry, School of Science, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033
Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033
The HFRE Division, ERATO, Japan Science Technology Agency (JST), Hongo, Bunkyo-ku, Tokyo 113-0033
(Received December 26, 2008; CL-081221; E-mail: shu kobayashi@chem.s.u-tokyo.ac.jp)
Strontium hexamethyldisilazide, combined with a chiral
Table 1. Screening of various strontium sources
bis(sulfonamide) ligand, was found to be very effective for the
catalytic asymmetric Michael addition of malonate to chalcone
derivatives.
Sr species (x mol%)
L* (1.2 x mol%)
O
Ph
O
n-PrO2C
+
n-PrO2C
Ph
Ph
Ph
n-PrO2C
toluene (0.1 M)
MS 4A, 25 °C, 7 h
CO2n-Pr
2a
1
3a
L* =
Ph
O2S NH NH SO2
Me Me
Ph
The Michael addition is among the most important carbon–
carbon bond transformations. Over the past few years, this reac-
tion has attracted much attention and significant advances in the
development of catalytic enantioselective protocols have been
achieved.1 In this context, asymmetric 1,4-additions of malo-
nates to enones catalyzed by chiral ionic liquids,2 phase-transfer
catalysts3 or organocatalysts,4 and proline salts5 have been re-
ported, while interestingly, many examples of chiral metal-based
catalysts have also been published for this type of transforma-
tion.6,7 Among those, however, only few examples were based
on the use of inexpensive and readily available alkaline earth
metals.6c–6g In addition, a large excess of malonate (4–6 equiv)
is typically required when chalcones are used as electro-
philes.3a,4a During our on-going efforts toward truly effective
metal catalysis for catalytic asymmetric carbon–carbon bond
formation, we have recently reported the first chiral strontium
catalyst.8 While the abundant group 2 element9 strontium is very
appealing for metal catalysis, only sporadic examples of its syn-
thetic use are known.10
Me
Me
Entry
Sr species
x/mol %
Yield/%a
ee/%b
1
2
3
4
5
6
7c
8c
Sr(Oi-Pr)2
Sr(OAc)2
SrCl2
5
5
5
5
5
5
3
2
92
7
6
11
4
97
99
96
99
36
À11
À8
8
SrI2
Sr(OH)2
Sr(HMDS)2
Sr(HMDS)2
Sr(HMDS)2
99
98
96
aIsolated yields. bDetermined by chiral HPLC analysis.
cReaction time: 12 h.
Table 2. Use of a cyclic chalcone derivative
Sr species (x mol%)
L* (1.2 x mol%)
O
Ph
O
In our earlier work,8 strontium isopropoxide [Sr(Oi-Pr)2] as
the Brønsted base, combined with a chiral bis(sulfonamide) li-
gand, proved to be most effective for asymmetric 1,4-additions.
We report here another strontium source, strontium hexamethyl-
disilazide [Sr(HMDS)2],10a,11 which is a new, more effective cat-
alyst precursor for asymmetric catalysis.
malonate 1 (y equiv)
∗
n-PrO2C
n-PrO2C
∗
Ph
toluene (0.1 M)
MS 4A, 25 °C, time
4
5
1
(y equiv) /h
Time Yielda drb eec
/% /% /%
Entry Sr species (x/mol %)
1
2
3
4
5
6
Sr(Oi-Pr)2 (5)
Sr(Oi-Pr)2 (5)
2.5
5.0
1.2
1.2
1.2
2.5
1.2
1
86
86
168
48
48
48
48
50 97:3 80
92 97:3 66
40 97:3 88
38 97:3 95
26 98:2 95
50 97:3 94
86 98:2 60
In initial experiments using di-n-propylmalonate (1) and
chalcone (2a) in toluene at room temperature, we examined sev-
eral strontium salts, combined with the chiral bis(sulfonamide)
ligand12 shown in Table 1. Compared with our previous best
result employing Sr(Oi-Pr)2 (Entry 1),8 the corresponding com-
mercially available acetate, chloride, iodide, and hydroxide salts
displayed both significantly lower catalytic activity and asym-
metric induction (Entries 2–5). On the other hand, Sr(HMDS)2,
as a stronger Brønsted base, proved to be most efficient in terms
of chemical yield and optical purity (Entry 6); interestingly, with
this precursor the catalytic loading could be decreased to
2 mol % with only marginal loss in enantiomeric excess (Entries
7 and 8). At this stage, we ascribe the better results with
Sr(HMDS)2 to more effective formation of the chiral catalyst.
With this new, more efficient catalyst precursor in hand, we
continued our investigations to further improve this strontium
catalysis.
Sr(Oi-Pr)2 (10)
Sr(HMDS)2 (10)
Sr(HMDS)2 (5)
Sr(HMDS)2 (10)
7d Sr(HMDS)2 (6)
aIsolated yields. Determined by H NMR analysis. The rela-
tive configuration was not assigned. cDetermined by chiral
HPLC analysis. dConcentration: 1 M.
b
We first investigated the use of a less reactive cyclic chal-
cone derivative 4 as the Michael acceptor (Table 2). Sr(Oi-
Pr)2 as the Brønsted base provided the desired product 5 with
high diastereoselectivity (97%) and an enantiomeric excess of
up to 88% (Entries 1–3); unfortunately, under the best conditions
the reaction was very slow (168 h) and the yield was low (40%;
Copyright ꢀ 2009 The Chemical Society of Japan

Chemistry Letters Vol.38, No.3 (2009)
297
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a,b,c
Sr(HMDS)2
for
acyclic
chalcones
employing
¨
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R
R
O
O
2
3
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n-PrO2C
n-PrO2C
Ph
CO2n-Pr
CO2n-Pr
F
3b R = 2-Cl: 82% yield, 95% ee
3c R = 4-Cl: 93% yield, 97% ee
3f R = 2-Cl: 92% yield, 93% ee
3g R = 4-F: 94% yield, 98% ee
4
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Ph
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CO2n-Pr
CO2n-Pr
3h 95% yield, 90% ee
3d R = 3-NO2: 86% yield, 96% ee
3e R = 4-NO2: 81% yield, 97% ee
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aConditions: Sr(HMDS)2 (5 mol %), LÃ (6 mol %), toluene (0.1 M),
MS 4A, 25 ꢀC, 7 h. bIsolated yields. cDetermined by chiral HPLC
analysis.
Entry 3). Importantly, Sr(HMDS)2 proved to be a better catalyst
precursor in terms of both asymmetric induction (up to 95% ee)
and reaction time (48 h; Entries 4–7). The best result so far ob-
tained produced Michael adduct 5 with 97% ds and 94% ee
(Entry 6). It is noted that much higher enantioselectivities were
obtained by using Sr(HMDS)2 compared with Sr(Oi-Pr)2, and
that this is the first example of the use of Sr(HMDS)2 as a cata-
lyst for C–C bond formation.
7
For a recent example of catalyst-free Michael additions, see: T. Kakinuma,
R. Chiba, T. Oriyama, Chem. Lett. 2008, 37, 1204.
Next, we examined the scope for several acyclic chalcones13
by using Sr(HMDS)2 as the Brønsted base (Table 3). In all
cases, the reactions proceeded well to afford the corresponding
Michael adducts 3b–3h in high yields with excellent enantiose-
lectivities (Table 3). In addition, Sr(HMDS)2 proved to be a
more efficient catalyst precursor than Sr(Oi-Pr)2 with respect
to both chemical yields and optical purities.8
In conclusion, we have discovered Sr(HMDS)2 as an unpre-
cedented Brønsted base for catalytic asymmetric 1,4-additions.14
The use of this strontium amide salt, combined with a chiral
bis(sulfonamide) ligand, was shown to be more efficient than
the use of Sr(Oi-Pr)2 with respect to substrate scope of both acy-
clic and cyclic chalcones. Most remarkably, the catalytic system
proved to be excellent under very mild conditions that are: (1)
the reaction proceeds at room temperature; (2) an external base
is not required; (3) an excess of malonate is not needed. Further
investigations to clarify catalyst structure and mechanism as well
as to develop novel Sr-catalyzed carbon–carbon bond-forming
reactions are now underway in our laboratories.
8
9
M. Agostinho, S. Kobayashi, J. Am. Chem. Soc. 2008, 130, 2430.
N. N. Greenwood, A. Earnshaw, Chemistry of the Elements, Oxford,
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A. G. M. Barrett, M. S. Hill, P. B. Hitchcock, P. A. Procopiou, Organome-
´
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11 For the preparation of strontium hexamethyldisilazide, see: M.
Westerhausen, Inorg. Chem. 1991, 30, 96, this strontium amide compound
appears to have a dimeric structure.
12 For the preparation of these types of bis(sulfonamide) ligands, see: a) R.
Hilgraf, A. Pfaltz, Adv. Synth. Catal. 2005, 347, 61. b) D. A. Evans,
S. G. Nelson, J. Am. Chem. Soc. 1997, 119, 6452.
13 For the preparation of chalcone derivatives, see: S. Bhagat, R. Sharma,
D. M. Sawant, L. Sharma, A. K. Chakraborti, J. Mol. Catal. A: Chem.
2006, 244, 20.
14 Typical experimental procedure for the Sr-catalyzed Michael addition: In a
flame-dried 30-mL flask, a suspension of Sr(HMDS)2 (6.1 mg, 0.015 mmol,
5 mol %), chiral ligand LÃ (9.9 mg, 0.018 mmol, 6 mol %), and MS 4A
(100 mg) in dry toluene (1.0 mL) was stirred for 2 h at room temperature
under an argon atmosphere. After this period, solutions of di-n-propyl
malonate (1; 67.1 mL, 0.36 mmol, 1.2 equiv) in toluene (1.0 mL) and the
corresponding chalcone 2 or 4 (0.30 mmol) in toluene (1.0 mL) were
successively added. After the indicated reaction time, the crude mixture
was quenched with sat. aq NH4Cl (10 mL). After addition of CH2Cl2, the
organic layer was separated and the aqueous layer was extracted with
CH2Cl2 (three times). The combined organic layers were then dried over
anhydrous Na2SO4, filtered and concentrated under reduced pressure.
The corresponding crude product was purified by preparative thin-layer
chromatography (PTLC; hexane–ethyl acetate) to afford the desired prod-
uct 3 or 5.
This work was partially supported by a Grant-in-Aid for
Scientific Research from the Japan Society for the Promotion
of Science (JSPS).
This paper is dedicated to Professor Ryoji Noyori on the
occasion of his 70th birthday.
References and Notes
1
For recent reviews on Michael additions, see: a) S. B. Tsogoeva, Eur. J.
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Org. Chem. 2007, 1701. b) D. Almasꢀi, D. A. Alonso, C. Najera, Tetra-
hedron: Asymmetry 2007, 18, 299. c) T. Hayashi, K. Yamasaki, Chem.
Rev. 2003, 103, 2829. d) J. Christoffers, A. Baro, Angew. Chem., Int. Ed.
Published on the web (Advance View) March 5, 2009; doi:10.1246/cl.2009.296