Synthesis of a novel sterically hindered chiral cyclic phosphoric acid derived from L-tartaric acid and application to the asymmetric catalytic Biginelli reaction

Article abstract of DOI:10.1016/j.tetasy.2016.11.014

A novel sterically hindered chiral cyclic phosphoric acid derived from L-tartaric acid was designed and synthesized based on highly regioselective cyclosulfitation of chiral 1,1,4,4-tetraphenylbutanetetraol. The asymmetric Biginelli reaction catalyzed by

Full text of DOI:10.1016/j.tetasy.2016.11.014

Tetrahedron: Asymmetry xxx (2016) xxx–xxx
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Synthesis of a novel sterically hindered chiral cyclic phosphoric acid
derived from L-tartaric acid and application to the asymmetric
catalytic Biginelli reaction
a
a
a
b,
Xiaoyun Hu a, , Rui Zhang , Jinsheng Xie , Zhongqiang Zhou , Zixing Shan
⇑
⇑
a College of Chemistry and Materials, South-Central University for Nationalities, Wuhan, China
b College of Chemistry and Molecular Sciences, Wuhan University, Wuhan, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel sterically hindered chiral cyclic phosphoric acid derived from L-tartaric acid was designed and
Received 10 September 2016
Revised 11 November 2016
Accepted 20 November 2016
Available online xxxx
synthesized based on highly regioselective cyclosulfitation of chiral 1,1,4,4-tetraphenylbutanetetraol.
The asymmetric Biginelli reaction catalyzed by this newly synthesized chiral phosphoric acid was exam-
ined, and enantioselectivities up to 99% ee was obtained.
Ó 2016 Elsevier Ltd. All rights reserved.
1. Introduction
as versatile chiral ligands in various syntheses and as chiral hosts
in supramolecular chemistry.12 However, asymmetric transforma-
Chiral cyclic phosphoric acids are considered to be powerful
Brønsted acid catalysts in asymmetric catalytic reactions.1 In
2004, both Akiyama et al. and Terada et al. independently reported
asymmetric Mannich reaction catalyzed by chiral BINOL-derived
phosphoric acids.2 Since then, novel chiral cyclic phosphoric acid
catalysts have been continuously developed and have achieved
great success in asymmetric selective CAH activations,3 Friedel-
Crafts reactions4 hetero-Diels-Alder reactions,5 Biginelli and Big-
inelli-like condensations,6 transfer hydrogenations,7 and so on.8
So far most of the studies have focused on the synthesis and
application of chiral phosphoric acids derived from enantiomeri-
cally pure 1,10-bi-2-naphthol and its derivatives; however, the
introduction of a substituent at the 3,30-position of 1,10-bi-2-naph-
thols, which is usually considered as a chiral control group, plays a
crucial role for their chiral induction ability.9 The cost of the syn-
thesis of 1,10-bi-2-naphthols and their derivatives is high because
of complicated preparative procedures (Scheme 1),10 although
some of them have been marketed. In 2011, an improved synthesis
route,11 in which the protection and deprotection procedure of the
hydroxyl groups was simplified, was reported, although an organo-
lithium reagent and Suzuki coupling reaction are still required.
Enantiomerically pure tartaric acid is an inexpensive chiral
starting material, and its derivatization is generally easy to carry
out. Chiral tetraaryl-1,3-dioxolane-4,5-dimethanols (TADDOLs), a
class of important derivatives of tartaric acid, have been utilized
tions catalyzed by chiral phosphoric acids derived from TADDOLs
have seldom been reported to date.13 Considering that (2R,3R)-
1,1,4,4-tetrasubstituted butanetetraols could be readily prepared
via a one step reaction of enantiomerically pure diethyl tartrate
with a Grignard reagent14 and our previous work,15 a novel
sterically hindered chiral cyclic phosphoric acid was designed and
synthesized based on regioselective cyclosulfitation reaction of
(2R,3R)-1,1,4,4-tetraphenylbutanetetraol
1
(Scheme 2). We
observed that the newly synthesized chiral cyclic phosphoric acid
showed an excellent chiral induction ability for asymmetric Big-
inelli reactions. Herein we report the first application of chiral cyclic
phosphoric acids derived from (2R,3R)-1,1,4,4-tetraphenylbu-
tanetetraol to asymmetric catalyzed Biginelli reactions.
2. Results and discussion
2.1. Design and synthesis of novel chiral phosphoric acid 4
During our continuing study of the chemistry of chiral 1,1,4,4-
tetrasubstituted butanetetraol,14,15 which can be readily prepared
via one-step arylation reaction of L-diethyl tartrate with a Grignard
reagent, we found that (2R,3R)-1 could undergo highly selective
2,3-cyclosulfitation reaction with SOCl2 to give cyclic sulfite ester
(4R,5R)-2 in excellent yield.16 Further studies found that (4R,5R)-
2 was stable toward acidic solutions and organic bases, such as
pyridine and triethyl amine, but the sulfite group can easily
undergo hydrolysis in NaOH solution to give (2R,3R)-1. Compared
with the deprotection of TADDOL, which is usually involved with
⇑
Corresponding authors.
http://dx.doi.org/10.1016/j.tetasy.2016.11.014
0957-4166/Ó 2016 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Hu, X.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2016.11.014

2
X. Hu et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
Ar
Br
1) Pd, ArB(OH)2
2) HCl
3) POCl3
1) NaH, MOMCl
2) n-BuLi
3) Br2
O
O
O
OH
OH
OMOM
OMOM
P
OH
Ar
Br
Scheme 1. General procedure for the synthesis of BINOL-derived phosphoric acids.
Ph
Ph
Ph
Ph
1) PCl3, NEt3
2) I2
COOEt
COOEt
O
O
HO
PhMgBr/THF
HO
HO
HO
HO
OH
OH
Ph
SOCl2/Py
S
O
HO
Ph
Ph
Ph
1
58%
2
92%
Ph
Ph
Ph
Ph
1) NaOH
O
2) H+
OH
O
O
O
O
O
P
O
O
S
P
O
S
OH
O
O
O
Ph
Ph
Ph
Ph
3
4
62%(2 steps)
Scheme 2. Synthesis of chiral phosphoric acid 4 based on the regioselective sulfitation of (2R,3R)-1.
the oxidation and reduction procedure with DDQ and LiALH4,17
selective 2,3-protection and deprotection of (2R,3R)-1 can be read-
ily realized. Based on the selective 2,3-cyclosulfitation of (2R,3R)-1,
we designed and synthesized chiral phosphoric acid 4.
As shown in Scheme 3, selective 2,3-cyclosulfitation of (2R,3R)-
1 with an equivalent of thionyl chloride was carried out in an ice-
bath, and stoichiometric organic bases such as triethylamine or
pyridine were used to promote this reaction. If the reaction was
carried out at high temperature and in the absence of organic
bases, the HCl generated in situ would break the CAC bond to
afford 5,5-diphenyl-2-diphenylmethyl-4-hydroxy-1,3-dioxolane
5, whose structure has been confirmed in our previous work.15a
afforded a solvate of 4 with an ethanol molecule, which has a C2
symmetric axis.
2.2. Asymmetric Biginelli reaction catalyzed by chiral
phosphoric acid 4
A chiral inducer with a C2-symmetry axis usually provides high
levels of absolute stereo chemical control. The newly synthesized
C2 chiral phosphoric acid 4 was employed to catalyze the asym-
metric Biginelli reaction. The Biginelli reaction of benzaldehyde,
thiourea and ethyl acetoacetate catalyzed by chiral phosphoric acid
4 was set as a model reaction. As shown in Table 1, the one-pot Big-
inelli reaction catalyzed by chiral phosphoric acid 4 was examined
under different conditions.
From Table 1, it can be seen that the reaction medium plays a
crucial role in promoting the reaction yield and enantioselectivity.
Using THF as the reaction solvent is favorable for the reaction yield,
but only gave moderate enantioselectivity (entry 1). Only trace
amounts of the product were afforded when CH2Cl2 was used as
the solvent, although displayed excellent enantioselectivity (entry
3). Lewis acid or protonic acid was added as an additive, it
increased the reaction yield, but decreased the enantioselectivity
(entries 6, 7). An improvement in the yield could be achieved by
elevating the reaction temperature, but the stereoselectivity
decreased (entry 9).
With the optimal conditions in hand, we explored the general-
ity of the phosphoric acid-catalyzed asymmetric Biginelli reaction.
Table 2 indicates that enantiomeric excess for the asymmetric Big-
inelli reaction catalyzed by chiral phosphoric acid 4 is in a close
relationship with the composition of aromatic aldehydes. It was
observed that the reaction with unsubstituted aromatic aldehyde
and the electron-rich aromatic aldehydes (3- or 4-MeO and 4-
Me2N-substituted aromatic aldehydes) generally gave excellent
asymmetric induction (entries 1–4, 6), except for 2-MeOC6H4CHO
(entry 5). For the electron-deficient aromatic aldehydes (entries
7–9), poor reaction yields and the enantioselectivities were
obtained, while the reaction for 3-NO2C6H4CHO showed no
enantioselectivity.
Ph
Ph
O
O
HO
Py/ THF
ice-bath
S
O
HO
Ph
Ph
Ph
Ph
Ph
2
HO
HO
OH
OH
Ph
SOCl2
+
Ph
HO
HO
Ph
Ph
O
O
THF
reflux
5
Scheme 3. Selective 2,3-cyclosulfitation of (2R,3R)-1 with SOCl2.
Direct phosphorylation of cyclosulfite 2 to cyclic phosphate 3
using POCl3, which is effective for the preparation of chiral
BINOL-phosphoric acids, was unsuccessful. Therefore, an alterna-
tive synthetic route18 was adopted, namely, cyclosulfite 2 was trea-
ted with PCl3, subsequently oxidized into 3 by I2, and finally 3 was
hydrolyzed by NaOH solution to give chiral phosphoric acid 4 in
good yield. As seen in Figure 1, recrystallization from ethanol
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X. Hu et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
3
Figure 1. ORTEP of chiral phosphoric acid 4 bearing one ethanol molecule.
Table 1
Influence of experimental conditions on the asymmetric Biginelli reaction catalyzed by chiral phosphoric acid 4a
O
Ph
∗
S
O
O
O
4 (10 mol%)
EtO
NH
+
+
H2N
NH2
solvent / 3 d
OEt
Ph
H
N
H
S
Entry
Solvent
Reaction temperature
Additive
Yield, %b
ee, %c
1
2
3
4
5
6
7
8
9
THF
PhMe
CH2Cl2
CH3COCH3
MeOH
CH3COCH3
CH3COCH3
CH3COCH3
CH3COCH3
rt
rt
rt
rt
rt
–
–
–
–
62
36
Trace
58
Trace
72
69
47
29
>99
>99
8
42
42
>99
47
–
rt
rt
HOAc
B(OH)3
–
–
0 °C
50 °C
Trace
66
a
Reaction conditions: benzaldehyde (0.2 mmol), thiourea (0.24 mmol), ethyl acetoacetate (0.6 mmol) and chiral phosphoric acid 4 (10 mol%) in 1 mL of solvent were
stirred vigorously for 3 days at room temperature.
b
Isolated yield based on aldehyde.
Determined by HPLC.
c
3. Conclusion
4. Experimental
4.1. General
A novel sterically hindered C2 chiral phosphoric acid 4 has been
synthesized by a convenient procedure based on the highly regios-
elective 2,3-cyclosulfitation of (2R,3R)-1 derived from
L
-tartaric
1H and 13C NMR spectra were performed on a Varian Mercury
VS 300 or Bruker Avance III 400. MS was recorded on a VG ZAB-
HF-3F spectrometer. Optical rotations were measured on a PE-
341 Mc polarimeter. Melting points were determined on a VEB
Wagetechnik Rapio PHMK05 instrument, and are uncorrected. Ee
values were analyzed by HPLC on a Chiralcel AD-H column at room
acid with thionyl chloride, and its asymmetric catalytic activity
to Biginelli reaction was preliminary examined. Chiral phosphoric
acid 4 showed excellent enantioselectivities of up to 99% ee for
unsubstituted and electron-rich aromatic aldehydes, while for
the electron-deficient nitro-substituted aromatic aldehydes, the
reaction gave very low yield and enantioselectivity. Further inves-
tigations on the type and the size of the substituent on the asym-
metric Biginelli reaction, as well as the asymmetric catalytic
activity of this novel chiral phosphoric acid in other asymmetric
reactions are currently underway in our laboratory.
temperature with n-hexane/i-propanol as eluent. Diethyl
L-tartrate
was prepared from -tartaric acid and ethanol. THF was freshly dis-
L
tilled after refluxing with Na, while SOCl2, Py, PCl3 and I2 were pur-
chased and used directly. Commercially available starting
materials were used without further purification if not specified.
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4
X. Hu et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
Table 2
Preliminary examination of asymmetric catalytic ability of chiral phosphoric acid 4a
O
Ar
∗
X
O
O
O
4 (10 mol%) / r.t.
EtO
NH
+
X = O or S
+
H2N
NH2
OEt
acetone / 3 d
Ar
H
N
H
X
Entry
Ar
X
Yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
9
Ph
Ph
O
S
S
S
S
S
S
S
S
56
58
65
61
63
66
23
20
21
>99
>99
97
>99
7
97
17
0
4-MeOC6H4
3-MeOC6H4
2-MeOC6H4
4-NMe2C6H4
2-NO2C6H4
3-NO2C6H4
4-NO2C6H4
17
a
Reaction conditions: aromatic aldehydes (0.2 mmol), urea or thiourea (0.24 mmol), ethyl acetoacetate (0.6 mmol) and chiral phosphoric acid 4 (10 mol%) in 1 mL of
acetone were stirred vigorously for 3 days at room temperature.
b
Isolated yield based on aldehyde.
Determined by HPLC.
c
4.2. Preparation of (2R,3R)-1
dropping funnel and reflux condenser with oil seal was charged
with 10 mL dry of THF and 2.1 mL of NEt3 (15 mmol). The flask
was cooled in an ice-bath for 15 min, after which 1 mL of PCl3
was added. The mixture was then stirred in an ice-bath for another
15 min. The pressure-equalizing dropping funnel was charged with
a solution of (4R,5R)-2 (4.3 g, 9 mmol) in dry THF (80 mL) and then
added dropwise into the flask. After the complete addition, the
mixture was stirred in an ice-bath for 1 h, and then warmed to
room temperature and stirred for an additional 0.5 h. Next,
1.0 mL of H2O was added, followed by 7.3 g of I2 and 4.7 mL of
Py and stirred for another 1 h. The mixture was poured into satu-
rated NaHSO3 solution and stirred so as to remove the excess I2.
The organic phase containing intermediate 3 was not further
purified and directly mixed with 2 M NaOH solution, stirred at
room temperature for 2 h, after which 2 M HCl was added to adjust
the pH to 2–3. The solution was then extracted with Et2O
(20 mL ꢀ 3), dried and concentrated. The residue was recrystal-
lized with 80% ethanol to afford 2.7 g of colorless bulk crystal 4,
PhMgBr was prepared via a conventional Grignard reaction pro-
cedure, followed by the careful dropwise addition of a solution of
(2R,3R)-diethyl tartrate (4.1 g, 20 mmol) in 20 mL of freshly dis-
tilled THF. After the addition, the mixture was allowed to stir for
an additional 0.5 h, and then refluxed for 1 h. After cooling to rt,
100 mL of saturated aqueous NH4Cl were added and stirred until
a two-phase solution was obtained. The solution was extracted
with Et2O (20 mL ꢀ 3), dried over Na2SO4, followed by removal of
most of the solvent, then steam distillation was carried out, and
the residue was recrystallized with 80% ethanol to give 4.9 g of
(2R,3R)-1 as white needle crystals, yield: 58%, mp: 148–151 °C,
[a]
25 = +154.2 (c 0.5, CHCl3). 1H NMR (CDCl3, 300 MHz): d 7.37–
D
7.13 (m, 20H, Ar-H), 4.65 (d, J = 7.2 Hz, 2H, OH), 4.41 (d,
J = 4.7 Hz, 2H, CH), 3.77 (d, J = 5.3 Hz, 2H, OH). 13C NMR (CDCl3,
75 MHz): d 143.8, 142.7, 134.6, 131.5, 129.3, 128.3, 128.2, 127.9,
127.5, 126.7, 125.5, 81.3, 69.7.
62%yield over 2 steps. Mp: 100–105 °C, [
a
]
D
25 = ꢁ76 (c 0.3, MeOH).
4.3. Preparation of (4R,5R)-2
1H NMR (400 MHz, DMSO): d 7.54–7.52 (q, 8H, Ar-H), 7.37–7.22
(m, 12H, Ar-H), 5.69 (s, 2H, OH), 4.78 (s, 2H, CH). 13C NMR
(100 MHz, DMSO): d 145.44, 141.25, 128.73, 127.80, 86.63, 71.63.
A single crystal suitable for X-ray structural analysis was
obtained by slowly cooling a hot methanol solution of (5R,6R)-4
to room temperature. A colorless crystal was mounted on a glass
fibre. X-ray diffraction intensity data collection and cell refinement
were performed on Bruker P4 four-circle diffractometer equipped
with a graphite monochromator. A total of 7579 unique reflections
A 50 mL dried round-bottomed flask was charged with (2R,3R)-
1 (4.26 g, 10 mmol), pyridine (2 mL, 25 mmol) and freshly distilled
THF (20 mL). The flask was sealed with a rubber septum and stirred
in an ice-bath for 10 min, after which thionyl chloride (0.8 mL,
11 mmol) was added slowly with a syringe. After complete addi-
tion, the mixture was allowed to stir for an additional 1 h in an
ice-bath. The mixture was treated with H2O, and the organic phase
was separated, and the aqueous phase extracted with Et2O
(10 mL ꢀ 3). The organic solutions were combined, dried and con-
centrated; 4.3 g of colorless crystals were obtained from THF and
were collected using Mok
sealed tube at 298(2) K, of which 6945 reflections had I > 2
a
(k = 0.71073 Å) radiation by fine-focus
(I)
r
and were used in the structure solution and refinements. The cor-
rections for Lp factors and empirical absorption were applied to the
intensity data. All calculations were performed on Enraf-Nonius
Molen/VAX Software using the program SHELXL-97. The structure
was solved by direct methods and refined on F2 using a full-matrix
least-squares technique. The non-hydrogen atoms were also
refined by a full-matrix least-squares technique, anisotropically,
and hydrogen atoms were included but not refined. Cell dimen-
sions were obtained by the least-squares refinement of well cen-
tered 350 reflections in the range of 1.77 < h < 29.99°.
Et2O solution in 94% yield, mp:165–167 °C, [a]
20 = +65.8 (c 0.2,
D
CHCl3). 1H NMR (300 MHz, CDCl3): d 7.50 (d, J = 8.1 Hz, 2H, Ar-H),
7.42 (d, J = 7.5 Hz, 2H, Ar-H), 7.34–7.19 (m, 8H, Ar-H), 7.03 (s, 8H,
Ar-H), 5.97 (d, J = 2.1 Hz, 1H, CH), 5.90 (d, J = 2.1 Hz, 1H, CH), 4.49
(s, 1H, OH, disappeared after adding D2O), 3.70 (t, J = 6.0 Hz, 4H),
2.37 (s, 1H, OH, disappeared after adding D2O). 13C NMR
(75 MHz, CDCl3): d 145.1, 143.3, 141.5, 141.0, 128.7, 128.5, 128.4,
128.0, 127.4, 127.1, 126.9, 125.9, 89.7, 89.6, 87.2, 87.1, 78.8, 77.7.
LC–MS(EI): 471 (40, [M+ꢁ1]), 408 (100, [M+ꢁ64 (SO2)]).
Crystal data for (4R,5R)-4: empirical formula, C30H31O7P; for-
mula weight, 534.52; calculated density, 1.299 g/cm3; volume
(V), 1366.1(3) Å3; crystal system, Monoclinic; space group, P2(1);
Z = 2; unit cell dimensions, a = 12.5539 (18), b = 9.4686 (14),
4.4. Preparation of (5R,6R)-4
Under Ar, a freshly dried three-necked round bottomed 150 mL
flask equipped with a magnetic bar, 100 mL pressure-equalizing
c = 12.5539 (18),
a = 90° b = 113.73°, c = 90°; absorption coefficient
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X. Hu et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
5
(l
), 0.147 mmꢁ1
;
independent reflections:7579[R(int) = 0.0972;
(Daicel Chiralpak AD-H, hexane/isopropanol = 80:20, flow
index ranges ꢁ15 6 h 6 17, ꢁ13 6 k 6 12, ꢁ17 6 l 6 17; F(000),
rate = 0.8 mL/min,
tR = 11.872 min(minor).
k = 220 nm):
tR = 10.047 min(major),
564; GOF, 1.030.
4.5. Typical procedure for asymmetric catalyzed Biginelli
reactions
4.5.6. 5-Ethoxycarbonyl-6-methyl-4-(4-dimethylaminophenyl)-
3,4-dihydropyrimidin-2(1H)-thione
Yield: 66%, [
a]
20 = ꢁ41.7 (c 0.25, EtOAc). 1H NMR (400 MHz,
D
After a solution of aromatic aldehyde (0.2 mmol), thiourea
(0.24 mmol) and chiral phosphoric acid 4 (0.02 mmol) in acetone
(1 mL) was stirred vigorously at room temperature for 2 h, ethyl
acetoacetate (0.6 mmol) was added. The resulting reaction mixture
was stirred vigorously at room temperature for 3 days and then
EtOAc (10 mL) and some silica gel were added. After removal of
the solvent, the residue was purified via the column chromatogra-
phy using petroleum ether:ethyl acetate (6:1).
DMSO-d6) d 10.20 (s, 1H, NH), 9.51 (s, 1H, NH), 6.99 (d, J = 8.7 Hz,
2H, Ar-H), 6.63 (d, J = 8.7 Hz, 2H, Ar-H), 5.03 (d, J = 3.6 Hz, 1H,
CH), 3.97 (q, J = 7.0 Hz, 2H, OCH2), 2.84 (d, J = 16.6 Hz, 6H, CH3),
2.25 (s, 3H, CH3), 1.06 (dt, J = 22.1, 7.1 Hz, 3H, CH3). Enantiomeric
excess: 96.8%, determined by HPLC (Daicel Chiralpak AD-H, hex-
ane/isopropanol = 95:5, flow rate = 0.8 mL/min, k = 220 nm):
tR = 12.967 min(major), tR = 14.940 min(minor).
4.5.7. 5-Ethoxycarbonyl-6-methyl-4-(4-nitrophenyl)-3,4-dihy-
4.5.1. Ethoxycarbonyl-6-methyl-4-phenyl-3,4-dihydropyrimidin-
dropyrimidin-2(1H)-thione
2(1H)-one
Yield: 23%, [
DMSO-d6):
a
]
20 = ꢁ32.6 (c 0.12, EtOAc). 1H NMR (400 MHz,
D
Yield: 56%, [
a]
20 = ꢁ63 (c 0.25, MeOH). 1H NMR (400 MHz,
d
10.49 (s, 1H, NH), 9.76 (s, 1H, NH), 8.25 (d,
D
DMSO-d6): d 9.18 (s, 1H, NH), 7.72 (s, 1H, NH), 7.37–7.07 (m, 5H,
Ar-H), 5.12 (d, J = 2.8 Hz, 1H, CH), 3.95 (q, J = 7.1 Hz, 2H, OCH2),
2.22 (s, 3H, CH3), 1.06 (t, J = 7.1 Hz, 3H, CH3). Enantiomeric excess:
>99%, determined by HPLC (Daicel Chiralpak AD-H, hexane/iso-
propanol = 80:20, flow rate = 0.8 mL/min, k = 220 nm): tR = 9.298 -
min(major), tR = 10.507 min(minor).
J = 8.8 Hz, 2H, Ar-H), 7.51 (d, J = 9.2 Hz, 2H, Ar-H), 5.33 (s,
J = 3.6 Hz, 1H, CH), 4.03 (q, J = 6.8 Hz, 2H, OCH2), 2.33 (s, 3H,
CH3), 1.12 (t, J = 6.8 Hz, 3H, CH3). Enantiomeric excess: 16.9%,
determined by HPLC (Daicel Chiralpak AD-H, hexane/iso-
propanol = 80:20,
flow
rate = 0.8 mL/min,
k = 220 nm):
tR = 15.347 min(major), tR = 19.545 min(minor).
4.5.2. 5-Ethoxycarbonyl-6-methyl-4-phenyl-3,4-dihydropyri-
4.5.8. 5-Ethoxycarbonyl-6-methyl-4-(3-nitrophenyl)-3,4-dihy-
midin-2(1H)-thione
dropyrimidin-2(1H)-thione
Yield: 58%, [
a]
20 = ꢁ68 (c 0.25, MeOH). 1H NMR (400 MHz,
Yield: 20%, [a]
20 = 0 (c 0.10, EtOAc). 1H NMR (400 MHz, DMSO-
D
D
DMSO-d6): d 10.32 (s, 1H, NH), 9.63 (s, 1H, NH), 7.38–7.16 (m,
5H, Ar-H), 5.16 (d, J = 3.6 Hz, 1H, CH), 3.98 (q, J = 7.1 Hz, 2H,
OCH2), 2.25 (d, J = 17.4 Hz, 3H, CH3), 1.11–0.97 (m, 3H, CH3). Enan-
tiomeric excess: >99%, determined by HPLC (Daicel Chiralpak AD-
d6): d 10.51 (s, 1H, NH), 9.77 (d, J = 1.6 Hz, 1H, NH), 8.19–8.16 (m,
1H, Ar-H), 8.10 (s, 1H, Ar-H), 7.72–7.69 (m, 2H, Ar-H), 5.36 (d,
J = 3.6 Hz, 1H, CH), 4.08–4.00 (m, 2H, OCH2), 2.34 (s, 3H, CH3),
1.12 (t, J = 6.4 Hz, 3H, CH3). Enantiomeric excess: 0.16%, deter-
mined by HPLC (Daicel Chiralpak AD-H, hexane/iso-
H,
hexane/isopropanol = 80:20,
flow
rate = 0.8 mL/min,
k = 220 nm): tR = 9.255 min(minor), tR = 10.923 min(major).
propanol = 90:10,
flow
rate = 0.8 mL/min,
k = 220 nm):
tR = 16.557 min(major), tR = 19.342 min(minor).
4.5.3. 5-Ethoxycarbonyl-6-methyl-4-(4-methoxyphenyl)-3,4-
dihydropyrimidin-2(1H)-thione
4.5.9. 5-Ethoxycarbonyl-6-methyl-4-(2-nitrophenyl)-3,4-dihy-
dropyrimidin-2(1H)-thione
Yield: 65%, [
a]
20 = ꢁ18.3 (c 0.24, EtOAc). 1H NMR (400 MHz,
D
DMSO-d6) d 10.27 (s, 1H, NH), 9.58 (s, 1H, NH), 7.10 (d, J = 8.6 Hz,
2H, Ar-H), 6.87 (d, J = 8.6 Hz, 2H, Ar-H), 5.09 (d, J = 3.4 Hz, 1H,
CH), 3.97 (q, J = 7.1 Hz, 2H, OCH2), 3.69 (s, 3H, CH3), 2.26 (s, 3H,
CH3), 1.13–0.99 (m, 3H, CH3). Enantiomeric excess: 97.5%, deter-
mined by HPLC (Daicel Chiralpak AD-H, hexane/iso-
Yield: 21%, [
a
]
20 = ꢁ52.0 (c 0.1,2 EtOAc). 1H NMR (400 MHz,
D
DMSO-d6): d10.46 (s, 1H, NH), 9.58 (s, 1H, NH), 7.94 (d, J = 8.0 Hz,
1H, Ar-H), 7.76 (t, J = 7.6 Hz, 1H, Ar-H), 7.57–7.52 (m, 2H, Ar-H),
5.97 (d, J = 2.4 Hz, 1H, CH), 3.92–3.84 (m, 2H, OCH2), 2.32 (s, 3H,
CH3), 0.94 (t, J = 6.8 Hz, 3H, CH3). Enantiomeric excess: 16.6%,
determined by HPLC (Daicel Chiralpak AD-H, hexane/
propanol = 95:5,
flow
rate = 0.8 mL/min,
k = 220 nm):
tR = 6.780 min(minor), tR = 7.840 min(major).
isopropanol = 80:20,
flow
rate = 0.8 mL/min,
k = 220 nm):
tR = 13.728 min(minor), tR = 15.340 min(major).
4.5.4. 5-Ethoxycarbonyl-6-methyl-4-(3-methoxyphenyl)-3,4-
dihydropyrimidin-2(1H)-thione
Acknowledgments
Yield 61%, [
a]
20 = ꢁ113.7 (c 0.31, EtOAc). 1H NMR (400 MHz,
D
CDCl3): d 8.46 (s, 1H, NH), 7.87 (s, 1H, NH), 7.22 (t, J = 7.6 Hz, 1H,
Ar-H), 6.87 (d, J = 7.6 Hz, 1H, Ar-H), 6.82–6.79 (m, 2H, CH), 5.36
(d, J = 3.2 Hz, 1H, CH), 4.14–4.06 (m, 2H, OCH2), 3.77 (s, 3H, CH3),
2.35 (s, 3H, CH3), 1.17 (t, J = 6.8 Hz, 3H, CH3). Enantiomeric excess:
>99%, determined by HPLC (Daicel Chiralpak AD-H, hexane/iso-
The Project was supported by the Nature Science Foundation of
Hubei Province of China (No. 2012FFB07410) and the National
Nature Science Foundation of China (No. 21302233) for financial
support.
propanol = 80:20,
tR = 12.982 min(minor), tR = 13.960 min(major).
flow
rate = 0.8 mL/min,
k = 220 nm):
A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetasy.2016.11.
014.
4.5.5. 5-Ethoxycarbonyl-6-methyl-4-(2-methoxyphenyl)-3,4-
dihydropyrimidin-2(1H)-thione
Yield: 63%, [
a
]
20 = ꢁ114.5 (c 0.2, EtOAc). 1H NMR (400 MHz,
D
DMSO-d6) d 10.20 (s, 1H, NH), 9.21 (s, 1H, NH), 7.23 (t, J = 7.7 Hz,
1H, Ar-H), 7.00 (dd, J = 20.2, 7.8 Hz, 2H, Ar-H, Ar-H), 6.87 (t,
J = 7.5 Hz, 1H, Ar-H), 5.48 (d, J = 3.4 Hz, 1H, CH), 3.91 (dd, J = 13.8,
6.7 Hz, 2H, OCH2), 3.76 (s, 3H, CH3), 2.26 (s, 3H, CH3), 1.01 (t,
J = 7.1 Hz, 3H, CH3). Enantiomeric excess: 7%, determined by HPLC
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