Enantioselective organocatalytic Michael additions of: N, N ′-dialkylbarbituric acids to enones

Article abstract of DOI:10.1039/c7ob02116j

N,N′-Dialkylbarbituric acids as cyclic malonamide donors were successfully used in the enantioselective Michael addition reaction of enones. Using cinchona alkaloid-based bifunctional squaramide as an organocatalyst, this Michael reaction of N,N′-di-tert-butylbarbituric acid with various enones features a highly enantioselective (91-99% ee) production of the corresponding optically active 5-substituted barbituric acid derivatives. The transformations of the Michael product for the barbituric acid structural unit were realized in two ways, deprotection to remove the N-tert-butyl group and alkylation to produce 5,5-disubstituted barbituric acid derivatives.

Full text of DOI:10.1039/c7ob02116j

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Enantioselective Organocatalytic Michael Additions of N,N'-
Dialkylbarbituric Acids to Enones
Received 00th January 20xx,
Accepted 00th January 20xx
Ying Liu, Yongna Zhang,* Hui-Xin Duan, Dong-Yan Wanyan and You-Qing Wang*
N,N'-Dialkylbarbituric acids as cyclic malonamide donors were successfully used in the enantioselective Michael addition
reaction of enones. Using cinchona alkaloid-based bifunctional squaramide as an organocatalyst, this Michael reaction of
N,N'-di-tert-butylbarbituric acid with various enones features a highly enantioselective (91-99% ee) production of the
corresponding optically active 5-substituted barbituric acid derivatives. The transformations of Michael product for the
barbituric acid structural unit were realized in two ways, deprotection to remove N-tert-butyl group and alkylation to
produce 5,5-disubstituted barbituric acid derivatives.
DOI: 10.1039/x0xx00000x
www.rsc.org/
synthetic organic chemistry.
Introduction
GWE
O
EWG
EWG
EWG
R
O
Chiral Catalyst
Michael addition reaction is characterized as a nucleophilic addition
reaction to electron-deficient olefins. In recent years, the catalytic
asymmetric Michael addition has made remarkable progress that
has been demonstrated by a number of examples with excellent
enantioselectivity.1 However, there still exist some challenging, such
as unexplored substrate species to be remaining to be studied, and
it is the desire to broaden the substrate scope, especially towards
the target- and diversity-oriented synthesis of the drug-like chiral
small molecules.2 Typically, active methylene compounds are being
used as the carbon nucleophiles for the addition to α,β-unsaturated
carbonyl compounds in the formation of C-C bonds producing a
chiral carbon stereocenter. As shown in Scheme 1 (EWG = Electron-
Withdrawing Group), active methylene compounds used as Michael
donors reported in the literature are mostly 1,3-dicarbonyl
derivatives including malonates,3 1,3-diketone,4 β-keto esters,3g,4a,5
dithiomalonates,6 malononitrile,4b,7 other electron-deficient
nitriles,8 and nitro esters9 etc. Meanwhile, exploring other new
Michael donors from simple, yet readily available reagents remains
a critical scientific goal. Among others, malonamide compounds
have received considerably less attention in the literature to be
used as precursors in the Michael reaction. A few examples of
precursors for the catalytic Michael addition using malonamide
compounds as substrates were previously only accessible in a
racemic manner.10-11 However, from a synthetic point of view, the
application of malonamide compounds in catalytic enantioselective
Michael reactions of enones remains an interesting topic in
+
∗
R
R
R
Various Michael Donors
Previous Work
O
O
O
O
O
O
O
O
C
C
C
O
S
S
CN
CN
R
CN
...
O
O
O
This Work: Manonamide compounds
O
X
O
R
N
N
N
N
O
up to 99% ee
O
X
O
R
Scheme 1 Catalytic asymmetric Michael reaction using various
active methylene compounds as Michael donors.
Barbituric acids, a class of organic compound based on a cyclic
malonamide skeleton, are widely distributed in varous biologically
relevant molecules.12 As a pharmacologically and physiologically
active structural unit, the development of asymmetric synthesis to
diversify chiral barbituric acid derivatives allows for the production
of large chemical libraries of potentially bioactive molecules. In
spite of the high demand for the asymmetric synthesis of chiral
barbituric acid derivatives, only
a few examples have been
described recently in the literature detailing the catalytic
asymmetric reaction of barbituric acid derivatives to achieve high
enantioselectivities (Scheme 2). Guo’s group13 as well as Zhao’s
group14 have developed the highly enantioselective annulation
reactions of barbiturate-derived alkenes to construct chiral
spirobarbiturate scaffolds through the separate use of chiral
phosphines and cinchona-based thioureas as organocatalysts. In
their works,13-14 the barbituric acid scaffold was incorporated into
an electron-deficient alkene used as an electrophilic acceptor
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subjected to nucleophilic attack by
a dipolar compound for better ee values (entry 11). Further solvent screening was
initiation of the reaction and eventually acting as a C2 synthon performed and o-xylene was found to be the best solvent for
leading to a corresponding [2+4] or [2+3] annulation (Scheme 2a). If achieving highest levels of asymmetric induction (entry 17).
N,N'-disubstituted barbituric acid could be directly used as the
substrate for the asymmetric catalytic reaction, the reaction
outcome is worth looking forward to the research. N,N'-
disubstituted barbituric acids as nucleophiles have been employed
in palladium-catalyzed allylation reactions, but with lower
enantioselectivity for most substrates and limited substrate scope
in the early stages.15 Considering that cyclic malonamide may
undergo a 1,3-prototropy process to afford a cyclic enol, we
speculated that the N,N'-disubstituted barbituric acids may
represent suitable Michael donors through organic tertiary amine
catalysis (Scheme 2b).16 In continuation of our interest in the
catalytic asymmetric addition reactions of cyclic imines to construct
OMe
OMe
N
N
CF3
iPr
O
NH
O
NH
S
N
N
S
N
CF3
H
iPr
iPr
C-1
C-2
OMe
OMe
N
N
NH
NH
chiral N-heterocycles,17 we now disclose that
a
highly
H
H
N
N
N
N
CF3
CF3
enantioselective Michael addition of N,N'-dialkylbarbituric acids as
the N-heterocycle substrates to enones18 catalyzed by cinchona
alkaloid squaramide.19
O
O
O
O
CF3
CF3
C-3
C-4
OMe
OMe
N
N
NH
NH
CF3
CF3
CF3
CF3
H
N
H
N
N
N
O
O
O
O
C-5
C-6
CF3
CF3
O
O
S
N
H
N
H
CF3
N
H
N
H
CF3
NMe2
NMe2
C-7
C-8
Figure 1 Several chiral catalysts screened.
Scheme
2 Highly enantioselective catalytic reactions for the
Table 1 Optimization of the reaction conditions.a
synthesis of chiral barbituric acid derivatives.
Results and discussion
The Michael addition between N,N'-dimethylbarbituric acid 1a and
chalcone 2a was selected as a model reaction to optimize the
reaction conditions (Table 1). Initial experiments were conducted
using commercially available quinine and quinidine as catalysts.7c,19b
Although the expected compound 3a was obtained in a good
product yield, enantioselectivity was found to be much lower
(entries 1-2). The subsequent screening of various catalysts focused
on different amine species, including modified cinchona alkaloids
and 1,2-cyclohexanediamine derivatives (Figure 1). The quinine-
derived bifunctional squaramide catalyst C-3 afforded good activity
and the best enantioselectivity with 78% ee (entry 5). Bifunctional
thiourea or squaramide catalysts containing double hydrogen bond
donors were found to be superior over hydroxyl or sulfonamide
catalysts bearing a single hydrogen bond donor (entries 4-8 vs. 1-3).
Chiral 1,2-cyclohexanediamine derived squaramide C-7 and
thiourea C-8 were both found to be efficient catalysts, providing
almost equal moderate enantioselectivities (entries 9-10). Upon
lowering the temperature to 0oC, the reaction progress required
more time for completion ensuring full conversion to produce
time
yield
(%)b
ee
entry
catalyst
solvent
T (oC)
(h)
(%)c
1
2
quinine
quinidine
C-1
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
25
25
25
25
25
25
25
25
25
25
0
1
1
68
81
57
95
88
93
81
83
63
95
78
15
<5
3
24
1
<5
4
C-2
55
5
C-3
1.5
5
78
6
C-4
-63d
7
C-5
1.5
5.5
5.5
1
47
8
C-6
-32d
55
9
C-7
10
11
C-8
58
C-3
36
81
2 | J. Name., 2012, 00, 1-3
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12
13
14
15
16
17
18
19
20
C-3
C-3
C-3
C-3
C-3
C-3
C-3
C-3
C-3
DCM
THF
0
0
0
0
0
0
0
0
0
23.5
24.5
29
57
70
70
71
80
72
36
82
70
71
63
72
78
58
88
58
62
63
bearing both electron-donating as well as electron-withdrawing
groups on the aromatic ring in different positions of R1, and in β-
position of enones 2 were shown to be compatible and furnished
the corresponding barbituric acid derivatives 4a–4m with excellent
enantioselectivities (95-98% ee) (entries 1-13). The characteristics
of R2 substituent on the carbonyl functionality of the enones were
vastly different and included para-methyl, fluoro, bromophenyl
(entries 14-16), and β-naphthyl (entry 17). Interestingly, for an
unsaturated ketone 2r with a phenyl ring bearing a hydroxyl group
as an active functional group, the Michael addition proceeded
smoothly to afford the corresponding product 4r in 91% yield with a
slightly lower ee of 91% (entry 18). Fortunately, the heteroaryl
enone was also found to tolerate the reaction conditions, affording
the desired pyridinyl Michael products 4s with excellent 99% ee
(entry 19). Enones, both bearing a variety of substituent groups on
two aromatic rings (R1 and R2), have also been shown to be suitable
Michael acceptors for this reaction (entries 20-26). These species
could be easily transformend into the corresponding barbituric acid
derivatives 4t–4z in high yields and with excellent
enantioselectivities (96-98% ee).
CH3CN
DCE
24.5
23
PhCF3
o-xylene
m-xylene
p-xylene
benzene
42
25.5
15
25
a
The reactions were conducted with 1a (0.05 mmol), 2a (0.075 mmol) and
b
c
catalyst (0.005 mmol) in 0.25 mL of solvent. Isolated yield. Determined by
d
HPLC using a chiral column. The minus ee value indicates that the opposite
enantiomer was obtained as the major form.
The effect of different N-substituents on the barbituric acids 1 for
the asymmetric Michael reaction was investigated in o-xylene using
C-3 as an organocatalyst at a temperature of 10oC. As shown in
Table 2, the obtained results suggest that N-substituents exhibit a
remarkable effect on the enantioselectivity. Among the
representative N-substituents screened, barbituric acid 1d carrying
a sterically demanding tert-butyl group, resulted in a good reactivity
and the best enantioselectivity (95% ee) for this Michael reaction,
probably due to the steric factor (entry 4). The reaction was found
to also proceed efficiently at room temperature (entry 5).
Interestingly, the different substrate ratios between 1d and enone
2a did not appear to alter the reaction results (entry 6). The
purification of product 4a from the excess of barbituric acid 1d was
Table 3. Substrate scope using different aromatic enones.a
quite tedious by column chromatography, because both Entry
R1/R2 (2)
Time (h)
4
Yield (%)b
ee (%)c
compounds have a similar Rf values on silica gel. Due to this reason,
1
C6H5/C6H5 (2a)
7
4a
4b
4c
4d
4e
4f
99
75
96
95
86
93
92
83
83
88
44
92
85
89
86
55
96
91
80
98
91
89
98
84
89
80
88
83
96
96
96
98
97
96
96
95
97
97
96
97
98
98
96
95
96
91
99
98
96
98
97
96
97
96
92
94
we chose an excess of enone (1.5 equiv) as the optimized reaction
conditions.
2
4-MeC6H4/C6H5 (2b)
4-MeOC6H4/C6H5 (2c)
3,4-(MeO)2C6H3/C6H5 (2d)
4-FC6H4/C6H5 (2e)
12
23
23
5
3
4
Table 2. Effects of different N-substituents of barbituric acids.a
5
6
4-ClC6H4/C6H5 (2f)
5
7
3-ClC6H4/C6H5 (2g)
12
30
12
24
10
12
12
12
7
4g
4h
4i
8
2-ClC6H4/C6H5 (2h)
9
4-CNC6H4/C6H5 (2i)
4-NO2C6H4/C6H5 (2j)
2-NO2C6H4/C6H5 (2k)
4-CF3C6H4/C6H5 (2l)
2-Naphthyl/C6H5 (2m)
C6H5/4-MeC6H4 (2n)
C6H5/4-FC6H4 (2o)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
4j
4k
4l
entry
R (1)
product
T (oC)
time (h)
yield (%)b
ee (%)c
4m
4n
4o
4p
4q
4r
1
2
Me (1a)
cC6H11 (1b)
Ph (1c)
3a
3b
3c
4a
4a
4a
10
10
10
10
25
25
12
20.5
33
78
95
72
90
94
99
88
94
74
95
96
96
3
C6H5/4-BrC6H4 (2p)
C6H5/2-Naphthyl (2q)
C6H5/2-OHC6H4 (2r)
C6H5/2-Pyridinyl (2s)
4-MeC6H4/4-MeC6H4 (2t)
4-ClC6H4/4-ClC6H4 (2u)
4-MeC6H4/4-MeOC6H4 (2v)
4-ClC6H4/4-MeC6H4 (2w)
4-MeOC6H4/4-ClC6H4 (2x)
4-FC6H4/4-MeOC6H4 (2y)
4-FC6H4/4-ClC6H4 (2y)
n-Pr/Ph (5a)
24
24
24
21
24
24
24
24
24
25
24
27
72
4
tBu (1d)
tBu (1d)
tBu (1d)
10
5
6
4s
4t
6d
17
a
4u
4v
4w
4x
4y
4z
6a
6b
Reaction conditions: barbituric acid
1 (0.05 mmol), 2a (0.075 mmol) and
b
c
C-3 (0.005 mmol) in o-xylene (0.25 mL) at 10°C.
Isolated yield.
Determined by HPLC using a chiral column. d Barbituric acid
1
(0.075 mmol)
and 2a (0.05 mmol) were used.
With the optimal reaction conditions established,20 the Michael
reaction of a series of aromatic enones 2 with tert-butyl substituted
barbituric acid 1d was carried out (Table 3). Various substitutions
Cyclohexyl/Ph (5b)
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29
30
31
CH2CH2Ph/Ph (5c)
35
24
24
6c
-
93
0
93
-
under standard conditions. However, six-member ring 2-
cyclohexen-1-one resulted no reaction.
Ph/Me (5d)
n-Pr/Me (5e)
-
0
-
Bu
tBu
O
t
O
a Reaction conditions: 1,3-di-tert-butylbarbituric acid 1 (0.12 mmol), 2 (0.1 mmol),
O
O
N
N
N
N
b
10 mol% C-3
o-xylene, rt
∗
and catalyst C-3 (0.001 mmol) in o-xylene (0.5 mL) at room temperature.
Isolated yield. c Determined by HPLC using a chiral column.
O
O
+
Bu
O
tBu
O
t
1d
7
The substrate scope of this reaction type could be extended to β-
alkyl substituted enones (Table 3, entries 27-29). Generally high
enantioselectivities were obtained (92-94% ee), albeit a slight ee
reduction could be observed in comparison to aromatic enones.
Three examples have been studied under optimized conditions,
84% yield, 29% ee
Scheme 3 Further substrate scope using cyclic enone as a Michael
acceptor.
Barbituric acid derivatives possessed pharmacologically active
qualities to attract the chemist’s attention to synthesize them. The
transformations centred around the barbituric acid structural unit
providing liner
n-propyl substituted 6a with 92% ee, branched
cyclohexyl substituted 6b with 94% ee, and an aryl-containing
phenylethyl substituted species 6c with 93% ee. Unfortunately, 2-
phenylvinyl methyl ketone 5d and dialkyl substituted enone 5e
were ineffective substrates for the Michael additions (Table 3,
entries 30-31).
have been realized in two ways, deprotection to remove
N-tert-
butyl group and alkylation to produce 5,5-disubstituted barbituric
acid derivatives (Scheme 4). For example, with Michael product 4a,
the tert-butyl group can be removed in the presence of AlCl3 in
On the basis of a single-crystal X-ray structure, the absolute
toluene to give chiral barbituric acid derivative 8,
compound in racemate.11c-e Compared with obtained chiral
dimethylbarbituric acid or N'-diphenylbarbituric acid derivatives
a
known
configuration of product 4w was determined to be
S
(Figure 2).21
N
,N'-
The cinchona alkaloid derivative C-3 that combine a tertiary amine
N
,
group with Brønsted base and squaramide with hydrogen-bond
that was not cleaved its nitrogen protective group in the
literatures,13-14,16 the removal of tert-butyl group from nitrogen is
easier than methyl or phenyl group.22 The Michael product 4a also
could be transformed to methylation 5,5-disubstituted barbituric
acid derivative 9. These transformations can completely retain their
optical purity, and provides an efficient pathway to the synthesis of
some optically active barbituric acid derivatives with molecular
diversity.
donor may act as
a bifunctional organocatalyst. A proposed
transition-state model for the Michael reaction is shown in Figure 3,
and Re-face attack of barbituric acid 1d in β-position of the acyclic
enones was found to be favored. Provided the same reaction
behaviour of this catalytic system takes place in all substrate
species, by analogy the configuration of all other Michael products
4 and 6 could be assigned.
Cl
O
HN
HN
Ph
AlCl3
O
O
toluene, rt
tBu
tBu
O
O
N
O
N
N
Ph
O
Ph
N
8
(S)
O
O
60% yield, 96% ee
O
O
O
Ph
tBu
O
4a
N
N
Ph
4w
CH3I, K2CO3
acetone, rt
=
96% ee
O
O
Figure 2 X-ray structure of product 4w.
Me
tBu
O
Ph
OMe
9
58% yield, 96% ee
N
Scheme 4 Transformation of Michael product 4a.
Bu
t
N
N
H
O
N
N
O
O
R2
N
Conclusions
tBu
O
In conclusion, we have developed a highly enantioselective
Michael addition of 1,3-di-tert-butyl barbituric acid to various
enones by using a bifunctional cinchona alkaloid-squaramide
O
R1
Re-face attack
organocatalyst.
A variety of enones bearing different
F3C
CF3
substituents, including aryl, heteroaryl and alkyl groups, were
found to be suitable. This study extends the scope of the
catalytic asymmetric Michael addition with interesting
biologically active molecules, providing novel and efficient
access to a series of optically active 5-substituted barbituric
acid derivatives.
Figure 3 Proposed transition state for the Michael reaction.
In addition, cyclic enones may also be used in the Michael
addition using the
N,N'-dialkylbarbituric acid, albeit with a much
lower enantioselectivity. As shown in Scheme 3, the reaction of 1d
with 2-cyclopentenone afforded product 7 in 84% yield with 29% ee
4 | J. Name., 2012, 00, 1-3
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enantiomeric excess was determined by HPLC. Racemic samples
Experimental
were prepared from
catalyzed by Et2NH.11b
N,N'-dialkylbarbituric acids and enones
General.
1H NMR, and 13C NMR spectra were recorded on 300 MHz Bruker
spectrometers. Chemical shifts were recorded in ppm (δ), and the
residual solvent peak was used as an internal reference: proton
(chloroform δ 7.26), carbon (chloroform δ 77.0). Flash column
chromatography was performed on silica gel (200-300 mesh). TLC
analysis was performed using glass-backed plates coated with 0.2
mm silica. After elution, plate was visualized under at 254 nm UV
illumination. The following abbreviations were used for elution
solvents: PE = petroleum ether, EA = ethyl acetate. All commercially
available compounds were used as provided without further
purification. The solvents were distilled from appropriate drying
(S)-1,3-dimethyl-5-(3-oxo-1,3-diphenylpropyl)pyrimidine-
2,4,6(1H,3H,5H)-trione (3a). Known compound in racemate;11b Rf =
1
0.6 (PE:EA/2:1); 87% ee, [α]23 = 13.9 (c 0.60, CHCl3); H NMR (300
D
MHz, CDCl3): δ = 8.02 (d, J = 7.4 Hz, 2H), 7.58-7.45 (m, 3H), 7.26 (s,
3H), 7.10 (s, 2H), 4.36 (s, 1H), 4.13-3.99 (m, 2H), 3.57-3.49 (m, 1H),
3.11 (s, 3H), 3.05 (s, 3H); HPLC (Lux Amylose-2 column,
CH3CN/H2O/TFA = 50/50/0.1, 1.0 mL/min, 254 nm): t1 = 11.8 min
(minor), t2 = 13.4 min (major, S).
(S)-1,3-dicyclohexyl-5-(3-oxo-1,3-diphenylpropyl)pyrimidine-
2,4,6(1H,3H,5H)-trione (3b). Colorless oil, 27.0 mg, 99% yield; Rf =
agents prior to use, unless otherwise noted. Copies of H, 13C NMR
1
1
0.6 (PE:EA/5:1); 94% ee, [α]13 = 8.69 (c 0.46, CHCl3); H NMR (300
D
spectra and HPLC chromatograms are available in the
Supplementary information.
MHz, CDCl3): δ = 8.11 (d,
J = 7.4 Hz, 2H), 7.66-7.35 (m, 3H), 7.34-
7.26 (m, 5H), 4.63-4.46 (m, 3H), 4.22-4.14 (m, 1H), 3.99 (s, 1H),
3.67-3.59 (m, 1H), 2.26-1.24 (m, 20H); 13C NMR (75 MHz, CDCl3): δ =
197.8, 168.5, 168.1, 150.5, 138.3, 136.8, 133.3, 128.8, 128.6, 128.1,
55.1, 55.0, 52.9, 44.3, 41.0, 29.1, 28.9, 28.7, 28.6, 26.4, 26.3, 26.2,
26.1, 25.2; HRMS (ESI): m/z calcd for C31H37N2O4+ [M+H]+ 501.2748,
found: 501.2749; HPLC (Chiralpak AD-H column, hexane/iPrOH =
95/5, 0.7 mL/min, 254 nm): t1 = 34.1 min (minor), t2 = 35.4 min
(major, S).
Preparation of barbituric acids derivatives.
Barbituric acid 1b was synthesized from DCC and malonic acid
according to the procedures reported in the literature.23 Barbituric
acids 1c and 1d were synthesized from malonyl chloride and
corresponding substituted urea according to the following
procedures.
1,3-Diphenyl-pyrimidine-2,4,6-trione (1c). To a mixture of
N,N'-
5-(3-oxo-1,3-diphenylpropyl)-1,3-diphenylpyrimidine-
diphenylurea (2 mmol, 424.5 mg) in CHCl3 (6 mL) was added the
malonyl chloride (2.4 mmol, 338.3 mg). This reaction mixture stirred
was refluxed for 4 hours. This reaction mixture was extracted with
DCM then the organic layer was dried over Na2SO4. After filtration
to collect filtrate and concentration under reduced pressure,
further purification by column chromatography on a silica gel
(PE/EA) gave the desired product 1c as yellow solid, 343.1 mg, 62%
2,4,6(1H,3H,5H)-trione (3c). Known compound in racemate;26 Rf =
0.7 (PE:EA/2:1); 74% ee, [α]13 = 8.35 (c 1.38, CHCl3); H NMR (300
1
D
MHz, CDCl3): δ = 7.99 (d,
J = 7.6 Hz, 2H), 7.56-7.39 (m, 14H), 7.12 (d,
J
= 6.9 Hz, 2H), 6.91 (m, 2H), 4.57 (s, 1H), 4.39 (s, 1H), 4.22-3.13 (m,
1H), 3.62-3.56 (m, 1H); 13C NMR (75 MHz, CDCl3): δ = 198.0, 167.8,
167.7, 150.4, 138.9, 136.7, 133.9, 133.4, 129.4, 129.3, 129.2, 129.0,
128.7, 128.3, 128.2, 128.1, 52.9, 44.3, 40.7; HPLC (Chiralpak AD-H
column, hexane/iPrOH = 70/30, 1.0 mL/min, 254 nm): t1 = 46.2 min
1
yield; known compound,24 Rf = 0.5 (PE:EA/2:1); H NMR (300 MHz,
CDCl3): δ = 7.50-7.48 (m, 6H), 7.25 (d, J = 6.8 Hz, 4H), 3.97 (s, 2H);
13C NMR (75 MHz, CDCl3): δ =164.5, 151.2, 133.9, 129.5, 129.4,
(minor), t2 = 70.5 min (major, S).
(S)-1,3-di-tert-butyl-5-(3-oxo-1,3-diphenylpropyl)pyrimidine-
128.4, 40.4.
2,4,6(1H,3H,5H)-trione (4a). Colorless oil, 44.4 mg, 99% yield; Rf =
1,3-Di-tert-butyl-pyrimidine-2,4,6-trione (1d). To a mixture of N,N'
-
0.7 (DCM); 96% ee, [α]13 = 8.35 (c 1.38, CHCl3); H NMR (300 MHz,
1
D
di(tert-butyl)urea (8.0 mmol, 1.3782 g) in CHCl3 (30 mL) was added
the malonyl chloride (9.6 mmol, 0.93 ml). This reaction mixture
stirred was refluxed for 4 hours. HCl (1 M) were added to reaction
mixture. This reaction mixture was extracted with DCM then the
organic layer was dried over Na2SO4. After filtration to collect
filtrate and concentration under reduced pressure, further
purification by column chromatography on a silica gel (PE/EA) gave
the desired product 1d as white solid, 984.1 mg, 51% yield; known
compound,25 Rf = 0.6 (PE:EA/5:1); 1H NMR (300 MHz, CDCl3): δ =
3.46 (s, 2H), 1.59 (s, 18H); 13C NMR (75 MHz, CDCl3): δ =164.5,
153.6, 62.0, 43.8, 29.2.
CDCl3): δ = 7.95 (d, J = 7.7 Hz, 2H), 7.52-7.37 (m, 3H), 7.20-7.14 (m,
5H), 4.23 (s, 1H), 4.06-3.97 (m, 1H), 3.66-3.48 (m, 2H), 1.40 (s, 9H),
1.38 (s, 9H); 13C NMR (75 MHz, CDCl3): δ = 197.7, 167.7, 167.1,
152.5, 138.4, 136.9, 133.2, 128.8, 128.6, 128.3, 128.1, 62.0, 61.9,
+
55.5, 43.6, 41.3, 29.1, 29.0; HRMS (ESI): m/z calcd for C27H33N2O4
[M+H]+ 449.2435, found: 449.2434; HPLC (Chiralpak IC-H column,
hexane/iPrOH = 70/30, 1.0 mL/min, 254 nm): t1 = 8.7 min (minor), t2
= 12.6 min (major, S).
(S)-1,3-di-tert-butyl-5-(3-oxo-3-phenyl-1-(p-
tolyl)propyl)pyrimidine-2,4,6(1H,3H,5H)-trione (4b). Yellow oil,
34.7 mg, 75% yield; Rf = 0.8 (DCM); 96% ee, [α]13 = 37.3 (c 1.44,
D
1
CHCl3); H NMR (300 MHz, CDCl3): δ = 8.00 (t,
J
= 7.7 Hz, 2H), 7.47-
Typical procedure for catalytic asymmetric Mannich reaction. To a
mixture of C-3 (0.01 mmol, 10 mol%) and barbituric acid derivative
7.42 (m, 3H), 7.06 (s, 1H), 4.24 (s, 1H), 4.08-3.99 (m, 1H), 3.69 (s,
1H), 3.58-3.50 (m, 1H), 2.30 (s, 3H), 1.47 (s, 9H), 1.45 (s, 9H); 13C
NMR (75 MHz, CDCl3): δ = 197.8, 167.9, 167.3, 152.4, 137.7, 137.0,
135.4, 133.1, 129.4, 128.6, 128.1, 61.9, 55.7, 43.2, 41.5, 29.1, 29.0,
1 (0.1 mmol) in o-xylene (0.5 mL) was added enone 2 or 5 (0.075
mmol). The reaction mixture was stirred at room temperature.
Direct purification reaction mixture by column chromatography on
a silica gel (PE, EA or DCM) to afford the desired products. The
+
21.2; HRMS (ESI): m/z calcd for C28H35N2O4 [M+H]+ 463.2590,
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
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DOI: 10.1039/C7OB02116J
ARTICLE
found: 463.2590; HPLC (Chiralpak IC-H column, hexane/iPrOH = CHCl3); 1H NMR (300 MHz, CDCl3): δ = 8.02 (d,
Journal Name
J
= 6.2 Hz, 2H), 7.57-
70/30, 1.0 mL/min, 254 nm): t1 = 8.3 min (minor), t2 = 12.2 min 7.47 (m, 3H), 7.26-7.09 (m, 4H), 4.30 (s, 1H), 4.09-4.01 (m, 1H),
(major,
S
).
3.69-3.59 (m, 2H), 1.49 (s, 9H), 1.47 (s, 9H); 13C NMR (75 MHz,
CDCl3): δ = 197.3, 167.3, 166.6, 152.5, 140.4, 136.7, 134.7, 133.3,
(S)-1,3-di-tert-butyl-5-(1-(4-methoxyphenyl)-3-oxo-3-
phenylpropyl)pyrimidine-2,4,6(1H,3H,5H)-trione (4c). Colorless oil, 130.2, 126.6, 62.2, 55.1, 43.3, 41.0, 29.1, 29.0; HRMS (ESI): m/z
+
46.0 mg, 96% yield; Rf = 0.7 (DCM); 96% ee, [α]13 = 35.0 (c 1.49, calcd for C27H32ClN2O4 [M+H]+ 483.2045, found: 483.2044; HPLC
D
1
CHCl3); H NMR (300 MHz, CDCl3): δ = 8.00 (d,
J
= 7.5 Hz, 2H), 7.57- (Chiralpak IC-H column, hexane/iPrOH = 70/30, 1.0 mL/min, 254
= 8.4 Hz, 2H), 4.24 (s, nm): t1 = 6.3 min (minor), t2 = 9.8 min (major, ).
= 3.75 Hz, 1H), 3.59- (S)-1,3-di-tert-butyl-5-(1-(2-chlorophenyl)-3-oxo-3-
7.42 (m, 3H), 7.10 (d,
J
= 8.4 Hz, 2H), 6.77 (d,
J
S
1H), 4.06-3.97 (m, 1H), 3.76 (s, 3H), 3.67 (d,
J
3.51 (m, 1H), 1.47 (s, 9H), 1.45 (s, 9H); 13C NMR (75 MHz, CDCl3): δ = phenylpropyl)pyrimidine-2,4,6(1H,3H,5H)-trione (4h). Colorless oil,
197.8, 167.8, 167.2, 159.4, 152.3, 136.9, 133.1, 130.3, 129.4, 128.6, 40.2 mg, 83% yield; Rf = 0.7 (DCM); 95% ee, [α]22 = 18.2 (c 0.43,
D
128.1, 114.1, 61.9, 61.8, 55.9, 55.3, 42.9, 41.6, 29.1, 29.0; HRMS CHCl3); 1H NMR (300 MHz, CDCl3): δ = 7.95 (d,
J
= 7.6 Hz, 2H), 7.54-
(ESI): m/z calcd for C28H35N2O5 [M+H]+ 479.2541, found: 479.2541; 7.34 (m, 5H), 7.20 (s, 2H); 4.82 (d,
J
= 6.1 Hz, 1H), 3.92-3.78 (m, 2H),
+
HPLC (Chiralpak IC-H column, hexane/iPrOH = 70/30, 1.0 mL/min, 3.58-3.50 (m, 2H), 1.52 (s, 9H), 1.47 (s, 9H); 13C NMR (75 MHz,
254 nm): t1 = 9.7 min (minor), t2 = 19.8 min (major,
S).
CDCl3): δ = 197.2, 167.5, 167.1, 152.9, 137.5, 136.5, 133.3, 130.2,
(S)-1,3-di-tert-butyl-5-(1-(3,4-dimethoxyphenyl)-3-oxo-3-
129.1, 128.8, 128.6, 128.1, 127.2, 62.2, 62.1, 55.8, 41.9, 38.7, 29.2,
+
phenylpropyl)pyrimidine-2,4,6(1H,3H,5H)-trione (4d). Colorless oil, 29.1; HRMS (ESI): m/z calcd for C27H32ClN2O4 [M+H]+ 483.2045,
48.3 mg, 98% yield; Rf = 0.5 (DCM); 98% ee, [α]22 = 16.9 (c 0.44, found: 483.2044; HPLC (Chiralpak IC-H column, hexane/iPrOH =
D
1
CHCl3); H NMR (300 MHz, CDCl3): δ = 8.00 (d,
J
= 7.6 Hz, 2H), 7.57- 70/30, 1.0 mL/min, 254 nm): t1 = 6.7 min (minor), t2 = 11.7 min
= 7.0 Hz, 3H), 4.24 (s, 1H), 4.01-3.97 (m, 1H), (major, ).
= 5.5 Hz, 6H), 3.69 (d,
7.42 (m, 3H), 6.72 (d,
J
S
3.82 (d,
J
J = 2.9 Hz, 1H), 3.60-3.52 (m, 1H), (S)-4-(1-(1,3-di-tert-butyl-2,4,6-trioxohexahydropyrimidin-5-yl)-3-
1.47 (s, 9H), 1.45 (s, 9H); 13C NMR (75 MHz, CDCl3): δ = 197.9, 167.8, oxo-3-phenylpropyl) benzoin-trile (4i). Colorless oil, 39.4 mg, 83%
167.3, 152.3, 148.8, 136.9, 133.2, 131.1, 128.6, 128.1, 120.2, 111.9, yield; Rf = 0.7 (DCM); 97% ee, [α]13 = 31.5 (c 2.0, CHCl3); 1H NMR
D
111.4, 61.8, 61.7, 56.0, 55.9, 55.8, 43.1, 41.8, 29.1, 29.0; HRMS (300 MHz, CDCl3): δ = 7.90 (d,
J = 7.5 Hz, 2H), 7.49-7.36 (m, 5H),
(ESI): m/z calcd for C29H37N2O6+ [M+H]+ 509.2646, found: 509.2646. 7.25 (s, 1H), 7.18 (s, 1H); 4.32-4.20 (m, 1H), 3.97-3.88 (m, 1H), 3.65-
HPLC (Chiralpak IC-H column, hexane/iPrOH = 70/30, 1.0 mL/min, 3.56 (m, 2H), 1.39 (s, 9H), 1.37 (s, 9H); 13C NMR (75 MHz, CDCl3): δ =
254 nm): t1 = 13.1 min (minor), t2 = 42.9 min (major,
S
).
197.1, 166.9, 166.6, 152.3, 144.4, 136.4, 133.5, 132.5, 128.7, 128.1,
118.6, 111.9, 62.3, 62.2, 55.2, 43.0, 41.1, 29.0, 28.9; HRMS (ESI):
(S)-1,3-di-tert-butyl-5-(1-(4-fluorophenyl)-3-oxo-3-
phenylpropyl)pyrimidine-2,4,6(1H,3H,5H)-trione (4e). Colorless oil, m/z calcd for C28H32N3O4+ [M+H]+ 474.2387, found: 474.2386; HPLC
40.0 mg, 86% yield; Rf = 0.8 (DCM); 97% ee, [α]22 = 25.4 (c 0.37, (Chiralpak IC-H column, hexane/iPrOH = 70/30, 1.0 mL/min, 254
D
1
CHCl3); H NMR (300 MHz, CDCl3): δ = 8.00 (d,
J
= 7.7 Hz, 2H), 7.58- nm): t1 = 11.5 min (minor), t2 = 16.1 min (major,
S).
7.43 (m, 3H), 7.16 (t,
J
= 6.1 Hz, 2H), 6.94 (t,
J
= 8.0 Hz, 2H), 4.30 (s, (S)-1,3-di-tert-butyl-5-(1-(4-nitrophenyl)-3-oxo-3-
1H), 4.06-3.97 (m, 1H), 3.67-3.54 (m, 2H), 1.47 (s, 9H), 1.45 (s, 9H); phenylpropyl)pyrimidine-2,4,6(1H,3H,5H)-trione (4j). White solid,
1
13C NMR (75 MHz, CDCl3): δ = 197.5, 167.5, 167.0, 162.5 (d, JC-F
=
43.5 mg, 96% yield; Rf = 0.7 (DCM); mp: 151-152 oC; 97% ee, [α]13
=
D
4
3
1
246.9 Hz), 152.4, 134.3 (d, JC-F = 3.4 Hz), 130.0 (d, JC-F = 8.1 Hz), 32.0 (c 3.55, CHCl3); H NMR (300 MHz, CDCl3): δ = 8.12 (d,
J
= 8.2
= 14.3 Hz, 1H), 7.48-7.40
= 2.34 Hz, 1H), 4.06-3.98 (m, 1H), 3.77-3.70 (m,
2
128.6, 128.1, 115.7 (d, JC-F = 21.3 Hz), 62.0, 61.9, 55.6, 42.8, 41.5, Hz, 2H), 7.98 (d,
29.1, 29.0; HRMS (ESI): m/z calcd for C29H37N2O6 [M+H]+ 509.2646, (m, 4H), 4.44 (d,
found: 509.2646; HPLC (Chiralpak IC-H column, hexane/iPrOH = 2H), 1.47 (s, 9H), 1.45 (s, 9H); 13C NMR (75 MHz, CDCl3): δ = 197.1,
J
= 7.5 Hz, 2H), 7.57 (t,
J
+
J
70/30, 1.0 mL/min, 254 nm): t1 = 5.9 min (minor), t2 = 9.3 min 166.8, 166.5, 152.3, 147.5, 146.5, 136.4, 133.5, 128.1, 123.9, 62.3,
(major,
S
).
62.3, 55.2, 42.8, 41.2, 29.0, 28.9; HRMS (ESI): m/z calcd for
C27H32N3O6+ [M+H]+ 494.2286, found: 494.2284; HPLC (Chiralpak IC-
(S)-1,3-di-tert-butyl-5-(1-(4-chlorophenyl)-3-oxo-3-
phenylpropyl)pyrimidine-2,4,6(1H,3H,5H)-trione (4f). Colorless oil, H column, hexane/iPrOH = 70/30, 1.0 mL/min, 254 nm): t1 = 7.7 min
45.0 mg, 93% yield; Rf = 0.6 (DCM); 96% ee, [α]23 = 26.5 (c 0.40, (minor), t2 = 9.7 min (major,
S
).
D
1
CHCl3); H NMR (300 MHz, CDCl3): δ = 8.00 (d,
J
= 7.5 Hz, 2H), 7.58- (S)-1,3-di-tert-butyl-5-(1-(2-nitrophenyl)-3-oxo-3-
7.43 (m, 3H), 7.24-7.13 (m, 4H); 4.28 (s, 1H), 4.05-3.96 (m, 1H), phenylpropyl)pyrimidine-2,4,6(1H,3H,5H)-trione (4k). Colorless oil,
3.67-3.54 (m, 2H), 1.48 (s, 9H), 1.46 (s, 9H); 13C NMR (75 MHz, 21.5 mg, 44% yield; Rf = 0.8 (DCM); 96% ee, [α]13 = 35.0 (c 1.49,
D
1
CDCl3): δ = 197.5, 167.4, 167.9, 152.3, 137.2, 136.7, 133.3, 129.7, CHCl3); H NMR (300 MHz, CDCl3): δ = 8.16-7.99 (m, 4H), 7.58-7.45
128.9, 128.6, 128.1, 62.1, 62.0, 55.5, 42.7, 41.4, 29.1, 29.0; HRMS (m, 5H), 4.50-4.42 (m,1H), 4.11-4.03 (m, 1H), 3.76-3.68 (m, 2H),
(ESI): m/z calcd for C27H32ClN2O4 [M+H]+ 483.2045, found: 1.44 (s, 18H); 13C NMR (75 MHz, CDCl3): δ = 197.1, 166.9, 166.3,
+
483.2046; HPLC (Chiralpak IC-H column, hexane/iPrOH = 70/30, 1.0 152.5, 148.4, 140.9, 133.5, 128.1, 123.1,123.0 62.4, 55.2, 42.8, 41.2,
mL/min, 254 nm): t1 = 5.4 min (minor), t2 = 8.0 min (major,
S).
29.0, 28.9; HRMS (ESI): m/z calcd for C27H32N3O6+ [M+H]+ 494.2286,
(S)-1,3-di-tert-butyl-5-(1-(3-chlorophenyl)-3-oxo-3-
found: 494.2285; HPLC (Chiralpak IC-H column, hexane/iPrOH =
phenylpropyl)pyrimidine-2,4,6(1H,3H,5H)-trione (4g). Colorless oil, 70/30, 1.0 mL/min, 254 nm): t1 = 7.1 min (minor), t2 = 9.2 min
44.3 mg, 92% yield; Rf = 0.7 (DCM); 96% ee, [α]22 = 25.2 (c 0.4, (major,
S
).
D
6 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C7OB02116J
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ARTICLE
(S)-1,3-di-tert-butyl-5-(3-oxo-3-phenyl-1-(4-
128.9, 128.4, 128.3, 128.2, 62.0, 61.9, 55.3, 43.6, 41.2, 29.1, 28.0;
+
(trifluoromethyl)phenyl)propyl)pyrimidine-2,4,6(1H,3H,5H)-trione
(4l). Colorless oil, 47.5 mg, 92% yield; Rf = 0.7 (DCM); 97% ee, [α]25
= 37.8 (c 0.79, CHCl3); 1H NMR (300 MHz, CDCl3): δ = 7.99 (d,
J = 7.5 mL/min, 254 nm): t1 = 9.1 min (minor), t2 = 14.1 min (major, S).
HRMS (ESI): m/z calcd for C27H32BrN2O4 [M+H]+ 527.1540, found:
527.1540; HPLC (Chiralpak IC-H column, hexane/iPrOH = 70/30, 1.0
D
Hz, 2H), 7.59-7.33 (m, 7H), 4.38 (s, 1H), 4.08-4.00 (m, 1H), 3.70-3.62 (S)-1,3-di-tert-butyl-5-(3-(naphthalen-2-yl)-3-oxo-1-
(m, 2H), 1.46 (s, 9H), 1.44 (s, 9H); 13C NMR (75 MHz, CDCl3): δ = phenylpropyl)pyrimidine-2,4,6(1H,3H,5H)-trione (4q). Colorless oil,
197.3, 167.2, 166.8, 152.2, 142.9, 136.6, 133.4, 130.0, 128.1, 125.7, 48.0 mg, 96% yield; Rf = 0.7 (DCM); 96% ee, [α]13 = 68.5 (c 2.8,
D
125.6, 122.2, 65.6, 62.2, 62.1, 55.4, 42.9, 41.3, 30.6, 29.0, 28.9, CHCl3); 1H NMR (300 MHz, CDCl3): δ = 8.56 (s, 1H), 8.07-7.86 (m,
+
19.2, 13.7; HRMS (ESI): m/z calcd for C28H32F3N2O4 [M+H]+ 4H), 7.62-7.52 (m, 2H), 7.26 (s, 5H), 4.36 (s, 1H), 4.25-4.16 (m, 1H),
517.2309, found: 517.2305; HPLC (Chiralpak IC-H column, 3.78-3.70 (m, 2H), 1.48 (s, 9H), 1.46 (s, 9H); 13C NMR (75 MHz,
hexane/iPrOH = 70/30, 1.0 mL/min, 254 nm): t1 = 4.3 min (minor), t2 CDCl3): δ = 197.6, 167.7, 167.1, 152.5, 138.4, 135.7, 134.3, 132.5,
= 6.3 min (major,
S
).
129.8, 129.6, 128.8, 128.4, 128.1, 127.8, 126.7, 123.9, 62.0, 61.9,
+
(S)-1,3-di-tert-butyl-5-(1-(naphthalen-2-yl)-3-oxo-3-
55.6, 43.8, 41.4, 29.1, 29.0; HRMS (ESI): m/z calcd for C31H35N2O4
phenylpropyl)pyrimidine-2,4,6(1H,3H,5H)-trione (4m). Colorless [M+H]+ 499.2591, found: 499.2590; HPLC (Chiralpak IC-H column,
oil, 42.3 mg, 85% yield; Rf = 0.8 (DCM); 98% ee, [α]16D = 59.6 (c 1.50, hexane/iPrOH = 70/30, 1.0 mL/min, 254 nm): t1 = 13.3 min (minor),
1
CHCl3); H NMR (300 MHz, CDCl3): δ = 8.03 (d,
J
= 7.5 Hz, 2H), 7.78- t2 = 22.0 min (major,
S
).
7.31 (m, 10H), 4.48 (s, 1H), 4.22-4.13 (m, 1H), 3.79-3.67 (m, 2H), (S)-1,3-di-tert-butyl-5-(3-(2-hydroxyphenyl)-3-oxo-1-
1.42 (s, 9H), 1.39 (s, 9H); 13C NMR (75 MHz, CDCl3): δ = 197.7, 167.7, phenylpropyl)pyrimidine-2,4,6(1H,3H,5H)-trione (4r). Colorless oil,
167.1, 152.3, 136.9, 136.0, 133.2, 133.1, 133.0, 128.7, 128.6, 128.2, 42.2 mg, 91% yield; Rf = 0.8 (DCM); 91% ee, [α]13 = 11.3 (c 2.2,
D
1
127.7, 127.3, 126.3, 126.1, 61.9, 61.8, 55.7, 43.7, 41.5, 29.1, 29.0; CHCl3); H NMR (300 MHz, CDCl3): δ = 12.14 (s, 1H), 7.90 (d,
J
= 8.0
= 7.7 Hz, 1H), 7.28-7.16 (m, 5H), 6.97-6.89 (m,
499.2590; HPLC (Chiralpak IC-H column, hexane/iPrOH = 70/30, 1.0 2H), 4.28-4.14 (m, 2H), 3.70-3.36 (m, 2H), 1.45 (s, 18H); 13C NMR (75
HRMS (ESI): m/z calcd for C31H35N2O4 [M+H]+ 499.2591, found: Hz, 1H), δ = 7.46 (t,
J
+
mL/min, 254 nm): t1 = 10.0 min (minor), t2 = 19.0 min (major,
S).
MHz, CDCl3): δ = 203.9, 167.6, 166.9, 162.4, 152.4, 137.9, 136.5,
(S)-1,3-di-tert-butyl-5-(3-oxo-1-phenyl-3-(p-
129.9, 128.9, 128.3, 128.2, 119.5, 119.0, 118.5, 62.1, 62.0, 55.2,
+
tolyl)propyl)pyrimidine-2,4,6(1H,3H,5H)-trione (4n). Colorless oil, 43.2, 40.6, 29.2, 29.0, 28.9; HRMS (ESI): m/z calcd for C27H33N2O5
41.1 mg, 89% yield; Rf = 0.8 (DCM); 98% ee, [α]13 = 46.7 (c 2.37, [M+H]+ 465.2384, found: 465.2384; HPLC (Chiralpak IC-H column,
D
1
CHCl3); H NMR (300 MHz, CDCl3): δ = 7.91 (d,
J
= 8.0 Hz, 2H), 7.26- hexane/iPrOH = 70/30, 1.0 mL/min, 254 nm): t1 = 5.2 min (minor), t2
= 3.5 Hz, 1H), = 23.5 min (major, ).
7.20 (m, 7H), 4.29 (s, 1H), 4.08-3.99 (m, 1H), 3.71 (d,
3.61-3.52 (m, 1H), 2.40 (s, 3H), 1.47 (s, 9H), 1.45 (s, 9H); 13C NMR (S)-1,3-di-tert-butyl-5-(3-oxo-1-phenyl-3-(pyridin-2-
J
S
(75 MHz, CDCl3): δ = 197.3, 167.7, 167.1, 152.5, 143.9, 138.5, 134.5, yl)propyl)pyrimidine-2,4,6(1H,3H,5H)-(trione (4s). Colorless oil,
129.3, 128.8, 128.3, 128.2, 128.0 , 62.0, 61.9, 55.6, 43.7, 41.1, 29.1, 35.8 mg, 80% yield; Rf = 0.3 (DCM); 99% ee; [α]25 = 13.4 (c 0.2,
D
+
1
29.0, 21.7; HRMS (ESI): m/z calcd for C28H35N2O4 [M+H]+ 463.2591, CHCl3); H NMR (300 MHz, CDCl3): δ = 8.70 (d,
J
= 3.5 Hz, 1H), 8.00
found: 463.2590; HPLC (Chiralpak IC-H column, hexane/iPrOH = (d, J = 7.7 Hz, 1H), 7.80 (t, J = 7.7 Hz, 1H), 7.47-7.43 (m, 1H), 7.26-
70/30, 1.0 mL/min, 254 nm): t1 = 11.6 min (minor), t2 = 19.6 min 7.22 (m, 5H), 4.29-4.20 (m, 2H), 3.97-3.87 (m, 1H), 3.77 (s, 1H), 1.45
(major,
S
).
(s, 18H); 13C NMR (75 MHz, CDCl3): δ = 199.5, 167.8, 166.7, 153.2,
(S)-1,3-di-tert-butyl-5-(3-(4-fluorophenyl)-3-oxo-1-
152.6, 149.0, 138.4, 136.8, 128.7, 128.5, 128.0, 121.8, 61.9, 61.9,
+
phenylpropyl)pyrimidine-2,4,6(1H,3H,5H)-trione (4o). Colorless oil, 55.7, 43.7, 40.6, 29.1, 29.0; HRMS (ESI): m/z calcd for C26H32N3O4
38.4 mg, 86% yield; Rf = 0.6 (DCM); 96% ee, [α]13 = 24.5 (c 0.69, [M+H]+ 450.2387, found: 450.2385; HPLC (Chiralpak IC-H column,
D
1
CHCl3); H NMR (300 MHz, CDCl3): δ = 8.03 (t,
J
= 6.4 Hz, 2H), 7.26- hexane/iPrOH = 70/30, 1.0 mL/min, 254 nm): t1 = 11.4 min (minor),
7.09 (m, 7H), 4.27 (s, 1H), 4.10-4.00 (m, 1H), 3.69 (s, 1H), 3.57-3.45 t2 = 23.6 min (major,
S
).
(m, 1H), 1.46 (s, 9H), 1.44 (s, 9H); 13C NMR (75 MHz, CDCl3): δ = (S)-1,3-di-tert-butyl-5-(3-oxo-1,3-di-p-tolylpropyl)pyrimidine-
1
196.2, 167.6, 167.1, 159.87 (d, JC-F = 260.3 Hz), 152.5, 138.3, 133.4 2,4,6(1H,3H,5H)-trione (4t). white solid, 46.7 mg, 98% yield; Rf = 0.6
4
1
(d, JC-F = 2.7 Hz), 130.8 (d, 3JC-F = 9.3 Hz), 128.9, 128.3, 128.2, 115.7 (DCM); mp: 145.6-145.8 oC; 98% ee, [α]13 = 9.3 (c 0.83, CHCl3); H
D
2
(d, JC-F = 22.0 Hz), 62.0, 61.9, 55.4, 43.6, 41.2, 29.01, 29.0; HRMS NMR (300 MHz, CDCl3): δ = 8.10 (d,
J
= 7.5 Hz, 2H), 7.44 (d,
J
= 8.1
(ESI): m/z calcd for C27H32FN2O4 [M+H]+ 467.2341, found: Hz, 2H), 7.26 (s, 3H), 4.24-4.16 (m, 1H), 3.88 (s, 1H), 3.77-3.69 (m,
467.2341; HPLC (Chiralpak IC-H column, hexane/iPrOH = 70/30, 1.0 1H), 2.60 (s, 3H), 2.51 (s, 3H), 1.67 (s, 9H), 1.65 (s, 9H); 13C NMR (75
+
mL/min, 254 nm): t1 = 7.3 min (minor), t2 = 9.7 min (major,
S).
MHz, CDCl3): δ = 197.4, 167.8, 166.3, 152.4, 143.9, 137.7, 135.5,
(S)-5-(3-(4-bromophenyl)-3-oxo-1-phenylpropyl)-1,3-di-tert-
134.5, 129.4, 129.2, 128.2, 128.1, 61.9, 61.8, 55.8, 43.3, 41.4, 29.1,
butylpyrimidine-2,4,6(1H,3H,5H)-trione (4p). Colorless oil, 29.2 mg, 29.0, 21.7, 21.2; HRMS (ESI): m/z calcd for C29H37N2O4 [M+H]+
+
55% yield; Rf = 0.7 (DCM); 95% ee, [α]23 = 39.0 (c 0.2, CHCl3); 1H 477.2748, found: 477.2746; HPLC (Chiralpak IC-H column,
D
NMR (300 MHz, CDCl3): δ = 7.87 (d,
J
= 7.6 Hz, 2H), 7.59 (d,
J
= 7.5 hexane/iPrOH = 70/30, 1.0 mL/min, 254 nm): t1 = 12.4 min (minor),
).
Hz, 2H), 7.30-7.16 (m, 5H), 4.26 (s, 1H), 4.08-4.00 (m, 1H), 3.68 (s, t2 = 27.2 min (major,
1H), 3.56-3.48 (m, 1H), 1.46 (s, 9H), 1.43 (s, 9H); 13C NMR (75 MHz, (S)-5-(1,3-bis(4-chlorophenyl)-3-oxopropyl)-1,3-di-tert-
S
CDCl3): δ = 196.8, 167.5, 167.0, 152.5, 138.1, 135.6, 131.9, 129.7, butylpyrimidine-2,4,6(1H,3H,5H)-trione (4u). Colorless oil, 47.1 mg,
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1
91% yield; Rf = 0.6 (DCM); 96% ee, [α]13 = 43.2 (c 1.8, CHCl3); 1H 115.5 (d, JC-F = 212.0 Hz) 113.7, 62.0, 61.9, 55.5, 42.9, 41.1, 29.1,
D
+
NMR (300 MHz, CDCl3): δ = 8.08 (d,
J
= 7.6 Hz, 2H), 7.58 (d,
J
= 7.6 29.0; HRMS (ESI): m/z calcd for C28H34FN2O5 [M+H]+ 497.2446,
Hz, 2H), 7.39-7.26 (m, 4H), 4.41 (s, 1H), 4.18-4.09 (m, 1H), 3.80-3.63 found: 497.2444; HPLC (Chiralpak IC-H column, hexane/iPrOH =
(m, 2H), 1.62 (s, 9H), 1.60 (s, 9H); 13C NMR (75 MHz, CDCl3): δ = 70/30, 1.0 mL/min, 254 nm): t1 = 11.0 min (minor), t2 = 26.8 min
196.3, 167.3, 166.9, 152.3, 139.8, 136.9, 135.0, 134.0, 129.6, 129.5, (major, S).
129.0, 62.1, 62.0, 55.3, 42.7, 41.4, 29.1, 29.0; HRMS (ESI): m/z calcd (S)-1,3-di-tert-butyl-5-(3-(4-chlorophenyl)-1-(4-fluorophenyl)-3-
+
for C27H31Cl2N2O4 [M+H]+ 517.1655, found: 517.1655; HPLC oxopropyl)pyrimidine-2,4,6(1H,3H,5H)-trione (4z). Colorless oil,
(Chiralpak IC-H column, hexane/iPrOH = 70/30, 1.0 mL/min, 254 40.1 mg, 80% yield; Rf = 0.7 (DCM); 96% ee, [α]24 = 52.3 (c 2.65,
D
1
nm): t1 = 5.6 min (minor), t2 = 10.5 min (major,
(S)-1,3-di-tert-butyl-5-(3-(4-methoxyphenyl)-3-oxo-1-(p-
tolyl)propyl)pyrimidine-2,4,6(1H,3H,5H)-trione (4v). white solid, 6.94 (d,
S
).
CHCl3); H NMR (300 MHz, CDCl3): δ = 7.93 (d,
J
= 8.2 Hz, 2H), 7.42
(d,
J
= 8.2 Hz, 2H), 7.15 (t,
J
= 6.5 Hz, 2H), 6.93 (d, = 8.2 Hz, 2H),
J
J
= 8.3 Hz, 2H), 4.27 (s, 1H), 4.04-3.95 (m, 1H), 3.65-3.48 (m,
43.8 mg, 89% yield; Rf = 0.7 (DCM); mp: 145.3-145.5 oC; 95% ee
[α]13D = 45.7 (c 0.74, CHCl3); 1H NMR (300 MHz, CDCl3): δ = 7.98 (d,
= 7.3 Hz, 2H), 7.05 (s, 4H), 6.91 (d,
,
2H), 1.47 (s, 9H), 1.44 (s, 9H); 13C NMR (75 MHz, CDCl3): δ = 196.4,
1
J
167.3, 166.9, 162.5 (d, JC-F = 247.2 Hz), 152.3, 139.7, 135.1, 134.1
= 7.3 Hz, 2H), 4.23 (s, 1H), 4.01- (d, 4JC-F = 3.2 Hz), 129.9 (d, 3JC-F = 8.1 Hz), 129.5, 128.9, 115.7 (d, 2JC-F
J
3.92 (m, 1H), 3.86 (s, 3H), 3.67 (s, 1H), 3.53-3.45 (m, 1H), 2.30 (s, = 21.3 Hz), 62.1, 62.0, 55.4, 42.7, 41.5, 29.1, 29.0; HRMS (ESI): m/z
+
3H), 1.46 (s, 9H), 1.44 (s, 9H); 13C NMR (75 MHz, CDCl3): δ = 196.3, calcd for C27H31ClFN2O4 [M+H]+ 501.1951, found: 501.1948; HPLC
167.8, 167.3, 163.5, 152.4, 137.6, 136.5, 130.4, 130.1, 129.4, 128.1, (Chiralpak IC-H column, hexane/iPrOH = 70/30, 1.0 mL/min, 254
113.7, 61.9, 61.8, 55.8, 55.5, 43.4, 41.1, 29.1, 29.0, 21.2; HRMS nm): t1 = 5.8 min (minor), t2 = 11.0 min (major, S).
(ESI): m/z calcd for C29H37N2O5+ [M+H]+ 493.2697, found: 493.2695; (S)-1,3-di-tert-butyl-5-(1-oxo-1-phenylhexan-3-yl)pyrimidine-
HPLC (Chiralpak IC-H column, hexane/iPrOH = 70/30, 1.0 mL/min, 2,4,6(1H,3H,5H)-trione (6a). white solid, 36.5 mg, 88% yield; Rf =
254 nm): t1 = 18.3 min (minor), t2 = 44.1 min (major,
(S)-1,3-di-tert-butyl-5-(1-(4-chlorophenyl)-3-oxo-3-(p-
tolyl)propyl)pyrimidine-2,4,6(1H,3H,5H)-trione (4w). white solid, 3H), 3.49-3.40 (m, 2H), 3.07-3.02 (m, 2H), 1.59 (s, 9H), 1.55 (s, 9H),
S).
0.6 (DCM); mp: 73.5-73.7 oC; 92% ee, [α]23 = -54.2 (c 0.30, CHCl3);
D
1H NMR (300 MHz, CDCl3): δ = 7.95 (d,
J = 7.7 Hz, 2H), 7.58-7.42 (m,
48.8 mg, 98% yield; Rf = 0.7 (DCM); mp: 140.6-145.8 oC; 97% ee
[α]13D = 51.7 (c 0.83, CHCl3); 1H NMR (300 MHz, CDCl3): δ = 7.89 (d,
,
1.44-1.25 (m, 4H), 0.92-0.90 (m, 3H); 13C NMR (75 MHz, CDCl3): δ =
J
199.0, 169.0, 168.2, 152.8, 136.9, 133.1, 128.6, 128.1, 61.9, 61.7,
= 7.5 Hz, 2H), 7.26-7.12 (m, 6H), 4.28-4.27 (m, 1H), 4.00-3.92 (m, 55.1, 40.1, 36.3, 34.3, 29.3, 29.2, 20.4, 14.0; HRMS (ESI): m/z calcd
1H), 3.67-3.53 (m, 2H), 2.40 (s, 3H), 1.48 (s, 9H), 1.46 (s, 9H); 13C for C24H35N2O4+ [M+H]+ 415.2591, found: 415.2591; HPLC (Chiralpak
NMR (75 MHz, CDCl3): δ = 197.0, 167.4, 167.0, 152.4, 144.1, 137.2, AD-H column, hexane/iPrOH = 70/30, 1.0 mL/min, 254 nm): t1 = 5.0
134.3, 133.8, 129.7, 129.3, 128.9, 128.2, 62.1, 62.0, 55.6, 42.8, 41.3, min (minor), t2 = 5.7 min (major S).
+
29.1, 29.0, 21.7; HRMS (ESI): m/z calcd for C28H34ClN2O4 [M+H]+ (R)-1,3-di-tert-butyl-5-(1-cyclohexyl-3-oxo-3-
497.2202, found: 497.2202; HPLC (Chiralpak IC-H column, phenylpropyl)pyrimidine-2,4,6(1H,3H,5H)-trione (6b). white solid,
hexane/iPrOH = 70/30, 1.0 mL/min, 254 nm): t1 = 7.8 min (minor), t2 40.0 mg, 88% yield; Rf = 0.8 (DCM); mp: 104.2-104.5 oC; 92% ee
,
= 15.6 min (major,
S).
[α]23D = -62.2 (c 0.24, CHCl3); 1H NMR (300 MHz, CDCl3): δ = 7.94 (d,
(S)-1,3-di-tert-butyl-5-(3-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-
J
= 7.7 Hz, 2H), 7.57-7.41 (m, 3H), 3.51-3.35 (m, 2H), 3.08-2.93 (m,
oxopropyl)pyrimidine-2,4,6(1H,3H,5H)-trione (4x). Colorless oil, 2H), 1.83-0.85 (m, 29H); 13C NMR (75 MHz, CDCl3): δ =199.1, 170.0,
43.1 mg, 84% yield; Rf = 0.7 (DCM); 96% ee, [α]13 = 53.2 (c 1.93, 167.8, 153.1, 136.9, 133.1, 128.6, 128.1, 61.7, 61.5, 54.4, 41.0, 40.1,
D
1
CHCl3); H NMR (300 MHz, CDCl3): δ = 7.94 (d,
J
= 8.0 Hz, 2H), 7.42 37.4, 31.8, 29.3, 29.1, 26.6, 26.4, 26.3; HRMS (ESI): m/z calcd for
+
(d,
2H), 4.22 (s, 1H), 4.03-3.95 (m, 1H), 3.78 (s, 3H), 3.65 (d,
1H), 3.53-3.45 (m, 1H), 1.47 (s, 9H), 1.45 (s, 9H); 13C NMR (75 MHz, min (minor), t2 = 7.3 min (major
J
= 8.0 Hz, 2H), 7.08 (d,
J
= 8.2 Hz, 2H), δ = 6.77 (d,
J
= 8.07 Hz, C27H39N2O4 [M+H]+ 455.2904, found: 455.2904; HPLC (Chiralpak
= 3.0 Hz, AD-H column, hexane/iPrOH = 70/30, 1.0 mL/min, 254 nm): t1 = 4.2
).
J
R
CDCl3): δ =196.7, 167.7, 167.2, 159.4, 152.3, 139.6, 136.3, 130.2, (S)-1,3-di-tert-butyl-5-(1-oxo-1,5-diphenylpentan-3-yl)pyrimidine-
129.6, 129.3, 128.9, 114.2, 61.9, 61.8, 55.7, 55.3, 42.9, 41.6, 29.1, 2,4,6(1H,3H,5H)-trione (6c). Colorless oil, 36.6 mg, 93% yield; Rf =
+
29.0; HRMS (ESI): m/z calcd for C28H34ClN2O5 [M+H]+ 513.2151, 0.7 (DCM); 93% ee, [α]25D = -14.1 (c 1.00, CHCl3); 1H NMR (300 MHz,
found: 513.2149; HPLC (Chiralpak IC-H column, hexane/iPrOH = CDCl3): δ = 7.94 (d,
J = 7.2 Hz, 2H), 7.56-7.14 (m, 8H), 3.53-3.45 (m,
70/30, 1.0 mL/min, 254 nm): t1 = 8.7 min (minor), t2 = 21.6 min 2H), 3.13 (d, = 3.5 Hz, 2H), 2.70-2.62 (m, 2H), 1.90-1.77 (m, 2H),
J
(major,
S
).
1.58 (s, 9H), 1.55 (s, 9H); 13C NMR (75 MHz, CDCl3): δ = 198.8, 168.8,
(S)-1,3-di-tert-butyl-5-(1-(4-fluorophenyl)-3-(4-methoxyphenyl)-3-
167.9, 152.8, 141.4, 136.8, 133.2, 128.6, 128.5, 128.3, 128.1, 126.1,
oxopropyl)pyrimidine-2,4,6(1H,3H,5H)-trione (4y). Colorless oil, 61.9, 61.8, 55.1, 40.1, 36.3, 34.2, 33.7, 29.3, 29.2; HRMS (ESI): m/z
41.2 mg, 89% yield; Rf = 0.5 (DCM); 97% ee, [α]24 = 33.1 (c 0.2, calcd for C29H37N2O4 [M+H]+ 477.2748, found: 477.2746; HPLC
+
D
1
CHCl3); H NMR (300 MHz, CDCl3): δ = 7.98 (d,
7.43 (m, 3H), 7.16 (d, = 5.7 Hz, 2H), 6.93 (d,
J
= 8.4 Hz, 2H), 7.56- (Chiralpak AD-H column, hexane/iPrOH = 70/30, 1.0 mL/min, 254
J
J
= 8.2 Hz, 2H), 4.29 (s, nm): t1 = 5.9 min (minor), t2 = 9.2 min (major ).
S
1H), 4.06-3.97 (m, 1H), 3.67-3.54 (m, 2H), 1.47 (s, 9H), 1.45 (s, 9H); 1,3-di-tert-butyl-5-(3-oxocyclopentyl)pyrimidine-2,4,6(1H,3H,5H)-
13C NMR (75 MHz, CDCl3): δ = 196.0, 167.5, 167.0, 163.6, 152.4, trione (7). white solid, 26.9 mg, 84% yield; Rf = 0.5 (PE:EA/5:1); mp:
4
3
134.4 (d, JC-F = 3.1 Hz) 130.4, 130.0, 129.9 (d, JC-F = 8.0 Hz) 115.8, 94.7-94.9 oC; 29% ee, [α]23 = 23.9 (c 0.43, CHCl3); 1H NMR (300
D
8 | J. Name., 2012, 00, 1-3
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ARTICLE
MHz, CDCl3): δ = 3.21 (d,
J = 6.8 Hz, 1H), 3.22-3.20 (m, 1H), 3.51-
Notes and references
3.35 (m, 2H), 2.42-2.09 (m, 5H), 1.96-1.78 (m, 1H), 1.57 (s, 18H); 13
C
NMR (75 MHz, CDCl3): δ = 216.0, 167.6, 167.3, 153.2, 62.2, 56.8,
1
a) S. Nayak, P. Panda, S. Bhakta, S. K. Mishra and S.
Mohapatra, RSC Adv., 2016, , 96154; b) Y. Zhang and W.
Wang, Catal. Sci. Technol., 2012, , 42; c) A. Ying, C. Wu, Y.
Fu, S. Ren and H. Liang, Chin. J. Org. Chem., 2012, 32, 1587; d)
M. Thirumalaikumar, Org. Prep. Proced. Int., 2011, 43, 67; e)
S. B. Tsogoeva, Eur. J. Org. Chem., 2007, 1701; f) D. Almasi,
D. A. Alonso and C. Najera, Tetrahedron: Asymmetry, 2007,
18, 299.
+
42.1, 39.6, 38.3, 29.2, 27.0; HRMS (ESI): m/z calcd for C17H27N2O4
6
[M+H]+ 323.1965, found: 323.1965; HPLC (Chiralcel OD-H column,
hexane/iPrOH = 70/30, 1.0 mL/min, 254 nm): t1 = 5.3 min (major), t2
= 7.1 min (minor).
2
Transformation of Michael product 4a.
(S)-5-(3-oxo-1,3-diphenylpropyl)pyrimidine-2,4,6(1H,3H,5H)-trione
(8). To a stirred solution of 4a (44.9 mg, 0.1 mmol) in toluene (0.5
ml) at room temperature was added AlCl3 (40.2 mg, 0.3 mmol)
under a N2 atmosphere. The reaction mixture was stirred for 1-2
hours and monitored by TLC. Then the reaction mixture was
quenched with water and extracted with ethyl acetate. The
combined organic phase was washed with brine, and concentrated
in vacuo. The residue was further purified by rapid column
chromatography to give the desired product 8 (20.2 mg, 60% yield).
A slower column chromatography could result in a few oxidation
2
3
J. Alemán and S. Cabrera, Chem. Soc. Rev., 2013, 42, 774.
For recent examples with excellent enantioselectivity (>95%
ee), see: a) D. Cao, G. Fang, J. Zhang, H. Wang, C. Zheng and
G. Zhao, J. Org. Chem., 2016, 81, 9973; b) Y. Kamito, A.
Masuda, H. Yuasa, N. Tada, A. Itoh, K. Nakashima, S.
Hirashima, Y. Koseki, T. Miura, Tetrahedron: Asymmetry,
2014, 25, 974; c) S. Hirashima, T. Sakai, K. Nakashima, N.
Watanabe, Y. Koseki, K. Mukai, Y. Kanada, N. Tada, A. Itoh
and T. Miura, Tetrahedron Lett., 2014, 55, 4334; d) K.
Dudziński, A. M. Pakulska and P. Kwiatkowski, Org. Lett.,
2012, 14, 4222; e) C. Luo, Y. Jin and D.-M. Du, Org. Biomol.
Chem., 2012, 10, 4116; f) M. Moritaka, N. Miyamae, K.
Nakano, Y. Ichikawa, H. Kotsuki, Synlett, 2012, 2554; g) P. A.
Dub, H. Wang, M. Watanabe, I. D. Gridnev and T. Ikariya,
Tetrahedron Lett., 2012, 53, 3452; h) Z. Mao, Y. Jia, W. Li and
R. Wang, J. Org. Chem., 2010, 75, 7428; i) N. Mase, M.
Fukasawa, N. Kitagawa, F. Shibagaki, N. Noshiro and K.
Takabe, Synlett, 2010, 2340; j) D. Chen, Z. Chen, X. Xiao, Z.
Yang, L. Lin, X. Liu and X. Feng, Chem. Eur. J., 2009, 15, 6807;
k) P. Li, S. Wen, F. Yu, Q. Liu, W. Li, Y. Wang, X. Liang and J. Ye,
Org. Lett., 2009, 11, 753; l) S. Kobayashi, M. Yamaguchi, M.
Agostinho and U. Schneider, Chem. Lett., 2009, 38, 296;
a) K. Aplander, R. Ding, M. Krasavin, U. M. Lindström and J.
Wennerberg, Eur. J. Org. Chem., 2009, 810; b) J. Wang, H. Li,
L. Zu, W. Jiang, H. Xie, W. Duan and W. Wang, J. Am. Chem.
Soc., 2006, 128, 12652.
byproducts. Known compound in racemate;11c-e Rf
(EA:MeOH/20:1); 96% ee, [α]20 = 15.2 (c 0.85, MeOH); 1H NMR
= 0.3
D
(300 MHz, CDCl3): δ = 11.05 (d,
Hz, 2H), 7.68-7.52 (m, 3H), 7.31-7.16 (m, 5H), 4.18-4.00 (m, 2H),
3.82 (d, = 3.7 Hz, 1H), 3.67-3.59 (m, 1H); HPLC (Chiralpak AS-H
column, hexane/iPrOH/TEA= 85/15/0.1, 1.0 mL/min, 254 nm): t1 =
43.6 min (minor), t2 = 48.2 min (major, ).
J = 14.6 Hz, 2H), δ = 7.99 (d, J = 7.2
J
S
(R)-1,3-di-tert-butyl-5-methyl-5-(3-oxo-1,3-
4
5
diphenylpropyl)pyrimidine-2,4,6(1H,3H,5H)-trione (9).
A round-
bottomed flask was charged with 4a (44.9 mg , 0.1 mmol), K2CO3
(27.6 mg, 0.2 mmol) and acetone (0.5 mL). Iodomethane (6.2 uL, 0.1
mmol) was added to the reaction mixture by a microsyringe at
room temperature. The reaction mixture was stirred for 12h and
monitored by TLC. Then the reaction mixture was quenched with
water and extracted with ethyl acetate. After usual work-up, further
purification by column chromatography on a silica gel (PE/EA) gave
the desired product 9 as a white solid (26.8 mg, 58% yield). Rf = 0.6
a) M. Yoshida, A. Kubara, Y. Nagasawa, S. Hara and M.
Yamanaka, Asian J. Org. Chem., 2014, 3, 523; b) Z. Jing, J. Liu,
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6
7
W. Ye, Z. Jiang, Y. Zhao, S. L. M. Goh, D. Leow, Y.-T. Soh and
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(PE:EA/10:1); mp: 105.0-105.2 oC; 96% ee, [α]20 = 60.9 (c 1.5,
D
For examples with excellent enantioselectivity (>95% ee), see:
a) J. Izquierdo, C. Ayats, A. H. Henseler and M. A. Pericàs, Org.
Biomol. Chem., 2015, 13, 4204; b) W. Yang, Y. Jia and D.-M.
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1
CHCl3); H NMR (300 MHz, CDCl3): δ = 7.93 (d,
J
= 9.3 Hz, 2H), 7.55-
7.39 (m, 3H), 7.20-7.17 (m, 5H), 4.17-4.12 (m, 1H), 3.90-3.69 (m,
2H), 1.60 (s, 3H), 1.53 (s, 9H), 1.39 (s, 9H); 13C NMR (75 MHz, CDCl3):
δ =197.9, 171.4, 170.9, 151.6, 139.0, 137.0, 133.0, 128.9, 128.6,
128.5, 128.1, 127.7, 61.9, 56.4, 48.2, 39.1, 29.0, 28.9, 23.5; HRMS
Deng, Org. Biomol. Chem., 2008, 6, 349.
+
(ESI): m/z calcd for C28H34N2O4 [M+H]+ 462.2591, found: 462.2593;
8
9
a) C.-L. Gu, L. Liu, Y. Sui, J.-L. Zhao, D. Wang and Y.-J. Chen,
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HPLC (Chiralpak IC-H column, hexane/iPrOH = 70/30, 1.0 mL/min,
254 nm): t1 = 4.7 min (major, R), t2 = 8.2 min (minor).
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3011; b) C. Liu and Y. Lu, Org. Lett., 2010, 12, 2278; c) T.
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Conflicts of interest
There are no conflicts to declare.
10 For an example of acyclic malonamide compounds, see: M. S.
Islam, A. Barakat, A. M. Al-Majid, H. A. Ghabbour, A. F. M. M.
Rahman, K. Javaid, R. Imad, S. Yousuf and M. I. Choudhary,
Bioorg. Med. Chem., 2016, 24, 1675.
11 For examples of cyclic malonamide compounds, see: a) A.
Barakat, S. M. Soliman, Y. A.M.M. Elshaier, M. Ali, A. M. Al-
Majid, H. A. Ghabbour, J. Mol. Struct., 2017, 1134, 99; b) A.
Barakat, M. S. Islam, A. M. Al-Majid, S. M. Soliman, Y. N.
Acknowledgements
This work is financially supported by the National Natural Science
Foundation of China (No. U1404211).
This journal is © The Royal Society of Chemistry 20xx
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DOI: 10.1039/C7OB02116J
ARTICLE
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enantioselective Michael addition of N,N'-dimethybarbituric
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20 The effect of several acid and base additives on the reaction
was tested. PhCO2H resulted in no reaction in 48 hours, and
K2CO3 resulted in 99% yield with 66% ee in 12 hours. It
suggested that tertiary amine group of the bifunctional
organocatalyst C-3 with base character play a leading role in
the Michael addition.
21 CCDC 1528351
(
4w
)
contains the supplementary
crystallographic data for this paper. The needle-like crystals
of the compound 4w were grown from its solution in
dichloromethane and hexane, and one of them is suitable for
X-ray diffraction analysis.
22 P. G. M. Wuts and T. W. Greene, Greene’s Protective Groups
in Organic Synthesis, Wiley-VCH, Weinheim, 4th edn, 2007,
Chapter 7.
10 | J. Name., 2012, 00, 1-3
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