Synthesis of Chiral Tertiary Amine-Thioureas Based on Spirobi indane and Application in Catalytic Asymmetric Michael Addition Reaction

Article abstract of DOI:10.1055/s-0039-1691643

A series of novel chiral bifunctional tertiary amine-thioureas based on spirobiindane were designed and synthesized as organo catalysts. One of these catalysts was shown to promote the asymmetric Michael addition reaction of 1,3-diphenylpropane-1,3-dione to nitro olefins, affording the desired products in good yields (up to 95%) and enantioselectivities (up to 98% ee).

Full text of DOI:10.1055/s-0039-1691643

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2020, 52, 1131–1139
paper
1131
de
Z. Han, X. Lin
Paper
Synthesis
Synthesis of Chiral Tertiary Amine–Thioureas Based on Spirobi-
indane and Application in Catalytic Asymmetric Michael Addition
Reaction
O
O
Zhao Han
Xufeng Lin*
0
0
0
0-
0
0
0
3-4
6
1
1-0
5
0
7
Ph
Ph
O
O
8a (10 mol%)
+
NO2
NO2
toluene, r.t.
Ar
Ar
Department of Chemistry, Zhejiang University, Hangzhou 310027,
Ph
Ph
P. R. of China
lxfok@zju.edu.cn
up to 95% yield
up to 98% ee
N
S
HN
CF3
HN
8a
CF3
Received: 19.11.2019
Accepted after revision: 18.12.2019
Published online: 04.02.2020
catalytic asymmetric reactions and new synthetic strate-
gies, the development of chiral bifunctional amine–
thiourea organocatalysts bearing novel backbone structures
is still highly desirable and challenging in a diverse range of
asymmetric catalysis. Herein, we describe our development
of a new series of chiral bifunctional tertiary amine–
thioureas based on spirobiindane as organocatalysts that
can effectively catalyze asymmetric Michael addition of
1,3-diphenylpropane-1,3-dione to nitroolefins.
DOI: 10.1055/s-0039-1691643; Art ID: ss-2019-h0642-op
Abstract A series of novel chiral bifunctional tertiary amine–thioureas
based on spirobiindane were designed and synthesized as organo-
catalysts. One of these catalysts was shown to promote the asymmetric
Michael addition reaction of 1,3-diphenylpropane-1,3-dione to nitro-
olefins, affording the desired products in good yields (up to 95%) and
enantioselectivities (up to 98% ee).
In the course of our work on the design and application
of novel chiral ligands and catalysts (Figure 1), we have re-
ported the first synthesis and application of SPINOL-
derived phosphoric acids (SPAs),5 which were shown to be
highly efficient in asymmetric synthesis and widely appli-
Key words organocatalysis, Michael addition, nitroolefins, spiro skele-
ton, thiourea
Over the past decade, enantioselective organocatalysis
has become a fruitful catalytic strategy, offering environ-
mentally benign and highly efficient methodologies for
asymmetric synthesis.1 Consequently, the development of
effective chiral organocatalysts has become one of the most
important and challenging goals of research in asymmetric
organocatalysis. Chiral urea and thiourea derivatives have
been recognized as privileged organocatalysts for a variety
of enantioselective transformations.2 The catalytic perfor-
mance of chiral organocatalysts usually depends on their
frameworks. Alongside new organocatalytic reactions, a va-
riety of structurally diverse chiral urea and thiourea or-
ganocatalysts have been developed and widely used in
many asymmetric reactions,3 mainly including the most
G
O
G
G
O
P
O
O
O
O
OH
OH
P
OH
P
OH
O
OH
O
O
G
G
G
SPAs
PPAs
TM-SPINOL
SPAs 2.0
R2
R1
O
O
PPh2
PPh2
OH
OH
Ph
Ph
N
N
N
PPh2
O
HMSI-PHOS
HMSI-PHOX
HM-SPINOL
HMSI-BOX
popular
Takemoto’s
amine–thioureas,
Jacobsen’s
Ph
N
ureas/thioureas, cinchona alkaloid based thioureas, and
other types of thiourea catalysts such as imidazole–
thioureas, guanidinethioureas, pyrrolidine–thioureas, and
oxazoline–thioureas. Notably, Shao and Kim developed
novel chiral bifunctional amine–thiourea organocatalysts
bearing both central and axial chiral elements, which
proved to be highly efficient in some asymmetric transfor-
mations.4 Despite a growing focus on efforts toward new
O
O
O
O
O
O
P
P
OR
P
O
R
Ph
HMSI-SMPE
HMSI-SMPO
HMSI-PPM
Figure 1 Chiral ligands and catalysts used by Lin’s group (G = Group)
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, 1131–1139
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

1132
Z. Han, X. Lin
Paper
Synthesis
cable in over 150 asymmetric reactions.6 Recently, we de-
veloped a novel class of planar chiral phosphoric acids
(PPAs) with a [2.2]paracyclophanyl backbone as organocat-
alysts and demonstrated their application in an asymmetric
aza-Friedel–Crafts reaction.7 Also recently, we disclosed our
successful design of a new exciting class of compounds with
the axially chiral 3,3,3′,3′-tetramethyl-1,1′-spirobiindane-
7,7′-diol (TM-SPINOL) core structure, and the correspond-
ing new axially chiral ligands and new, second generation
of SPAs.8 With this innovative design principle in mind, we
prepared the new hexamethyl-1,1′-spirobiindane-based
chiral tertiary amine–thiourea organocatalysts (HMSI-CAT),
bearing both central and axial chiral elements.
We started the synthesis of HMSI-CAT from the axially
chiral (S)-1 (HMSIOL) (Scheme 1), which was prepared by
acid-catalyzed rearrangement of bisphenol C according to
our previously published procedure.8c The Duff reaction of
HMSIOL with hexamethylenetetramine (HMTA) afforded
the corresponding product 2 in 86% yield. The subsequent
esterification with trifluoromethanesulfonic anhydride
(Tf2O) afforded diester 3 in 95% yield. Then, Pd-catalyzed
selective reduction with triethylsilane furnished spiro dial-
dehyde 4 in 96% yield. Bis-bromide 6 was obtained in 72%
yield over two steps by reduction and subsequent bromina-
tion. Finally, the target hexamethyl-1,1′-spirobiindane-
based chiral tertiary amine–thiourea (HMSI-CAT) 8a was
obtained in 50% yield over two steps by cyclization of 6
with (S,S)-1,2-diaminocyclohexane 9a, followed by addition
of 7a with 3,5-bis(trifluoromethyl)phenyl isothiocyanate.
Next, the efficiency and catalytic potential of the design
of new organocatalyst HMSI-CAT was tested in the Michael
addition9 of 1,3-diphenylpropane-1,3-dione (10) to ni-
troolefins (Table 1). We first examined the use of chiral or-
ganocatalyst 8a in the asymmetric reaction of 10 and trans-
alkene 11a in toluene at room temperature; this gave the
desired adduct 12a in 95% yield and 98% ee. The absolute
configuration of (S)-12a was confirmed by comparison with
known data.4g We also designed and synthesized catalyst
8b, which has the same absolute configuration of the spiro-
biindane unit, but differs in the two stereogenic centers of
the cyclohexyl scaffold, by following the procedure de-
scribed in Scheme 1. Similarly, organocatalysts 8c and 8d
were derived from bis-bromide 6 and chiral 1,2-diamino-
1,2-diphenylethane. However, organocatalysts 8b–d exhib-
ited completely different catalytic properties when com-
pared to 8a, leading to the corresponding product 12a in
low to moderate yields (17–74%) with poor stereochemical
control (14–35% ee). In addition, the absolute configuration
of product 12a is determined by the central chiral element
of the organocatalyst, as shown in Table 1. The performanc-
es of 8a–d clearly indicate that the two chiral elements in
OTf
OH
OH
OH
Table 1 Evaluation of Catalysts in the Michael Addition Reactiona–c
Tf2O, pyridine
HMTA, TFA
CHO
CHO
CHO
CHO
r.t., CH2Cl2
95%
AcOH
reflux
86%
O
O
OTf
OH
catalyst 8 (10 mol%)
O
O
Ph
Ph
NO2
+
2
3
1
NO2
toluene, r.t.
Ph
Ph
Ph
Ph
HMSIOL
10
11a
12a
PdCl2(PPh3)2 (cat.)
dppp (cat.)
NaBH4
CH2OH
CH2OH
CHO
CHO
THF
100%
Et3SiH
80 °C, DMF
88%
N
N
5
4
HN
HN
HN
HN
S
S
CF3
CF3
H2N
NH2
9a
8a
8b
PPh3Br2
CH2Br
CH2Br
N
CF3
CF3
r.t.
K2CO3, MeCN
reflux
74% yield, –35% ee
95% yield, 98% ee
H2N
72%
58%
6
7a
CF3
CF3
Ph
Ph
N
N
S
C N
Ph
S
Ph
S
HN
HN
HN
N
HN
87%
CF3
HN
HN
CF3
S
8c
8d
17% yield, –20% ee
CF3
CF3
CF3
8a
HMSI-CAT
43% yield, 14% ee
a Reaction conditions: 10 (0.2 mmol), 11a (0.1 mmol), catalyst 8 (10
mol%), toluene (1 mL), 16 h.
CF3
Scheme 1 Synthesis of the spirobiindane-based chiral bifunctional
amine–thiourea organocatalyst HMSI-CAT (8a)
b Yields are of isolated products.
c Enantioselectivity was determined by chiral HPLC.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, 1131–1139

1133
Z. Han, X. Lin
Paper
Synthesis
chiral tertiary amine–thiourea catalyst 8a based on the
spirobiindane backbone and 1,2-diaminocyclohexane are
matched, which is essential for obtaining high catalytic ac-
tivity and excellent stereochemical control. Thus, the chiral
tertiary amine–thiourea 8a was chosen as the ideal catalyst
for further study.
Further reaction optimization was performed by using
the bifunctional organocatalyst 8a (Table 2); the effect of
temperature was first investigated. We tried lower tem-
peratures (–40 °C and –10 °C) in toluene, but although ex-
cellent enantioselectivities resulted, the yield was reduced,
despite prolonged reaction times (entries 1–3). Next, the
influence of the solvent was examined; the reaction could
be carried out in other solvents, including dichlorometh-
ane, chloroform, acetonitrile, ethyl acetate, tetrahydrofuran,
dimethyl sulfoxide, and diethyl ether, with all providing the
corresponding product 12a in good to excellent yields (84–
96%), but with only moderate enantioselectivities (54–75%;
entries 4–10). Therefore, toluene was still the best reaction
solvent at room temperature (entry 1).
affect the reactivity and enantioselectivity of the reaction.
The reaction with the nitroolefin bearing 2,4-dimethoxy-
phenyl proceeded efficiently to give the desired product
12m in 90% yield, but only with 51% ee. Nitroolefins bear-
ing heterocyclic groups were also successfully employed in
the asymmetric Michael addition reaction, providing the
desired products 12n and 12o in excellent yields and good
enantioselectivities. The nitroolefin bearing ferrocene was
also examined. Interestingly, the transformation proceeded
smoothly, giving 12p in moderate yield and
enantioselectivity.
O
O
catalyst 8a (10 mol%)
O
O
Ph
Ph
NO2
+
NO2
toluene, r.t.
R
Ph
Ph
R
11
10
12
O
O
O
O
O
O
O
O
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
NO2
NO2
NO2
NO2
OMe
Br
Cl
12c
12a
95% yield, 98% ee
12b
83% yield, –93% ee
12d
87% yield, 85% ee
84% yield, 83% ee
With the optimal conditions in hand, we turned our at-
tention to investigating the reaction substrate scope when
using 8a as the chiral organocatalyst (Scheme 2). Substitu-
ents with different electronic properties, such as Br, Cl,
OMe, and ethynyl on the aromatic ring of nitroolefin 11,
were all tolerated, to give the corresponding products 12a–e
in good yields and enantioselectivities. Nitroolefin reagents
11 in which the aromatic rings were substituted at different
positions (ortho, meta, and para) were also successfully em-
ployed, with the substitution position not appearing to
O
O
O
O
O
O
O
O
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
NO2
NO2
NO2
NO2
OMe
Br
12h
Cl
82% yield, 82% ee
12g
12e
12f
86% yield, 88% ee
75% yield, 87% ee
91% yield, 93% ee
O
O
O
O
O
O
O
O
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
NO2
NO2
NO2
NO2
Cl
Me
Br
MeO
12k
94% yield, 96% ee
12j
92% yield, 90% ee
12l
12i
87% yield, 74% ee
Table 2 Reaction Optimizationa–c
89% yield, 85% ee
O
O
O
O
O
O
Ph
O
O
O
Ph
Ph
Ph
Ph
Ph
Ph
O
catalyst 8a (10 mol%)
O
O
Ph
Ph
Fe
NO2
+
NO2
Ph
Ph
NO2
OMe
Ph
Ph
Ph
O
NO2
NO2
S
NO2
MeO
10
11a
12a
12n
94% yield, –91% ee
12m
12o
91% yield, 83% ee
12p
90% yield, 51% ee
62% yield, –67% ee
Entry
Temp
Solvent
Time (h) Yield (%) ee (%)
Scheme 2 Substrate scope for the asymmetric Michael addition
1
2
r.t.
–40 °C
–10 °C
r.t.
toluene
toluene
toluene
CH2Cl2
CHCl3
MeCN
EtOAc
THF
16
36
24
16
16
16
16
16
16
16
95
87
89
90
84
92
96
89
93
90
98
96
94
71
69
64
59
75
54
70
According to the dual activation model of chiral amine–
thiourea,3,4 we propose the catalytic interaction shown in
Figure 2. The organocatalyst simultaneously activates the
3
4
5
r.t.
6
r.t.
7
r.t.
S
H
CF3
CF3
N
8
r.t.
N
N
N
H
9
r.t.
DMSO
Et2O
H
O
O
O
O
10
r.t.
Ph
Ph
a Reaction conditions: 10 (0.2 mmol), 11a (0.1 mmol), catalyst 8a (10
mol%) solvent (1 mL).
R
b Yields are of isolated products.
Figure 2 Proposed action of organocatalyst
c Enantioselectivity was determined by chiral HPLC.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, 1131–1139

1134
Z. Han, X. Lin
Paper
Synthesis
two substrates, 1,3-diphenylpropane-1,3-dione and the ni-
troolefin, involved in the Michael reaction through hydro-
gen bonding.
and dried over anhyd Na2SO4. After removal of the solvent, the residue
was purified by flash chromatography (silica gel, EtOAc/PE, 1:50); this
gave product (S)-3.
20
Yield: 3.1 g (95%); white solid; mp 156–157 °C; []D +158.5 (c 1.0,
In summary, we have developed a novel class of chiral
bifunctional tertiary amine–thiourea organocatalysts, bear-
ing both axial and central elements, based on a spirobiin-
dane backbone. The organocatalysts were employed in the
catalytic asymmetric Michael addition of 1,3-diphenylpro-
pane-1,3-dione to nitroolefins. The performances of the
newly developed organocatalysts 8 clearly indicated that
the two chiral elements in chiral amine–thiourea catalyst
8a are matched, which is essential for affording the desired
products in high yields (up to 95%) and excellent enantio-
selectivities (up to 98% ee).
CH2Cl2).
IR (film): 2962, 2865, 1704, 1563, 1423, 1407, 1213, 1183, 1142,
1043, 990, 880, 799, 736, 621 cm–1
.
1H NMR (400 MHz, CDCl3):  = 9.79 (s, 2 H), 7.35 (s, 2 H), 2.51 (d, J =
12.8 Hz, 2 H), 2.45 (s, 6 H), 2.41 (d, J = 12.8 Hz, 2 H), 1.50 (s, 6 H), 1.40
(s, 6 H).
13C NMR (100 MHz, CDCl3):  = 186.46, 153.54, 148.31, 146.25,
130.61, 129.76, 123.53, 119.01, 115.83, 57.67, 56.54, 42.11, 31.42,
27.96, 15.85.
19F NMR (376 MHz, CDCl3):  = –73.14.
HRMS (EI): m/z calcd for C27H26O8S2F6: 656.0973; found: 656.0973.
(S)-3,3,3′,3′,5,5′-Hexamethyl-2,2′,3,3′-tetrahydro-1,1′-spirobi-
[indene]-7,7′-dicarbaldehyde (4)
All reagents and solvents were purchased from commercial sources.
NMR spectra were recorded on a Bruker DPX 400 NMR spectrometer
at 400 MHz for 1H NMR, 100 MHz for 13C, and 376 MHz for 19F NMR.
The samples were prepared in CDCl3 or DMSO-d6 with tetramethylsi-
lane (TMS) as internal standard. IR spectra were recorded on a Nicolet
NEXUS 470 spectrophotometer. HRMS data were collected on Waters
GCT Premier and Bruker Ultraflex mass spectrometers. Optical rota-
tions were measured on a Perkin Elmer Model 341 polarimeter. The
ee values were determined on the basis of separations done by chiral
high-performance liquid chromatography. HPLC analysis was per-
formed using Chiralcel columns (Chiralcel AS-H, AD-H).
Under N2, a mixture of bis-triflate (S)-3 (1.97 g, 3 mmol), Pd(OAc)2
(135 mg, 0.6 mmol), and 1,3-bis(diphenylphosphino)propane (248
mg, 0.6 mmol) in DMF (150 mL) was stirred to give a clear solution.
Then triethylsilane (7.2 mL, 45 mmol) was added slowly. After addi-
tion was completed, the solution was warmed to 80 °C for 6 h. After
cooling to r.t., the resulting mixture was diluted with Et2O and
washed sequentially with H2O, sat. aq NaHCO3, and brine. The organic
layer was dried over anhyd Na2SO4 and concentrated under reduced
pressure. The residue was purified by flash chromatography (silica
gel, EtOAc/PE, 1:15) to afford product (S)-4.
Yield: 0.95 g (88%); yellow solid; mp 217–219 °C; []D20 +181.2 (c 1.0,
CH2Cl2).
(S)-6,6′-Dihydroxy-3,3,3′,3′,5,5′-hexamethyl-2,2′,3,3′-tetrahydro-
1,1′-spirobi[indene]-7,7′-dicarbaldehyde (2)
IR (film): 3360, 2963, 2925, 2876, 1685, 1605, 1577, 1460, 1394,
HMSIOL [(S)-(–)-1; 3.4 g, 10 mmol) was dissolved in TFA (120 mL) un-
der N2, and HMTA (11.2 g, 80 mmol) was added in one portion. The
yellow solution was refluxed overnight and glacial AcOH (120 mL)
was added the next day. The solution then was kept refluxing for 3 d.
When the starting phenols were converted, 4 M aq HCl (120 mL) was
added after the mixture had cooled to 95 °C, and then the mixture
was stirred for 5 h. Then, after cooling to r.t., the mixture was poured
into H2O and finally filtered to give product (S)-2.
1383, 1314, 1245, 1161 cm–1
.
1H NMR (400 MHz, CDCl3):  = 9.56 (s, 2 H), 7.53 (s, 2 H), 7.25 (s, 2 H),
2.56 (d, J = 13.3 Hz, 2 H), 2.43 (d, J = 17.1 Hz, 8 H), 1.45 (s, 6 H), 1.39 (s,
6 H).
13C NMR (100 MHz, CDCl3):  = 189.51, 152.38, 149.14, 137.24,
129.55, 128.42, 128.20, 58.80, 56.20, 42.40, 31.39, 28.57, 20.13.
HRMS (EI): m/z calcd for C25H28O2: 360.2089; found: 360.2096.
Yield: 3.37g (86%); yellow solid; mp 256–258 °C; []D20 +131.0 (c 1.0,
CH2Cl2).
(S)-(3,3,3′,3′,5,5′-Hexamethyl-2,2′,3,3′-tetrahydro-1,1′-spirobi-
[indene]-7,7′-diyl)dimethanol (5)
IR (film): 3375, 2966, 2924, 2876, 1637, 1605, 1468, 1393, 1384,
1273, 1162, 1090 cm–1
.
A portion of aldehyde (S)-4 (1.14 g, 3.2 mmol) was dissolved in THF
(30 mL); NaBH4 (0.6 g, 16 mmol) was added at 0 °C and the mixture
was stirred for 10 min. The mixture was then allowed to warm to r.t.
and stirred for 3 h. After the mixture had cooled to 0 °C, H2O (100 mL)
was added and stirring continued for 8 h. The resulting mixture was
diluted with Et2O and washed sequentially with H2O and brine. The
organic layer was dried over anhyd Na2SO4 and concentrated under
reduced pressure. The residue was purified by flash chromatography
(silica gel, EtOAc/PE, 1:4) to afford product (S)-5.
1H NMR (400 MHz, CDCl3):  = 12.01 (s, 2 H), 9.57 (s, 2 H), 7.20 (s, 2
H), 2.57 (d, J = 13.5 Hz, 2 H), 2.38 (d, J = 13.5 Hz, 2 H), 2.26 (s, 6 H),
1.37 (s, 6 H), 1.35 (s, 6 H).
13C NMR (100 MHz, CDCl3):  = 194.66, 162.35, 149.60, 141.77,
132.63, 127.96, 113.72, 60.29, 57.78, 43.01, 32.02, 30.12, 15.63.
HRMS (EI): m/z calcd for C25H28O4: 392.1988; found: 392.1985.
(S)-7,7′-Diformyl-3,3,3′,3′,5,5′-hexamethyl-2,2′,3,3′-tetrahydro-
1,1′-spirobi[indene]-6,6′-diyl Bis(trifluoromethanesulfonate) (3)
20
Yield: 1.16 g (100%); white solid; mp 82–84 °C; []D –10.3 (c 1.00,
CH2Cl2).
Tf2O (3.4 mL, 20 mmol) was added dropwise to a solution of dialde-
hyde (S)-2 (1.97 g, 5 mmol) and pyridine (3.3 mL, 40 mmol) in CH2Cl2
(40 mL), at 0 °C under a N2 atmosphere. The mixture was allowed to
warm to r.t. and stirred overnight. The reaction solution was diluted
with CH2Cl2, washed with 5% aq HCl, brine, sat. aq NaHCO3, and brine,
IR (film): 3355, 2954, 2926, 2862, 1959, 1742, 1609, 1463, 1383,
1361, 1309, 1230, 1167, 1148, 1020, 862, 738 cm–1
.
1H NMR (400 MHz, CDCl3):  = 7.10 (s, 2 H), 6.95 (s, 2 H), 4.13 (q, J =
11.8 Hz, 4 H), 2.38 (d, J = 11.5 Hz, 8 H), 2.24 (s, 1 H), 2.16 (s, 2 H), 1.67
(s, 1 H), 1.38 (s, 6 H), 1.33 (s, 6 H).
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, 1131–1139

1135
Z. Han, X. Lin
Paper
Synthesis
13C NMR (101 MHz, CDCl3):  = 152.38, 144.48, 137.96, 135.91,
129.95, 123.02, 60.62, 58.82, 43.13, 32.64, 30.09, 21.45.
(Sa,1R,2R)-2-(2,4,4,7,7,9-Hexamethyl-4,5,6,7-tetrahydro-11H-di-
indeno[7,1-cd:1′,7′-ef]azocin-12(13H)-yl)cyclohexan-1-amine (7b)
HRMS (ESI): m/z [M + Na]+ calcd for C25H32NO2: 387.2300; found:
387.2292
Prepared according to the general procedure; yield: 748 mg (53%);
white solid; mp 88–90 °C; []D20 –201.2 (c 1.00, CH2Cl2).
IR (film): 3361, 2923, 2855, 1743, 1669, 1608, 1463, 1361, 1261,
(S)-7,7′-Bis(bromomethyl)-3,3,3′,3′,5,5′-hexamethyl-2,2′,3,3′-tetra-
hydro-1,1′-spirobi[indene] (6)
1086, 1026, 858, 804 cm–1
.
1H NMR (400 MHz, CDCl3):  = 6.89 (s, 2 H), 6.79 (s, 2 H), 3.72 (s, 2 H),
3.14 (d, J = 12.7 Hz, 2 H), 2.66–2.55 (m, 1 H), 2.38 (d, J = 12.7 Hz, 2 H),
2.34 (s, 6 H), 2.22 (s, 1 H), 2.04 (s, 1 H), 1.97 (dd, J = 9.0, 5.3 Hz, 1 H),
1.92 (d, J = 12.6 Hz, 2 H), 1.55 (dd, J = 16.2, 13.8 Hz, 2 H), 1.49 (s, 6 H),
1.24 (s, 6 H), 1.20–1.05 (m, 4 H), 0.79 (dt, J = 32.2, 10.9 Hz, 2 H).
13C NMR (101 MHz, CDCl3):  = 151.23, 146.44, 137.53, 129.51,
122.19, 71.10, 57.67, 57.61, 52.45, 41.97, 35.17, 32.38, 30.43, 27.34,
26.15, 25.31, 21.38.
Dimethanol (S)-5 (1.16 g, 3.2 mmol) and triphenylphosphine dibro-
mide (7.1g, 16 mmol) were placed in a 100 mL flask. Then the re-
agents were dissolved in CH2Cl2 (30 mL) and stirred for 3 h under an
atmosphere of N2. Then H2O (100 mL) was added to quench the reac-
tion. The mixture was extracted with CH2Cl2, washed with H2O and
sat. aq brine, dried over Na2SO4, and concentrated under reduced
pressure. The residue was purified by flash chromatography (silica
gel, EtOAc/PE, 1:50) to afford product (S)-6.
HRMS (ESI): m/z [M+] calcd for C31H42N2: 443.3426; found: 443.3424.
Yield: 1.12 g (72%); white solid; mp 242–245 °C; []D20 –117.3 (c 1.00,
CH2Cl2)
(Sa,1S,2S)-2-(2,4,4,7,7,9-Hexamethyl-4,5,6,7-tetrahydro-11H-di-
indeno[7,1-cd:1′,7′-ef]azocin-12(13H)-yl)-1,2-diphenylethan-1-
amine (7c)
IR (film): 3726, 3704, 3626, 3599, 3446, 2953, 2861, 1959, 1610,
1464, 1382, 1361, 1311, 1262, 1230, 1208, 1029, 680, 669, 656 cm–1
.
1H NMR (400 MHz, CDCl3):  = 6.99 (s, 2 H), 6.87 (s, 2 H), 3.94 (d, J =
10.2 Hz, 2 H), 3.81 (d, J = 10.2 Hz, 2 H), 2.44 (d, J = 13.4 Hz, 2 H), 2.28
(s, 7 H), 2.24 (s, 1 H), 1.35 (s, 6 H), 1.27 (s, 6 H).
13C NMR (101 MHz, CDCl3):  = 152.71, 144.32, 138.20, 133.39,
131.86, 123.85, 57.33, 56.80, 43.26, 32.57, 30.20, 29.90, 21.25.
Prepared according to the general procedure; yield: 973 mg (56%);
white solid; mp 96–99 °C; []D20 –58.0(c 1.00, CH2Cl2).
IR (film): 3445, 2923, 2856, 1743, 1607, 1464, 1361, 1261, 1079,
1024, 858, 803, 669 cm–1
.
1H NMR (400 MHz, CDCl3):  = 7.23 (d, J = 2.6 Hz, 1 H), 7.22 (d, J = 1.8
Hz, 2 H), 7.18 (s, 2 H), 7.17 (d, J = 2.2 Hz, 2 H), 7.16 (s, 1 H), 7.15 (s, 1
H), 7.13 (d, J = 2.1 Hz, 1 H), 6.87 (s, 2 H), 6.56 (s, 2 H), 4.39 (d, J = 4.1
Hz, 1 H), 3.67 (d, J = 4.1 Hz, 1 H), 3.48 (dd, J = 30.4, 12.8 Hz, 4 H),
2.34(s, 6 H), 2.33 (d, J = 8.3 Hz, 2 H), 1.84 (d, J = 12.5 Hz, 2 H), 1.64 (br
s, 2 H), 1.46 (s, 6 H), 1.20 (s, 6 H).
13C NMR (101 MHz, CDCl3):  = 151.25, 146.72, 143.88, 140.61,
136.94, 130.17, 129.89, 129.69, 127.81, 127.67, 127.33, 127.19,
126.47, 122.26, 71.61, 57.59, 57.56, 56.38, 48.58, 41.99, 32.36, 30.40,
21.49.
HRMS (EI): m/z calcd for C25H32Br2: 488.0714; found: 488.0711
Diamines 7; General Procedure
Dibromide (S)-6 (1.16 g, 3.2 mmol) was placed in a 100 mL flask fol-
lowed by chiral 1,2-diaminocyclohexane or 1,2-diamino-1,2-di-
phenylethane (12.8 mmol) and K2CO3 (1.33 g, 9.6 mmol). Then the re-
agents were dissolved in MeCN (70 mL) under an atmosphere of N2
and the mixture was heated under reflux overnight. After cooling of
the mixture to r.t., the solvent was removed under reduced pressure.
Then the resulting mixture was diluted with Et2O and washed se-
quentially with H2O, sat. aq NaHCO3, and brine. The organic layer was
dried over anhyd Na2SO4 and concentrated under reduced pressure.
The residue was purified by flash chromatography (silica gel, EtO-
Ac/PE, 1:6 + 5% Et3N) to give the desired product 7.
HRMS (ESI): m/z [M + H]+ calcd for C39H44N2: 541.3512; found:
541.3574.
(Sa,1R,2R)-2-(2,4,4,7,7,9-Hexamethyl-4,5,6,7-tetrahydro-11H-di-
indeno[7,1-cd:1′,7′-ef]azocin-12(13H)-yl)-1,2-diphenylethan-1-
amine (7d)
(Sa,1S,2S)-2-(2,4,4,7,7,9-Hexamethyl-4,5,6,7-tetrahydro-11H-di-
indeno[7,1-cd:1′,7′-ef]azocin-12(13H)-yl)cyclohexan-1-amine (7a)
Prepared according to the general procedure; yield: 778 mg (45%);
white solid; mp 98–102 °C; []D20 –17.0 (c 1.00, CH2Cl2).
Prepared according to the general procedure; yield: 822 mg (58%);
IR (film): 3384 2956, 2858, 1742, 1603, 1452, 1382, 1262, 1069, 1029,
white solid; mp 84–86 °C; []D20 –183.4 (c 1.00, CH2Cl2).
860, 804, 702 cm–1
.
IR (film): 3384, 3303, 3060, 3027, 2956, 2920, 2858, 1958, 1736,
1H NMR (400 MHz, CDCl3):  = 7.15 (m, 5 H), 6.96–6.89 (m, 3 H), 6.80
(s, 2 H), 6.74 (dd, J = 6.6, 2.9 Hz, 2 H), 6.68 (s, 2 H), 4.44 (d, J = 8.5 Hz, 1
H), 3.92 (d, J = 8.5 Hz, 1 H), 3.82 (d, J = 12.9 Hz, 2 H), 3.44 (d, J = 12.9
Hz, 2 H), 2.33 (d, J = 12.5 Hz, 2 H), 2.25 (s, 6 H), 1.87 (br s, 2 H), 1.46 (s,
6 H), 1.18 (s, 6 H).
13C NMR (101 MHz, CDCl3):  = 150.91, 146.09, 143.83, 139.06,
137.14, 130.28, 130.16, 129.17, 127.88, 127.77, 126.97, 126.67,
126.29, 122.03, 75.32, 58.35, 57.52, 50.46, 41.77, 32.25, 30.28, 21.25.
1603, 1452, 1361, 1309, 1263, 1073, 1028, 858, 804, 750, 698 cm–1
.
1H NMR (400 MHz, CDCl3):  = 6.88 (d, J = 14.0 Hz, 4 H), 3.86 (d, J =
13.1 Hz, 2 H), 3.29 (d, J = 13.1 Hz, 2 H), 2.85 (td, J = 10.1, 4.1 Hz, 1 H),
2.38 (d, J = 17.1 Hz, 8 H), 2.02 (d, J = 11.1 Hz, 1 H), 1.93 (d, J = 12.6 Hz,
2 H), 1.66 (dd, J = 22.7, 13.4 Hz, 4 H), 1.51 (s, 6 H), 1.44–1.31 (m, 2 H),
1.26 (s, 6 H), 1.07 (dtd, J = 14.5, 12.5, 2.7 Hz, 4 H).
13C NMR (101 MHz, CDCl3):  = 150.90, 146.17, 137.23, 131.31,
130.56, 122.00, 72.78, 57.56, 57.54, 51.69, 48.23, 41.69, 35.64, 32.51,
30.34, 28.31, 26.43, 25.17, 21.32.
HRMS (ESI): m/z [M + H]+ calcd for C39H44N2: 541.3512; found:
541.3579.
HRMS (ESI): m/z [M + H]+ calcd for C31H42N2: 443.3426; found:
443.3422.
Thioureas 8; General Procedure
Diamine 7 (1 mmol) was added to a 50 mL flask and dissolved in
CH2Cl2 (30 mL). Then 3,5-bis(trifluoromethyl)phenyl isothiocyanate
(271 mg 1 mmol ) was added and the mixture was stirred for 18 h.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, 1131–1139

1136
Z. Han, X. Lin
Paper
Synthesis
The resulting mixture was diluted with CH2Cl2 and washed sequen-
tially with H2O, sat. aq NaHCO3, and brine. The organic layer was dried
over anhyd Na2SO4 and concentrated under reduced pressure. The
residue was purified by flash chromatography (silica gel, EtOAc/PE,
1:4) to afford the desired product 8.
13C NMR (101 MHz, CDCl3):  = 151.21, 146.67, 139.52, 139.15,
137.08, 131.91 (JF-C = 33.4), 130.04, 129.33, 128.37, 128.13, 128.00,
126.85, 124.21, 123.44, 122.67, 121.50, 118.29, 77.16, 60.42, 57.54,
57.28, 48.87, 41.77, 32.10, 30.11, 21.02.
19F NMR (376 MHz, CDCl3):  = –62.85.
HRMS (ESI): m/z [M + H]+ calcd for C40H45F6N3S: 812.3473; found:
812.3467.
(Sa)-1-[3,5-Bis(trifluoromethyl)phenyl]-3-[(1S,2S)-2-(2,4,4,7,7,9-
hexamethyl-4,5,6,7-tetrahydro-11H-diindeno[7,1-cd:1′,7′-ef]azo-
cin-12(13H)-yl)cyclohexyl]thiourea (8a)
(Sa)-1-[3,5-Bis(trifluoromethyl)phenyl]-3-[(1R,2R)-2-(2,4,4,7,7,9-
hexamethyl-4,5,6,7-tetrahydro-11H-diindeno[7,1-cd:1′,7′-ef]azo-
cin-12(13H)-yl)-1,2-diphenylethyl]thiourea (8d)
Prepared according to the general procedure; yield: 620 mg (87%);
white solid; mp 135–137 °C; []D20 –70.4 (c 1.00, CH2Cl2).
IR (film): 3294, 2924, 2855, 1741, 1466, 1382, 1277, 1138, 1097,
Prepared according to the general procedure; yield: 685 mg (84%);
1024, 860, 803, 699 cm–1
.
white solid; mp 135–137 °C; []D20 –36.7 (c 1.00, CH2Cl2).
1H NMR (400 MHz, DMSO):  = 10.03 (s, 1 H), 8.28 (s, 2 H), 7.71 (s, 1
H), 6.88 (d, J = 8.8 Hz, 4 H), 4.63 (s, 1 H), 3.61 (d, J = 13.0 Hz, 2 H), 3.30
(d, J = 13.1 Hz, 2 H), 2.75 (t, J = 8.4 Hz, 1 H), 2.29 (d, J = 14.5 Hz, 8 H),
2.24–2.16 (m, 1 H), 1.75 (d, J = 12.5 Hz, 2 H), 1.64–1.47 (m, 3 H), 1.43
(s, 6 H), 1.26–1.21 (m, 2 H), 1.18 (s, 6 H), 0.88–0.79 (m, 4 H).
13C NMR (101 MHz, CDCl3):  = 151.58, 146.57, 140.17, 137.57, 133.02
(JF-C = 33.7 Hz), 130.21, 127.19, 124.48, 122.78, 121.76, 119.05,
117.85, 68.62, 57.86, 57.37, 48.77, 41.81, 33.21, 32.48, 30.24, 28.78,
25.90, 24.66, 21.24.
IR (film): 3277, 2926, 2858, 1680, 1532, 1470, 1278, 1178, 1135, 885,
861, 804, 682 cm–1
.
1H NMR (400 MHz, CDCl3):  = 8.59 (s, 1 H), 7.55 (d, J = 16.7 Hz, 3 H),
7.13 (d, J = 16.5 Hz, 3 H), 7.02–6.84 (m, 5 H), 6.69 (s, 2 H), 6.51 (s, 4 H),
5.16 (s, 1 H), 4.12–3.98 (m, 1 H), 3.80 (d, J = 12.6 Hz, 2 H), 3.29 (d, J =
12.8 Hz, 2 H), 2.24 (d, J = 12.6 Hz, 2 H), 2.03 (s, 6 H), 1.75 (d, J = 12.6
Hz, 2 H), 1.35 (s, 6 H), 1.18 (t, J = 6.5 Hz, 1 H), 1.09 (s, 6 H).
13C NMR (101 MHz, CDCl3):  = 151.26, 146.24, 140.32, 137.51,
137.32, 132.19 (JF-C = 35.4 Hz), 130.51, 129.10, 128.94, 128.79, 127.52,
124.38, 122.70, 121.67, 118.95, 73.57, 62.37, 57.65, 57.56, 50.30,
41.92, 32.27, 30.36, 21.13, 1.14.
19F NMR (376 MHz, CDCl3):  = –62.91 (s).
HRMS (ESI): m/z [M + H]+ calcd for C40H45F6N3S: 714.3317; found:
714.3308.
19F NMR (376 MHz, CDCl3):  = –62.87.
HRMS (ESI): m/z [M + H]+ calcd for C40H45F6N3S: 812.3473; found:
812.3472.
(Sa)-1-[3,5-Bis(trifluoromethyl)phenyl]-3-[(1R,2R)-2-(2,4,4,7,7,9-
hexamethyl-4,5,6,7-tetrahydro-11H-diindeno[7,1-cd:1′,7′-ef]azo-
cin-12(13H)-yl)cyclohexyl]thiourea (8b)
Asymmetric Michael Addition of 1,3-Diphenylpropane-1,3-dione
(10) to Nitroolefins 11; General Procedure
Prepared according to the general procedure; yield: 527 mg (74%);
white solid; mp 221–222 °C; []D20 –174.0 (c 1.00, CH2Cl2).
To a solution of 1,3-diphenylpropane-1,3-dione (10; 44.8 mg, 0.2
mmol, 2 equiv) and nitroolefin 11 (0.1 mmol, 1 equiv) in toluene (1
mL) was added catalyst 8a (0.01 mmol, 0.1 equiv). The resulting mix-
ture was stirred at r.t. for 16 h. After the reaction was completed, the
corresponding product was isolated and purified by flash chromatog-
raphy (silica gel, EtOAc/hexane, 1:10 to 1:3).
IR (film): 3254, 2925, 2857, 1739, 1464, 1382, 1277, 1136, 1023, 966,
862, 803, 682 cm–1
.
1H NMR (400 MHz, DMSO-d6):  = 9.45 (s, 1 H), 8.01 (s, 2 H), 7.56 (s, 1
H), 7.37 (s, 1 H), 6.80 (s, 4 H), 4.27 (s, 1 H), 3.67 (s, 2 H), 3.18 (d, J =
12.5 Hz, 2 H), 2.29 (d, J = 12.6 Hz, 2 H), 2.05 (s, 6 H), 1.93 (s, 1 H), 1.78
(d, J = 12.5 Hz, 2 H), 1.57–1.40 (m, 2 H), 1.37 (s, 6 H), 1.31–1.18 (m, 2
H), 1.14 (s, 6 H), 1.11–0.79 (m, 4 H).
(S)-2-(2-Nitro-1-phenylethyl)-1,3-diphenylpropane-1,3-dione
13C NMR (101 MHz, DMSO-d6):  = 151.69, 147.21, 142.49, 137.88,
132.13, (JF-C = 33.3), 130.78, 128.28, 125.58, 123.56, 122.83, 120.17,
117.45, 68.47, 58.34, 58.30, 57.44, 42.42, 33.39, 32.50, 30.56, 29.81,
28.78, 26.11, 25.59, 21.12.
19F NMR (376 MHz, CDCl3):  = –58.12 (s).
HRMS (ESI): m/z [M + H]+ calcd for C40H45F6N3S: 714.3317; found:
(12a)
Prepared according to the general procedure; yield: 35.4 mg (95%).
HPLC (Chiralpak AS-H, hexane/i-PrOH, 85:15, flow rate 1 mL/min,  =
210 nm): tR (major) = 27.4 min, tR (minor) = 37.4 min; 98% ee.
1H NMR (400 MHz, CDCl3):  = 7.79 (d, J = 7.7 Hz, 2 H), 7.71 (d, J = 7.6
Hz, 2 H), 7.45 (dt, J = 15.1, 7.4 Hz, 2 H), 7.30 (dt, J = 15.1, 7.7 Hz, 5 H),
7.12 (dt, J = 9.0, 7.2 Hz, 5 H), 5.77 (d, J = 8.0 Hz, 1 H), 4.92 (d, J = 6.8 Hz,
2 H), 4.55 (dd, J = 14.5, 7.0 Hz, 1 H).
714.3314.
13C NMR (101 MHz, CDCl3):  = 194.25, 193.62, 136.78, 136.18,
135.81, 134.09, 133.82, 128.98, 128.85, 128.79, 128.62, 128.26,
128.18, 77.31, 59.87, 44.03.
(Sa)-1-[3,5-Bis(trifluoromethyl)phenyl]-3-[(1S,2S)-2-(2,4,4,7,7,9-
hexamethyl-4,5,6,7-tetrahydro-11H-diindeno[7,1-cd:1′,7′-ef]azo-
cin-12(13H)-yl)-1,2-diphenylethyl]thiourea (8c)
Prepared according to the general procedure; yield: 734 mg (90%);
ESI-MS: m/z = 374.3 [M + H]+.
yellow solid; mp 136–138 °C; []D20 –75.3 (c 1.00, CH2Cl2).
IR (film): 3244, 2924, 2856, 1698, 1471, 1384, 1277, 1137, 1029, 957,
(S)-2-[1-(2-Bromophenyl)-2-nitroethyl]-1,3-diphenylpropane-
1,3-dione (12b)
861, 803, 682 cm–1
.
1H NMR (400 MHz, CDCl3):  = 7.50–7.40 (m, 3 H), 7.18–7.02 (m, 11
H), 6.79 (s, 2 H), 6.30 (s, 2 H), 3.70–3.30 (m, 4 H), 2.25 (d, J = 12.6 Hz, 2
H), 2.11 (s, 5 H), 1.75 (d, J = 12.6 Hz, 2 H), 1.37 (s, 6 H), 1.14 (d, J = 7.2
Hz, 1 H), 1.12 (s, 6 H).
Prepared according to the general procedure; yield: 37.4 mg (83%).
HPLC (Chiralpak AD-H, hexane/i-PrOH, 90:10, flow rate 1 mL/min,  =
210 nm): tR (minor) = 21.6 min, tR (major) = 23.2 min; –93% ee.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, 1131–1139

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Z. Han, X. Lin
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Synthesis
1H NMR (400 MHz, CDCl3):  = 7.94–7.84 (m, 2 H), 7.75 (d, J = 7.4 Hz, 2
H), 7.61–7.56 (m, 1 H), 7.53 (t, J = 7.4 Hz, 2 H), 7.37 (q, J = 8.1 Hz, 4 H),
7.19–7.13 (m, 1 H), 7.10–7.02 (m, 2 H), 6.04 (d, J = 5.2 Hz, 1 H), 5.18 (s,
1 H), 5.13–5.03 (m, 2 H).
13C NMR (101 MHz, CDCl3):  = 194.66, 193.59, 136.21, 135.92,
135.60, 134.13, 133.96, 133.88, 132.51, 129.59, 128.97, 128.92,
128.75, 128.73, 128.68, 127.84, 127.21, 75.42, 57.18, 42.22.
HPLC (Chiralpak AS-H, hexane/i-PrOH, 85:15, flow rate 1 mL/min,  =
210 nm): tR (major) = 29.0 min, tR (minor) = 53.1 min; 88% ee.
1H NMR (400 MHz, CDCl3):  = 7.94 (d, J = 7.3 Hz, 2 H), 7.84 (d, J = 7.6
Hz, 2 H), 7.57 (d, J = 7.2 Hz, 2 H), 7.43 (d, J = 7.8 Hz, 5 H), 7.27 (d, J = 6.1
Hz, 2 H), 7.18 (s, 1 H), 7.10 (t, J = 7.6 Hz, 1 H), 6.10 (d, J = 6.5 Hz, 1 H),
5.18 (d, J = 5.2 Hz, 1 H), 5.14 (s, 1 H), 4.17 (q, J = 7.0 Hz, 1 H).
13C NMR (101 MHz, CDCl3):  = 192.55, 191.99), 137.48, 132.92,
132.67, 128.88, 127.71, 127.60, 127.43, 127.26, 127.19, 127.09,
125.23, 75.68, 58.08, 42.28.
HRMS (ESI): m/z [M + Na]+ calcd for C23H18BrNO4: 474.0371; found:
474.0308.
ESI-MS: m/z = 453.3 [M + H]+.
(S)-2-[1-(2-Chlorophenyl)-2-nitroethyl]-1,3-diphenylpropane-
1,3-dione (12c)
(S)-2-[1-(3-Chlorophenyl)-2-nitroethyl]-1,3-diphenylpropane-
Prepared according to the general procedure; yield: 34.2 mg (84%).
1,3-dione (12g)
HPLC (Chiralpak AD-H, hexane/i-PrOH, 90:10, flow rate 0.8 mL/min, 
= 254 nm): tR (major) = 25.8 min, tR (minor) = 27.2 min; 83% ee.
1H NMR (400 MHz, CDCl3):  = 7.96–7.92 (m, 2 H), 7.87–7.81 (m, 2 H),
7.61–7.57 (m, 2 H), 7.45–7.41 (m, 5 H), 7.29–7.25 (m, 2 H), 7.19–7.17
(m, 1 H), 7.13–7.07 (m, 2 H), 6.13–6.07 (m, 1 H), 5.19–5.16 (m, 2 H),
5.15–5.08 (m, 1 H), 4.20–4.14 (m, 1 H).
13C NMR (101 MHz, CDCl3):  = 193.66, 192.59, 135.21, 134.92,
134.60, 133.13, 132.96, 132.88, 131.51, 128.59, 127.97, 127.92,
127.75, 127.68, 126.84, 126.21, 74.42, 56.18, 39.17.
Prepared according to the general procedure; yield: 33.4 mg (82%).
HPLC (Chiralpak AS-H, hexane/i-PrOH, 85:15, flow rate 1 mL/min,  =
254 nm): tR (major) = 24.9 min, tR (minor) = 45.4 min; 82% ee.
1H NMR (400 MHz, CDCl3):  = 7.87–7.78 (m, 3 H), 7.77–7.69 (m, 2 H),
7.51–7.46 (m, 2 H), 7.38–7.29 (m, 6 H), 7.07 (s, 3 H), 5.78–5.70 (m, 1
H), 4.95–4.87 (m, 2 H), 4.58–4.46 (m, 1 H).
13C NMR (101 MHz, CDCl3):  = 193.91, 193.34, 138.83, 135.99,
135.63, 134.81, 134.28, 134.03, 130.23, 129.07, 128.96, 128.79,
128.61, 128.54, 128.45, 126.59, 77.08, 59.44, 43.63.
ESI-MS: m/z = 408.1 [M + H]+.
HRMS (ESI): m/z [M + Na]+ calcd for C23H18ClNO4: 430.0822; found:
430.0816.
(S)-2-[1-(2-Methoxyphenyl)-2-nitroethyl]-1,3-diphenylpropane-
1,3-dione (12d)
(S)-2-[1-(3-Methoxyphenyl)-2-nitroethyl]-1,3-diphenylpropane-
Prepared according to the general procedure; yield: 35.1 mg (87%).
1,3-dione (12h)
HPLC (Chiralpak AD-H, hexane/i-PrOH, 85:15, flow rate 1 mL/min,  =
210 nm): tR (major) = 16.9 min, tR (minor) = 23.2 min; 85% ee.
Prepared according to the general procedure; yield: 36.7 mg (91%).
HPLC (Chiralpak AD-H, hexane/i-PrOH, 85:15, flow rate 1 mL/min,  =
220 nm): tR (major) = 20.0 min, tR (minor) = 32.6 min; 93% ee.
1H NMR (400 MHz, CDCl3):  = 7.92–7.83 (m, 4 H), 7.52 (ddd, J = 7.7,
5.4, 1.2 Hz, 2 H), 7.42–7.33 (m, 4 H), 7.20–7.08 (m, 2 H), 6.81–6.71 (m,
2 H), 6.07 (d, J = 8.0 Hz, 1 H), 5.23 (dd, J = 13.1, 9.9 Hz, 1 H), 4.91 (dd,
J = 13.1, 4.1 Hz, 1 H), 4.81 (ddd, J = 9.9, 8.0, 4.1 Hz, 1 H), 3.84 (d, J = 2.5
Hz, 3 H).
13C NMR (101 MHz, CDCl3):  = 194.51, 194.35, 157.17, 136.49,
136.04, 133.84, 132.59 (s), 131.09 (s), 129.44, 128.98, 128.77, 128.67,
124.27, 121.13, 111.00, 75.93, 57.20, 55.35, 41.05.
1H NMR (400 MHz, CDCl3):  = 7.90–7.84 (m, 2 H), 7.82–7.76 (m, 2 H),
7.58–7.47 (m, 2 H), 7.38 (dt, J = 11.4, 7.8 Hz, 4 H), 7.11 (t, J = 7.9 Hz, 1
H), 6.82 (d, J = 7.7 Hz, 1 H), 6.76–6.72 (m, 1 H), 6.69 (dd, J = 8.2, 1.9 Hz,
1 H), 5.83 (d, J = 7.9 Hz, 1 H), 4.98 (dd, J = 6.8, 3.4 Hz, 2 H), 4.59 (td, J =
8.1, 5.3 Hz, 1 H), 3.67 (s, 3 H).
13C NMR (101 MHz, CDCl3):  = 194.29, 193.61, 159.83, 138.35,
136.21, 135.84, 134.12, 133.83, 130.06, 128.99, 128.87, 128.82,
128.65, 120.36, 114.28, 113.59, 77.26, 59.71, 55.20, 44.05.
ESI-MS: m/z = 404.1 [M + H]+.
ESI-MS: m/z = 404.1 [M + H]+.
(S)-2-[1-(2-Ethynylphenyl)-2-nitroethyl]-1,3-diphenylpropane-
1,3-dione (12e)
(S)-2-[1-(4-Bromophenyl)-2-nitroethyl]-1,3-diphenylpropane-
Prepared according to the general procedure; yield: 29.8 mg (75%).
1,3-dione (12i)
HPLC (Chiralpak AD-H, hexane/i-PrOH, 85:15, flow rate 1 mL/min,  =
254 nm): tR (major) = 18.6 min, tR (minor) = 21.2 min; 87% ee.
1H NMR (400 MHz, CDCl3):  = 7.92–7.86 (m, 2 H), 7.83–7.78 (m, 2 H),
7.55–7.48 (m, 4 H), 7.41–7.33 (m, 4 H), 7.17 (s, 1 H), 7.16–7.11 (m, 2
H), 6.19 (d, J = 6.9 Hz, 1 H), 5.27–5.18 (m, 1 H), 5.11 (s, 2 H), 3.49 (s, 1
H).
13C NMR (101 MHz, CDCl3):  = 194.55, 193.60, 139.09, 136.29,
135.74, 134.25, 134.10, 133.87, 129.39, 128.97, 128.82, 128.77,
128.72, 127.88, 83.69, 81.84, 75.66, 57.72, 41.93.
Prepared according to the general procedure; yield: 39.2 mg (87%).
HPLC (Chiralpak AD-H, hexane/i-PrOH, 85:15, flow rate 1 mL/min,  =
220 nm): tR (major) = 29.8 min, tR (minor) = 40.9 min; 74% ee.
1H NMR (400 MHz, CDCl3):  = 7.93–7.86 (m, 2 H), 7.82–7.76 (m, 2 H),
7.59–7.50 (m, 2 H), 7.39 (dt, J = 14.0, 7.8 Hz, 4 H), 7.33 (d, J = 8.4 Hz, 2
H), 7.12 (d, J = 8.5 Hz, 2 H), 5.81 (d, J = 8.2 Hz, 1 H), 4.94 (d, J = 7.1 Hz,
2 H), 4.60 (dd, J = 14.7, 7.2 Hz, 1 H).
13C NMR (101 MHz, CDCl3):  = 194.06, 193.45, 136.08, 135.89,
135.76, 134.40, 134.14, 132.21, 130.12, 129.18, 129.07, 128.89,
128.71, 122.35, 59.69, 43.65.
HRMS (ESI): m/z [M + Na]+ calcd for C25H19NO4: 420.1212; found:
420.1204.
ESI-MS: m/z = 453.3 [M + H]+.
(S)-2-[1-(3-Bromophenyl)-2-nitroethyl]-1,3-diphenylpropane-
1,3-dione (12f)
(S)-2-[1-(4-Chlorophenyl)-2-nitroethyl]-1,3-diphenylpropane-
1,3-dione (12j)
Prepared according to the general procedure; yield: 38.8 mg (86%).
Prepared according to the general procedure; yield: 37.4 mg (92%)
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Z. Han, X. Lin
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HPLC (Chiralpak AS-H, hexane/i-PrOH, 85:15, flow rate 1 mL/min,  =
210 nm): tR (major) = 27.6 min, tR (minor) = 38.3 min; 90% ee.
(R)-2-[1-(2-Furyl)-2-nitroethyl]-1,3-diphenylpropane-1,3-dione
(12n)
1H NMR (400 MHz, CDCl3):  = 7.93–7.86 (m, 2 H), 7.82–7.75 (m, 2 H),
7.58–7.53 (m, 2 H), 7.45–7.37 (m, 4 H), 7.18 (s, 4 H), 5.84–5.76 (m, 1
H), 4.98–4.91 (m, 2 H), 4.66–4.57 (m, 1 H).
Prepared according to the general procedure; yield: 34.1 mg (94%).
HPLC (Chiralpak AS-H, hexane/i-PrOH, 85:15, flow rate 1 mL/min,  =
210 nm): tR (minor) = 20.7 min, tR (major) = 25.1 min; –91% ee.
13C NMR (101 MHz, CDCl3):  = 194.0, 193.3, 136.0, 135.7, 135.2,
134.3, 134.1, 134.0, 1297, 129.2, 129.1, 129.0, 128.8, 128.68, 77.24,
59.78, 43.5.
1H NMR (400 MHz, CDCl3):  = 7.90–7.81 (m, 4 H), 7.55 (t, J = 7.3 Hz, 2
H), 7.40 (dd, J = 13.2, 7.6 Hz, 4 H), 7.21 (s, 1 H), 6.11 (t, J = 2.9 Hz, 2 H),
6.02 (d, J = 7.8 Hz, 1 H), 4.94 (dd, J = 9.4, 6.4 Hz, 2 H), 4.72 (d, J = 4.2 Hz,
1 H).
HRMS (ESI): m/z [M + Na]+ calcd for C23H18ClNO4: 430.0822; found:
13C NMR (101 MHz, CDCl3):  = 193.76, 149.77, 142.49, 135.88,
135.43, 134.12, 133.95, 129.01, 128.93, 128.64, 110.71, 108.96, 75.57,
56.71, 37.80.
430.0818.
(S)-2-[2-Nitro-1-(p-tolyl)ethyl]-1,3-diphenylpropane-1,3-dione
(12k)
ESI-MS: m/z = 364.5 [M + H]+.
Prepared according to the general procedure; yield: 36.4 mg (94%).
HPLC (Chiralpak AS-H, hexane/i-PrOH, 85:15, flow rate 1 mL/min,  =
54 nm): tR (major) = 20.7 min, tR (minor) = 28.1 min; 96% ee.
(R)-2-[2-Nitro-1-(2-thienyl)ethyl]-1,3-diphenylpropane-1,3-di-
one (12o)
1H NMR (400 MHz, CDCl3):  = 7.91–7.85 (m, 2 H), 7.83–7.76 (m, 2 H),
7.52 (ddd, J = 7.4, 5.8, 3.1 Hz, 3 H), 7.38 (dt, J = 12.3, 7.8 Hz, 4 H), 7.12
(d, J = 8.1 Hz, 2 H), 7.00 (d, J = 7.9 Hz, 2 H), 5.84 (d, J = 8.1 Hz, 1 H),
4.99–4.92 (m, 2 H), 4.63–4.55 (m, 1 H), 2.22 (s, 3 H).
13C NMR (101 MHz, CDCl3):  = 194.36, 193.68, 137.91, 136.23,
135.88, 134.07, 133.78, 133.68, 129.66, 128.97, 128.83, 128.67,
128.13, 127.21, 77.55, 60.03, 43.78, 21.03.
Prepared according to the general procedure; yield: 34.5 mg (91%).
HPLC (Chiralpak AS-H, hexane/i-PrOH, 85:15, flow rate 1 mL/min,  =
262 nm): tR (major) = 23.9 min, tR (minor) = 26.8 min; 83% ee.
1H NMR (400 MHz, CDCl3):  = 7.91–7.83 (m, 4 H), 7.57–7.52 (m, 2 H),
7.41 (t, J = 7.8 Hz, 4 H), 7.12 (dd, J = 5.1, 0.9 Hz, 1 H), 6.87 (d, J = 2.8 Hz,
1 H), 6.80 (dd, J = 5.1, 3.6 Hz, 1 H), 5.96 (d, J = 7.3 Hz, 1 H), 5.00 (d, J =
6.0 Hz, 2 H), 4.89 (dd, J = 13.0, 7.0 Hz, 1 H).
13C NMR (101 MHz, CDCl3):  = 194.16 (s), 193.64 (s), 139.35 (s),
136.10 (s), 135.71 (s), 134.28 (s), 134.14 (s), 129.13 (s), 129.09 (s),
128.85 (s), 128.81 (s), 127.28 (s), 127.20 (s), 125.56 (s), 78.09 (s),
60.00 (s), 39.60 (s).
ESI-MS: m/z = 388.3 [M + H]+.
(S)-2-[1-(4-Methoxyphenyl)-2-nitroethyl]-1,3-diphenylpropane-
1,3-dione (12l)
ESI-MS: m/z = 380.4 [M + H]+.
Prepared according to the general procedure; yield: 35.9 mg (89%).
HPLC (Chiralpak AD-H, hexane/i-PrOH, 70:30, flow rate 1 mL/min,  =
230 nm): tR (major) = 10.7 min, tR (minor) = 21.6 min; 85% ee.
(S)-2-[1-Ferrocenyl-2-nitroethyl)-1,3-diphenylpropane-1,3-dione
(12p)
1H NMR (400 MHz, CDCl3):  = 7.89 (dd, J = 8.4, 1.1 Hz, 2 H), 7.79 (dd,
J = 8.4, 1.1 Hz, 2 H), 7.58–7.47 (m, 3 H), 7.43–7.32 (m, 4 H), 7.18–7.12
(m, 2 H), 6.75–6.68 (m, 2 H), 5.81 (d, J = 8.2 Hz, 1 H), 4.94 (d, J = 6.7 Hz,
2 H), 4.65–4.52 (m, 1 H).
Prepared according to the general procedure; yield: 29.8 mg (62%).
HPLC (Chiralpak AD-H, hexane/i-PrOH, 70:30, flow rate 1 mL/min,  =
254 nm): tR (minor) = 11.6 min, tR (major) = 13.1 min; –67% ee.
13C NMR (101 MHz, CDCl3):  = 194.37, 193.75, 159.27, 136.22,
135.92, 134.11, 133.81, 129.44, 129.00, 128.87, 128.83, 128.66,
128.53, 114.36, 77.71, 60.13, 55.23, 43.49.
1H NMR (400 MHz, CDCl3):  = 7.81–7.75 (m, 4 H), 7.57–7.47 (m, 2 H),
7.44–7.31 (m, 4 H), 5.90–5.83 (m, 1 H), 5.27–5.09 (m, 2 H), 4.28–4.19
(m, 1 H), 4.13 (s, 5 H), 4.06–3.96 (m, 4 H).
13C NMR (101 MHz, CDCl3):  = 194.82, 194.34, 136.01, 135.96,
133.77, 133.74, 128.86, 128.83, 128.64, 128.56, 87.13, 77.76, 69.29,
69.05, 68.41, 67.79, 66.64, 59.59, 38.60.
ESI-MS: m/z = 404.1 [M + H]+.
(S)-2-[1-(2,4-Dimethoxyphenyl)-2-nitroethyl]-1,3-diphenylpro-
pane-1,3-dione (12m)
HRMS (ESI): m/z [M + Na]+ calcd for C27H23FeNO4: 504.0874; found:
Prepared according to the general procedure; yield: 39.0 mg (90%).
504.0871.
HPLC (Chiralpak AD-H, hexane/i-PrOH, 70:30, flow rate 1 mL/min,  =
230 nm): tR (major) = 11.2 min, tR (minor) = 14.4 min; 51% ee.
Funding Information
1H NMR (400 MHz, CDCl3):  = 7.95–7.78 (m, 4 H), 7.52 (dd, J = 16.0,
7.5 Hz, 2 H), 7.38 (dt, J = 11.6, 7.8 Hz, 4 H), 7.06 (d, J = 8.9 Hz, 1 H),
6.37–6.23 (m, 2 H), 6.04 (d, J = 8.2 Hz, 1 H), 5.18 (dd, J = 12.8, 10.1 Hz,
1 H), 4.84 (dd, J = 12.8, 4.2 Hz, 1 H), 4.73 (ddd, J = 10.0, 8.3, 4.2 Hz, 1
H), 3.81 (s, 3 H), 3.69 (s, 3 H).
This work was funded by the National Natural Science Foundation of
China (21572200).
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13C NMR (101 MHz, CDCl3):  = 194.49 (s), 194.30 (s), 160.65 (s),
158.12 (s), 136.46 (s), 136.06 (s), 133.80 (s), 133.63 (s), 131.74 (s),
128.89 (s), 128.68 (s), 128.63 (s), 128.58 (s), 116.39 (s), 104.48 (s),
99.06 (s), 76.09 (s), 57.42 (s), 55.29 (d, J = 2.9 Hz), 40.73 (s).
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0039-1691643.
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orit
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gInformati
o
n
HRMS (ESI): m/z [M + Na]+ calcd for C23H23NO6: 456.1423; found:
456.1418.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, 1131–1139

1139
Z. Han, X. Lin
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Synthesis
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© 2020. Thieme. All rights reserved. Synthesis 2020, 52, 1131–1139