Methylene-bridged bis(imidazoline)-derived 2-oxopyrimidinium salts as catalysts for asymmetric Michael reactions

Article abstract of DOI:10.1002/anie.201300614

In nothing flat: The title salts, having planar nitrogen centers, were utilized successfully as phase-transfer catalysts for asymmetric Michael reactions of tert-butyl glycinate benzophenone Schiff base with vinyl ketone and chalcone derivatives, thus providing excellent levels of diastereo- and enantiocontrol (see scheme). Copyright

Full text of DOI:10.1002/anie.201300614

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DOI: 10.1002/anie.201300614
Asymmetric Synthesis
Methylene-Bridged Bis(imidazoline)-Derived 2-Oxopyrimidinium
Salts as Catalysts for Asymmetric Michael Reactions**
Andrey E. Sheshenev, Ekaterina V. Boltukhina, Andrew J. P. White, and King Kuok (Mimi) Hii*
Conjugate addition of glycine-derived imine esters (1) to
Michael acceptors can generate highly functionalized mole-
cules with up to three contiguous stereogenic centers
(Scheme 1), which is an attractive strategy for assembling
molecular complexity from achiral precursors in a single step
without byproducts.[1]
Figure 1. Effective catalysts containing planar nitrogen atoms for
Scheme 1. Conjugate addition of glycine imine esters (1) to a,b-
asymmetric Michael reactions.
unsaturated carbonyl compounds.
Presently, nonmetal-based phase-transfer catalysts
(PTCs) and organocatalysts[2] have been deployed to great
effect for these reactions.[3] Corey et al. first reported the
conjugate addition of 1 to acrylates and enones with notable
enantioselectivity (> 90% ee) in the presence of an N-
alkylated cinchonidine salt.[4] Subsequently, the scope of the
reaction was expanded with other modified cinchona alka-
loids[5] as well as new catalysts, comprising largely of
quaternary bis(ammonium) and N-spiro ammonium moieties
derived from tartrates,[6] axially-chiral 1,1’-biaryl units,[5f,7]
inositol-derived crown ethers,[8] and a calix[4]arene amino
acid.[9] The use of these pH-neutral catalysts requires strong
bases to generate the nucleophile, thus very low temperatures
(typically ꢀ40 to ꢀ788C) were necessary to suppress com-
petitive reactions.
enantioselectivities, but reactions were sluggish. They
required days to complete even without using any solvents,
which may account for the lack of development of this type of
catalyst in the ensuing decade. However, two recent break-
throughs have rekindled interest in this area, with independ-
ent reports of the pentanidium derivative 3[11] and cyclo-
propenimine 4[12] (Figure 1), which can deliver very favorable
catalytic turnovers and enantioselectivities between room
temperature and ꢀ208C.
Herein, we describe the preparation of a family of
structurally novel 2-oxopyrimidinium salts (5), and their
performance as asymmetric PTCs in the conjugate addition of
the glycine imine ester 1a (R1 = tBu) to vinyl ketone and
chalcone derivatives.
The structure of 5 is derived from chiral methylene-
bridged bis(imidazolines) (MBI), previously reported by
Pfaltz and co-workers as a variant of bisoxazoline ligands
for asymmetric catalysis.[13] The C2-symmetrical architecture
was assembled in five steps from the N-Boc-protected amino
acids 6a–c (Scheme 2): the MBIs 10a–j were prepared by
a modified literature procedure, and subsequently treated
with triphosgene to afford the 2-oxo-pyrimidinium salts 5.
Single-crystal X-ray diffraction analysis of the n-butyl-sub-
stituted derivative 5b (Figure 2) revealed planar fused rings,
corroborating a highly mesomeric tricyclic system.
The addition of the tert-butyl ester glycinate benzophe-
none Schiff base (1a; Table 1) to MVK (11a) in the presence
of 5a was chosen for reaction optimization, including
extensive screening of solvent, dilution, inorganic base,
catalyst loading, and stoichiometry (see Tables S1–S6, in the
Supporting Information). Under phase-transfer conditions,
the solvent exerts an important effect. When using Cs2CO3 as
a base at a 5 mol% catalyst loading, the reaction was
complete within an hour at ambient temperature in toluene
In contrast, deployment of catalysts containing planar
nitrogen entities received far less attention. In 2001, Ishikawa
et al. showed that the modified guanidine derivative 2
(Figure 1) can be employed as a chiral Brønsted superbase
for Michael reactions.[10] The basicity of the catalyst allowed
reactions to proceed under ambient conditions in good
[*] Dr. A. E. Sheshenev, E. V. Boltukhina, A. J. P. White, K. K. Hii
Department of Chemistry, Imperial College London
Exhibition Road, South Kensington, London SW7 2AZ (UK)
E-mail: mimi.hii@imperial.ac.uk
Homepage: http://www.ch.ic.ac.uk/mimi
[**] A.E.S. was supported by a Marie Curie Intra-European Fellowship
within the 7th European Community Framework Programme (FP7,
Project 252247).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201300614.
Re-use of this article is permitted in accordance with the Terms and
Conditions set out at http://angewandte.org/open.
6988
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Table 1: Conjugate addition of tert-butyl glycinate benzophenone Schiff
base (1a) to MVK (11a).[a]
Entry
Catalyst[b]
(mol%)
Solvent
T
[8C]
t
Yield
[%][c]
ee [%][d]
[min]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
5a (5)
5a (5)
5a (5)
5b (5)
5c (5)
5d (5)
5e (5)
5 f (5)
5g (5)
5h (5)
5i (5)
5j (5)
5c (2)
5c (2)
5c (2)
toluene
o-xylene
CH2Cl2
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
o-xylene
RT
65
45
120
65
65
65
65
35
45
45
65
45
300
1440
300
82
78
85
88
85
84
87
82
87
86
80
90
85
76[e]
79
81 (S)
82 (S)
2 (S)
84 (S)
88 (S)
24 (R)
6 (S)
79 (S)
35 (R)
32 (R)
16 (S)
48 (R)
93 (S)
93 (S)
93 (S)
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
0
ꢀ20
Figure 2. Structure of (R,R)-5b as determined by single-crystal X-ray
0
crystallography (nonstereogenic hydrogen atoms omitted).[17]
[a] Reactions were performed using 1a (0.05 mmol), 11a (0.1 mmol),
and Cs2CO3 (0.075 mmol) in 0.5 mL of solvent. [b] Catalyst loading is
indicated within parentheses. [c] Yield of the isolated product after
purification by column chromatography. Reactions were complete (TLC),
unless otherwise indicated. [d] Determined by HPLC using a chiral
stationary phase. Absolute configuration assigned by comparison with
literature data. [e] 97% conversion (1H NMR spectroscopy).
(entries 6 and 7). The level of enantioselectivity was restored
with the N-benzyl derivative 5 f, which also afforded a faster
reaction (entry 8). In contrast, attempts to replace the phenyl
substituents on the stereogenic centers of the catalyst with
isopropyl (entries 9–11) or benzyl (entry 12) groups did not
lead to any improvement. Concurrently, the study also
revealed a highly synergistic relationship between the N and
C substituents in determining the stereochemical outcome.
For catalysts containing phenyl substituents at the stereogenic
centers, the selectivity for the S isomer can be overturned by
changing the N-alkyl substituent to a phenyl group (Table 1,
entry 6 versus entries 1, 4, 5, 7, and 8). The same effect was
also observed for the isopropyl-substituted series (entry 11
versus entries 9 and 10).
Eventually, the best yield and ee value were attained with
2 mol% of 5c within 2 hours at 08C in toluene or o-xylene
(Table 1, entries 13 and 15). Additional lowering of temper-
ature led only to a slower reaction with no detectable
improvement in the product ee value (entry 14). With these
optimized reaction conditions in hand, five additional vinyl
ketone substrates (11b–f) were evaluated (Table 2). In all
cases, the product can be obtained with good to excellent
yields and enantioselectivities, which compare favorably with
previously reported systems.
Scheme 2. Synthesis of chiral 2-oxopyrimidinium salts (5) from the N-
Boc amino acids 6a–c: a) N-methylmorpholine, ClCO2iBu, R’NH2 (74–
96%). b) AcCl, MeOH, 08C!RT. c) LiAlH4, THF, reflux (73–98% over
2 steps). d) CH2(C(=NH)OEt)2·2HCl (9), CH2Cl2, RT!reflux, (65–
100%). e) 10% aq. NaOH/CH2Cl2. f) triphosgene, CH2Cl2, NEt3,
08C!RT (84–93% over 2 steps). Boc=tert-butoxycarbonyl.
or xylene, furnishing the Michael adduct 12a with greater
than 80% ee (Table 1, entries 1 and 2). In comparison, the use
of dichloromethane was detrimental for both productivity and
enantiodiscrimination (entry 3).
As might be expected, variations in the structure of the
catalyst have a profound effect on the reaction outcome.
Extending the N-alkyl chain (from methyl to n-butyl and
neopentyl) led to an increase in the product ee value to 88%
(Table 1, entries 4 and 5), whereas the substitution with
phenyl and bulky tert-butyl groups has the opposite effect
Chalcone derivatives are a particularly challenging class
of Michael acceptors. To date, only two catalysts have been
reported to have broad generality for these substrates:
a
dimeric
binol-derived
(binol = 2,2’-dihydroxy-1,1’-
binaphthyl) N-spiroammonium salt (ꢁ 96% de, 93% ee),[7e]
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Table 2: Addition of 1a to vinyl ketones catalyzed by 5c.[a]
Entry
R
Product
t [h]
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
Me
Et
nPr
CH2CH2Ph
Ph
12a
12b
12c
12d
12e
12 f
5
10
3
2
12
24
85
92
95
94
82
76
93
90
92
85
80
83
Scheme 3. Synthesis of chiral dihydropyrrole derivatives 15.
2-naphthyl
[a] Reactions were performed using 1a (0.05 mmol), 11 (0.1 mmol), 5c
(1 mmol), and Cs2CO3 (0.075 mmol) in toluene (0.5 mL) at 08C. [b] Yield
of the isolated product after purification by column chromatography.
[c] Determined by HPLC using a chiral stationary phase. Absolute
stereochemistry established by comparison with literature data.
As the Michael adduct of the methoxy-substituted chal-
cone 13p was prone to retro-Michael reaction at ambient
temperature, it was subjected to deprotection/cyclization to
afford the dihydropyrrole derivative 15a prior to analysis
[Scheme 3, Eq. (1)]. This strategy was employed to achieve an
expedient synthesis of a dihydropyrrole derivative on a semi-
preparative scale [Eq. (2)]. Using a catalytic loading of
0.5 mol%, a telescoped Michael addition/deprotection/cycli-
zation sequence furnished the product 15b within a reason-
able timescale in high yields and enantiopurity, without the
need for column chromatography.
and the pentanidium derivative 3 (100% de, ꢁ 94% ee).[11a]
Hence, we were delighted to find that 5c is not only
catalytically active, but furnishes the Michael adducts as
single diastereoisomers with excellent yields and enantiose-
lectivities (Table 3) under adjusted reaction conditions (see
The synthetic utility of the methodology was further
demonstrated by the preparation of the novel proline/nicotine
hybrid molecule (2S,3R,5S)-16,[14] containing three well-
defined stereogenic centers, in just three steps (Scheme 4).
Table 3: Conjugate addition of 1a to chalcone derivatives 13.[a]
Entry Ar
R1
Product t [h] Yield [%][b] ee [%][c]
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
14a
14b
14c
14d
14e
14 f
14g
14h
14i
3
2
4
5
2
4
3
3
6
6
2
3
2
2
3
98
96
94
94
92
96
96
98
88
92
90
87
93
90
96
93
90
91
93
91
85
93
93
85
86
87
90
85
83
88
4-NO2C6H4
4-ClC6H4
2-F-5-BrC6H3 Ph
4-CF3C6H4
2-naphthyl
2-pyridyl
3-pyridyl
Ph
Ph
Ph
Scheme 4. Synthesis of the novel nicotine/proline hybrid (2S,3R,5S)-
16: a) 1a, 5c (2 mol%), mesitylene, ꢀ208C, 3 h. b) 1N HCl, THF,
08C, 1.5 h. c) NaBH4, MeOH, 08C!RT, 24 h. THF=tetrahydrofuran.
Ph
Ph
Ph
Ph
9
4-BrC6H4
2-naphthyl 14j
4-ClC6H4
2-furyl
2-thienyl
10
11
12
13
14
15
Following the previous procedure, the dihydropyrrole inter-
mediate 15c was obtained in good yield and selectivity.
Reduction of the imine moiety with sodium borohydride
furnished (2S,3R,5S)-16 as a single diastereoisomer with
excellent optical purity (94% ee).[15]
14k
14l
14m
Ph
Ph
Ph
Ph
4-CF3C6H4 14n
4-pyridyl 14o
In conclusion, a new family of 2-oxopyrimidinium salts
has been shown to be highly effective catalysts for the
asymmetric Michael addition of a glycine imine ester to vinyl
ketones and chalcones under synthetically practical condi-
tions. Although these catalysts contain only planar nitrogen
moieties (Figure 2), they are entirely devoid of Brønsted
basicity.[16] Thus, it is tantalizing to suggest that these first-in-
class compounds may offer a greater reaction scope, partic-
ularly towards substrates with base-labile moieties. Future
work will include delineating the mechanism of these
reactions, and applications in other asymmetric processes.
[a] Reactions were performed using 1a (0.05 mmol), 13 (0.051 mmol),
5c (1 mmol) and Cs2CO3 (0.25 mmol) in mesitylene (0.5 mL) at ꢀ208C
for the indicated time. [b] Yield of the isolated product after purification
by column chromatography. [c] HPLC using a chiral stationary phase.
Absolute stereochemistry established by comparison with literature data.
Table S7 in the Supporting Information). In terms of reaction
scope, a variety of aryls and heteroaryls can be accommo-
dated within the Michael acceptor. Reactions catalyzed by the
2-oxopyrimidinium salt 5c appeared to be faster than those
mediated by the pentanidium catalyst 3. Under practically
identical reaction conditions, reactions were complete within
6 hours, compared to the 10 or more hours provided in the
earlier report.
Received: January 23, 2013
Revised: March 12, 2013
Published online: May 27, 2013
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[17] CCDC 919960 [(R,R)-5b] contains the supplementary crystallo-
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