Cycloaddition of Fluorenone N-Aryl Nitrones with Methylenecyclopropanes and Sequential 1,3-Rearrangement: An Entry to Synthesis of Spirofluorenylpiperidin-4-ones

Article abstract of DOI:10.1021/acs.joc.6b02544

A facile synthesis of various spirofluorenylpiperidin-4-ones has been achieved in good yields from fluorenone N-aryl nitrones and methylenecyclopropanes. This method involved an initial cycloaddition to form a 5-spirocyclopropane-isoxazoline, which underwent a highly selective 1,3-rearrangement to give the desired product. The stereochemistry of the spirofluorenylpiperidin-4-one could be controlled by the cycloaddition and sequential rearrangement strategy. Furthermore, the spirofluorenylpiperidin-4-ones could be not only prepared in one-pot procedure but also converted to useful scaffolds by reduction or oxidation conditions.

Full text of DOI:10.1021/acs.joc.6b02544

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Article
Cycloaddition of Fluorenone N-Aryl Nitrones with
Methylenecyclopropanes and Sequential [1,3]-Rearrangement:
An Entry to Synthesis of Spirofluoenylpiperidin-4-ones
Xiao-Pan Ma, Jie-Feng Zhu, Si-Yi Wu, Chun-Hua Chen, Ning Zou, Cui Liang, Gui-Fa Su, and Dong-Liang Mo
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02544 • Publication Date (Web): 16 Dec 2016
Downloaded from http://pubs.acs.org on December 18, 2016
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Cycloaddition
of
Fluorenone
N-Aryl
Nitrones
with
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7
8
9
Methylenecyclopropanes and Sequential [1,3]-Rearrangement: An
Entry to Synthesis of Spirofluoenylpiperidin-4-ones
XiaoꢀPan Ma, JieꢀFeng Zhu, SiꢀYi Wu, ChunꢀHua Chen, Ning Zou, Cui Liang,
GuiꢀFa Su*, and DongꢀLiang Mo*
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State Key Laboratory for Chemistry and Molecular Engineering of Medicinal
Resources, Ministry of Science and Technology of China; School of Chemistry &
Pharmaceutical Sciences, Guangxi Normal University, 15 Yu Cai Road, Guilin
541004, China.
O
R3
Ar
Ar
O
N
N
R1
R1
R3
R2
1,3-dipolar cycloaddition
1,3-rearrangement
R2
15 examples
46-87% yields
ABSTRACT： A facile synthesis of various spirofluorenylpiperidinꢀ4ꢀones has been
achieved in good yields from fluorenone Nꢀaryl nitrones and methylenecyclopropanes.
This
method
involved
an
initial
which
cycloaddition
underwent
to
form
a
5ꢀspirocyclopropaneꢀisoxazoline,
a
highly
selective
1,3ꢀrearrangement to give the desired product. The stereochemistry of the
spirofluorenylpiperidinꢀ4ꢀone could be controlled by the cycloaddition and sequential
rearrangement strategy. Furthermore, the spirofluorenylpiperidinꢀ4ꢀones could be not
only prepared in oneꢀpot procedure but also converted to useful scaffolds by reduction
or oxidation conditions.
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INTRODUCTION
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6
7
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9
The development of new and efficient methods for synthesis of piperidinone
derivatives represents an important research field because these piperidinone scaffolds
showed the unique biological activities and served as valuable intermediates in
organic synthesis.1,2 1,3ꢀDipolar cycloaddition of nitrones to the double bond of
methylenecyclopropanes is one of the most extensively studied cycloaddition
reactions due to the rich chemistry of 5ꢀspirocyclopropaneꢀisoxazoline cycloadducts
formed in the reactions.3,4 5ꢀSpirocyclopropaneꢀisoxazolines could undergo
BrandiꢀGuarna rearrangement to afford piperidinꢀ4ꢀones or related compounds
because of the highly strained spirocyclopropane ring.5 In 1989, Brandi and
coworkers found that the reaction of (Z)ꢀNꢀaryl aldonitrones and
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methylenecyclopropane
could
form
4ꢀspirocyclopropaneꢀisoxazoline
and
5ꢀspirocyclopropaneꢀisoxazoline which could be converted to a mixture of enamine,
piperidinꢀ4ꢀone and benzoazocinone (Scheme 1ꢀA).6 A further study on the
regioselective formation of 5ꢀspirocyclopropaneꢀisoxazoline and its 1,3ꢀ or
3,3ꢀrearrangement was reported by Molchanov and coworkers (Scheme 1ꢀB).7 The
effect of substituted groups on both nitrones and methylenecyclopropanes to the NꢀO
bond
rearrangement
was
studied.
Although
the
rearrangement
of
5ꢀspirocyclopropaneꢀisoxazoline has been studied, the yields and selectivities
observed in the 1,3ꢀ and 3,3ꢀrearrangement of 5ꢀspirocyclopropaneꢀisoxazoline are
generally poor for Nꢀaryl nitrones. During the studies on the rearrangement of NꢀO
bond in our group,8 we envisaged that methylenecyclopropanes bearing an
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alkoxycarbonyl group would regioselectively react with Nꢀaryl nitrones bearing a
5
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7
rigid
and
sterically
encumbered
9ꢀfluorenyl
group
to
give
8
9
5ꢀspirocyclopropaneꢀisoxazolines, which might undergo a controllable rearrangement
process. Fluorenone nitrones are distinct from traditional nitrones because the rigidity
and steric hindrance of the fluorene.9 This property can be exploited by NꢀO bond
cleavage10 to afford spirofluorenylpiperidinones that exhibits privileged scaffolds
present in bioactive pharmaceuticals and organic materials.11 Herein, we reported a
facile synthesis of spirofluorenylpiperidinꢀ4ꢀones in good yields from fluorenone
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nitrones and methylenecyclopropanes (MCP) (Scheme 1ꢀC).
A) Brandi' work, mixture of [3,3]- and [1,3]-rearrangement
Ph
Ph
PhHN
+
N
O
Ph
O
20%
O
14%
O
Ph
H
N
O
Ph
+
Ph
N
N
H
Ph
Ph
35%
14%
B) Molchanov's work, substituted groups effect on [3,3]- and [1,3]-rearrangement
CO2Me
CO2Me
OH
CO2Me
Ph
O
CO2Me
CO2Me
N
CO2Me
R
R
+
N
R
R
N
Ph
R
R = Ph, CO2Me
R
10-16% yield
2-54% yield
C) This work, high selective [1,3]-rearrangement
Ar
O
O
Ar
Ar
N
CO2R
O
N
N
O
OH
OR
only observed
Scheme 1. The rearrangement of NꢀO cyclopropane intermediates
RESULTS and DISCUSSION
We initially evaluated the formation of 5ꢀspirocyclopropaneꢀisoxazoline via the
cycloaddition reaction of Nꢀaryl fluorenone nitrone and methylenecyclopropane.
NꢀPhenyl fluorenone nitrone 1a and methylenecyclopropane 2a were chosen as model
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substrates for this reaction. As shown in Table 1, the desired cycloadduct 3a was
isolated in excellent yield from a variety of different solvents, including toluene,
1,2ꢀdichloroethane (DCE), MeCN, THF, DMSO and MeOH following 18−24 h at
40 °C (Table 1, entries 1–6). Reducing the reaction temperature to room temperature
led to an increase in the yield of 3a to 99%, albeit after extending the reaction time to
36 h (Table 1, entry 7). In contrast, increasing the reaction temperature to 60 °C led to
a decrease in the yield of 3a (Table 1, entry 8). Furthermore, no product 3a was
observed when the reaction was conducted at 80 °C, with the starting materials 1a and
2a being recovered unchanged (Table 1, entry 9).
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Table 1. Optimization of the Cycloaddition Reaction Conditions.a
Ph
O
Ph
O
Ph
N
O
N
Ph
conditions
O
+
O
O
1a
2a
3a
entry
solvent
toluene
DCE
T (°C)
40
3a,yield%b
1
2
3
4
5
6
7
8
98
98
96
97
79
94
99c
84
40
MeCN
THF
40
40
DMSO
MeOH
DCE
40
40
25
DCE
60
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DCE
80
<5
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a Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol, 2.0 equiv), solvent (2 mL), 18
−24 h; b Isolated yield; c Reaction time: 36 h.
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The cycloaddition reactions of various Nꢀaryl fluorenone nitrones 1 with
methylenecyclopropane 2a were conducted under the optimal conditions. As shown in
Table 2, these reactions proceeded smoothly to afford the desired products in good to
excellent yields. This reaction was found to be compatible with several useful
functional groups on the nitrone substrates, including methoxy, bromide, ester and
nitro groups at the para, ortho, or metaꢀposition. However, nitrones 1b and 1k bearing
a paraꢀmethoxy and orthoꢀbromide, respectively, afforded low yields of the
corresponding cycloadducts 3b and 3k (Table 2, entries 2 and 11). Notably, nitrone
1m with a 1:1 ratio of E/Zꢀisomer gave product 3m with a dr value of 1:1 when it
reacted with 2a under the optimal conditions (Table 2, entry 13).
Table 2. The Scope of the Nitrones 1.a
R
R
Ph
O
N
Ph
O
O
N
O
O
DCE
R1
+
R2
R1
25 °C
O
R2
1
2a
3
entry
1
R, R1, R2
3
yield (%)b
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
R = H, R1, R2 = H
3a
3b
3c
3d
3e
3f
99
37
76
79
86
82
73
62
R = 4ꢀMeO, R1, R2 = H
R = 4ꢀPhO, R1, R2 = H
R = 4ꢀMe, R1, R2 = H
R = 4ꢀiꢀPr, R1, R2 = H
R = 4ꢀBr, R1, R2 = H
R = 4ꢀF, R1, R2 = H
1g
1h
3g
R = 4ꢀCO2Me, R1, R2 = H 3h
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1i
R = 3,5ꢀMe2, R1, R2 = H
R = 3ꢀNO2, R1, R2 = H
R = 2ꢀBr, R1, R2 = H
R = H, R1, R2 = Br
3i
94
10
11
12
13
1j
3j
92
1k
1l
3k
3l
47
86
1m
R = H, R1 = H, R2 = Br
3m
93 (1:1)c
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a Reaction conditions: 1 (0.2 mmol), 2a (0.4 mmol, 2.0 equiv), solvent (2 mL), 18−36
h; b Isolated yield; c dr value
In addition to the nitrone moiety, we also investigated a variety of different
methylenecyclopropane substrates 2a–j to determine the substituent effect on the
cycloaddition reaction. All of these compounds provided the desired cycloadduct 3 in
good to excellent yields (Table 3). Notably, when (–)ꢀMenthol
methylenecyclopropane 2h was evaluated as a substrate to explore the
diastereoselectivity of the cycloaddition reaction, the corresponding product 3ah was
1
isolated in 58% yield with a dr value of 3.5:1, which was determined by H NMR
(Table 3, entry 8). This result revealed that the stereochemistry of the cycloadduct
could be controlled by installing a chiral auxiliary in the methylenecyclopropane
substrate. The ketoneꢀsubstituted methylenecyclopropane 2i gave the corresponding
cycloadduct 3ai in 73% yield (Table 3, entry 9). However, the reaction of
methylenecyclopropane 2j bearing a primary alcohol failed to afford the desired
cycloadduct 3aj, and nitrone 1a and methylenecyclopropane 2j were recovered
unchanged (Table 3, entry 10).
Table 3. Scope of the Methylenecyclopropane Substrate 2. a
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O
Ph
O
R
Ph
N
N
DCE
+
R
25 °C
7
8
1a
2
3a-3aj
9
entry
2
R
3
yield (%)b
99
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O
O
1
2
3
2a
3a
O
Ph
Ph
2b
2d
3ab
75
96
O
Me
O
3ac
O
Ph
4
5
6
7
2d
2e
2f
CO2Bn
3ad
3ae
3af
3ag
97
81
90
71
CO2nꢀBu
CO2Et
2g
CO2tꢀBu
Me
O
O
8
2h
3ah
58 (3.5 :1)c
Me
Me
O
9
2i
2j
3ai
3aj
73
0
Ph
10
CH2OH
a Reaction conditions: 1a (0.2 mmol), 2 (0.4 mmol, 2.0 equiv), DCE (2 mL), 18−36 h;
b Isolated yield; c dr value
Having fully evaluated the scope of the cycloaddition reaction, we proceeded to
investigate the rearrangement of 5ꢀspirocyclopropaneꢀisoxazoline 3. When 3a was
heated at 100 °C, the nitrone 1a was recovered with 35% yield,
Nꢀ(9Hꢀfluorenꢀ9ꢀylidene)aniline was isolated in 20% yield, and the enolated
1,3ꢀrearrangement product 4a’ was obtained in 10% yield (Scheme 2ꢀ1). This
experiment revealed that the cycloaddition reaction might be reversible and the
desired selective rearrangement could be achieved through improving the rigidity of
cycloaddition intermediate. In order to inhibit the reversible reaction and promote the
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efficiency of the rearrangement process, the 5ꢀspirocyclopropaneꢀisoxazoline 3a was
reduced by LiAlH4 to provide alcohol 3aj. When 3aj was heated at 40 °C for 36 h, no
desired product 4a was observed and only starting material 3aj was recovered. To our
delight, only 1,3ꢀrearrangement product 4a was obtained in 64% yield while 3aj was
heated at 80 °C for 18 h, and the solvent played an important role on the yield of
product 4a (Scheme 2ꢀ2). The optimal conditions for the rearrangement of 3aj to 4a
were in MeCN at 120 °C.
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1) Thermal reaction of cycloadduct 3a
Ph
N
O
1a (35%)
+
Ph
N
toluene
100 °C
O
20%
O
Ph
N
OH
Ph
3a
O
Ph
O
4a'
(10%)
3aj
2) Optimization of thermal reaction of
O
Ph
N
O
Ph
N
OH
OH
LiAlH4
92%
Conditions
3a
3aj
4a
4a yield%
temperature
solvent
toluene
toluene
toluene
toluene
0%
40 °C
80 °C
64%
67%
71%
100 °C
120 °C
DMF
66%
44%
120 °C
120 °C
dioxane
MeCN
90%
120 °C
Scheme 2. The thermal rearrangement conditions of 3aj to 4a
With the optimal conditions, we found that the reduction of 3a with LiAlH4,
followed by the rearrangement of the resulting alcohol in MeCN at 120 °C afforded
product 4a in 70% isolated yield in two steps. As shown in Table 4, the rearrangement
products 4 were obtained in yields of 46–87% from the corresponding cycloadduct 3
by sequential reduction and rearrangement reactions (method A) or sequential
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reduction, protection (with an alkyl bromide) and rearrangement reactions (method B)
in a singleꢀflask. The reaction was compatible with electronꢀwithdrawing and
electronꢀdonating groups on the aryl rings. Furthermore, 3h containing two ester
groups reacted smoothly to give product 4h in 73% yield bearing two hydroxyl
groups (Table 4, entry 7), which indicated that the two ester groups of 3h were
reduced by LiAlH4.
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Table 4. Scope of the Rearrangement of Cycloadduct 3 a
R3
R
O
Ph
O
N
N
O
OR4
R2
A
B
method or
R1
R1
O
R2
3
4
A
method : 1) LiAlH4; 2) MeCN, 120 °C
method : 1) LiAlH4; 2) R4Br, Et3N, 3) MeCN, 120 °C
B
yield
(%)b
entry
3
R3
R4
method
4
1
3a
3c
3d
3e
3f
H
H
H
H
H
H
H
H
H
H
H
H
A
A
A
A
A
A
A
A
A
A
A
4a
4c
4d
4e
4f
70
87
74
77
47
82
73c
63
50
56
65
2
4ꢀPhO
4ꢀMe
4ꢀiꢀPr
4ꢀBr
3
4
5
6
3g
3h
3i
4ꢀF
4g
4h
4i
7
4ꢀCH2OH
3,5ꢀMe2
3ꢀNO2
2ꢀBr
8
9
3j
4j
10
11
3k
3l
4k
4l
H
46
(1:1)d
12
3m
H
H
A
4m
13
14
3a
3a
H
H
Bn
B
B
4n
4o
64
68
allyl
a Reaction conditions: method A: 1) 3 (0.2 mmol), LiAlH4 (2.0 equiv), THF, 0 °C, 30
min; 2) MeCN (2 mL), 120 °C, 18−24 h; method B: 1) 3 (0.2 mmol), LiAlH4 (2.0
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equiv), THF, 0 °C, 10−30 min; 2) R4Br (2.0 equiv), 2−10 h; 3) MeCN (2 mL), 120 °C,
5
6
7
b
c
18−24 h; Isolated yield; The methoxycarbonyl group in 3h was also reduced; d dr
8
9
value
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The stereochemistry of the cycloaddition and rearrangement steps was investigated
using the reaction shown in Scheme 3. Reduction of cycloadduct 3ah with LiAlH4
afforded the corresponding alcohol 3aj in 86% yield and 35% ee value. The desired
rearrangement product 4a was obtained in 89% yield and 37% ee value when chiral
3aj was subjected to the optimal conditions. This result suggested that the absolute
stereochemistry of the spiropiperidinꢀ4ꢀone could be controlled through this
cycloaddition and rearrangement process.
O
Me
O
Ph
Ph
N
N
O
Ph
N
O
OH
LiAlH4
MeCN
120 °C
OH
O
Me
3ah
Me
4a
(89% yield, 37% ee)
3aj
86% yield, 35% ee
dr = 3.5:1
Scheme 3. The stereochemistry in the rearrangement step
The types of nitrones were also examined to the cycloaddition and rearrangement
process (Scheme 4). When fluorenone Nꢀmethyl nitrone 1n reacted with
methylenecyclopropane 2a in DCE at room temperature and followed by reduction
LiAlH4, the alcohol 3na was obtained in 95% yield. However, the rearrangement of
3na did not occur in the optimal conditions and only the alcohol 3na was recovered
(Scheme 4ꢀ1). To our surprising, both (Z)ꢀNꢀphenyl benzaldehyde nitrone 1o and
(Z)ꢀNꢀmethyl benzaldehyde nitrone 1p with 2a could not provide the cycloadducts at
room temperature and the reaction turned messy (Scheme 4ꢀ2 and 4ꢀ3 ). When nitrone
1a reacted with methylenecyclopropane 2k whatever at room temperature or high
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temperature, no desired cycloadduct or rearrangement product was obtained with
starting materials being recovered (Scheme 4ꢀ4). The results revealed that the types of
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nitrones and methylenecyclopropanes are important for these transformations.
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O
N
Me
Me
O
O
N
OH
N
MeCN Me
120 °C
1) DCE, 25 °C
2) LiAlH4
95%
OH
2a
+
1)
2)
3na
0%
1n
O
N
O
Ph
DCE, 25 °C
N
Ph
O
O
2a
+
Ph
Ph
H
H
O
O
Ph
Ph
1o
0%
O
N
O
Me
H
DCE, 25 °C
N
Me
3)
2a
+
Ph
Ph
H
1p
0%
Ph
O
N
Ph
DCE, 100 °C
+
No reaction
4)
2k
1a
Scheme 4. The effect of type of nitrones and methylenecyclopropanes on the
cycloaddition and rearrangement
To explore the utility of this cascade process, we further studied the efficiency of
oneꢀpot process and the usefulness of spiropiperidinꢀ4ꢀone. Pleasingly,
spiropiperidinꢀ4ꢀone 4a was prepared in 83% yield in total three steps via a oneꢀpot
reaction from nitrone 1a and methylenecyclopropane 2a (Scheme 5ꢀ1). Reduction of
4a with NaBH4 afforded the corresponding 1,3ꢀdiol 5 in 82% yield with a dr value of
20:1. Treatment of 4a with DessꢀMartin Periodinane (DMP) gave compound 6 in 88%
yield.12 The ability to install useful functional groups on spiropiperidinꢀ4ꢀone will
undoubtedly lead to these compounds in more applications.
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4a
1a
1) Single-flask preparation of
from nitrone
Ph
Ph
O
Ph
N
O
N
O
1) DCE, r.t., 36 h
2) LiAlH4, THF
O
OH
+
6
3) MeCN, 120 °C
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1a
2a
4a
83% yield in total
4a
2) Transformations of
Ph
O
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N
OH
OH
OH
N
Ph
NaBH4
82%
DMP
4a
88%
5 (dr > 20:1)
6
Scheme 5. Transformation studies
CONCLUSIONS
We have developed an efficient synthesis of fluorenylꢀsubstituted
spiropiperidinꢀ4ꢀones from Nꢀaryl fluorenone nitrones and methylenecyclopropanes.
This reaction involved initial cycloaddition, reduction and sequential thermal
rearrangement steps to give spirofluorenylpiperidinꢀ4ꢀones, and exhibited functional
group compatibility towards halide, ester, alcohol, and nitro groups. The
1,3ꢀrearrangement of the N–O bond could be controlled by the rigidity of the
fluorenyl in the nitrone. Notably, this reaction allowed for the oneꢀpot synthesis of
spirofluorenylpiperidinꢀ4ꢀone, providing a powerful platform for the construction of
numerous other diverse scaffolds.
EXPERIMENTAL SECTION
General Methods. All reactions were performed under an atmosphere of air.
Commercially available reagents were used without further purification. The NMR
spectra were recorded in CDCl3 or DMSOꢀd6 on 400 or 500 MHz instrument with
TMS as the internal standard. NMR data are represented as follows: chemical shift
(ppm), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet),
coupling constants in hertz (Hz), and integration. IR spectra were recorded on FTꢀIR
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spectrometer, and only major peaks are reported in cm‒1. HRMS were measured in
ESI mode and the mass analyzer of the HRMS was TOF. Flash column
chromatography was performed on silica gel (300−400 mesh).
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General procedure A for synthesis of cycloadduct 3 (Table 2 and Table 3): In a
Teflonꢀsealed reaction flask was charged with nitrone 1 (0.2 mmol) and
methylenecyclopropane 2 (0.4 mmol, 2.0 equiv) under air atmosphere, DCE (2.0 mL)
was added via syringe. And then, the reaction vessel was sealed with a Teflon cap.
The reaction mixture was stirred vigorously at 25 °C for 24−36 h until the substrate 1
disappeared (monitored by TLC). At this time, the solvent was removed under
reduced pressure and the crude product was purified by flash chromatography (the
crude residue was dry loaded with silica gel, 1/100 to 1/50, ethyl acetate/petroleum
ether) to provide product 3.
1
3a, a white solid, 0.096 g, 99% yield. mp: 120−121 °C; H NMR (400 MHz,
DMSOꢀd6): δ 7.84 (d, J = 6.4 Hz, 1H), 7.76 (d, J = 6.0 Hz, 1H), 7.61 (d, J = 5.6 Hz,
1H), 7.48−7.42 (m, 3H), 7.35−7.32 (m, 2H), 7.27−7.22 (m, 3H), 7.19−7.16 (m, 1H),
7.13 (t, J = 6.0 Hz, 1H), 6.83−6.80 (m, 2H), 6.66 (t, J = 6.0 Hz, 1H), 6.34 (d, J = 6.4
Hz, 2H), 6.14 (d, J = 12.8 Hz, 1H), 5.58−5.52 (m, 1H), 4.38 (s, 1H), 4.14−4.04 (m,
2H), 1.45−1.39 (m, 2H), 1.22−1.19 (m, 1H), 1.10−1.05 (m, 1H); 13C NMR (100 MHz,
DMSOꢀd6): δ 168.3, 146.7, 145.6, 141.9, 140.9, 136.2, 132.8, 129.8, 129.3, 129.0,
128.7, 128.3, 128.1, 127.3, 126.8, 126.7, 126.6, 125.0, 123.1, 122.8, 120.8, 120.2,
116.9, 81.1, 64.5, 63.6, 61.3, 12.8, 9.0; IR (thin film) 3054, 2914, 2862, 1743, 1448,
1303, 1184, 969, 742, 693 cm−1; HRMS (ESI) m/z calcd for C33H28NO3 (M+H)+
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486.2069, found 486.2053.
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3b, a white solid, 0.038 g, 37% yield. mp: 105−106 °C; H NMR (400 MHz,
CDCl3): δ 7.84−7.82 (m, 1H), 7.70−7.68 (m, 1H), 7.50−7.48 (m, 1H), 7.38−7.34 (m,
3H), 7.31−7.21 (m, 3H), 7.18 (d, J = 7.2 Hz, 2H), 7.12−7.10 (m, 2H), 6.48 (d, J = 8.8
Hz, 2H), 6.36 (d, J = 8.8 Hz, 2H), 6.12 (d, J = 16.0 Hz, 1H), 5.54−5.47 (m, 1H), 4.29
(s, 1H), 4.19−4.07 (m, 2H), 3.53 (s, 3H), 1.61−1.55 (m, 1H), 1.49−1.35 (m, 2H),
0.94−0.88 (m, 1H); 13C NMR (100 MHz, CDCl3): δ 168.4, 155.6, 144.7, 141.4, 141.2,
140.7, 139.2, 136.1, 133.4, 129.1, 128.7, 128.4, 128.3, 127.8, 127.1, 126.9, 126.5,
124.5, 122.2, 119.9, 119.6, 119.4, 112.7, 81.7, 64.7, 63.1, 61.1, 55.0, 12.8, 9.0; IR
(thin film) 3021, 2930, 2838, 1735, 1504, 1178, 966, 832, 741 cm−1; HRMS (ESI) m/z
calcd for C34H30NO4 (M+H)+ 516.2175, found 516.2160.
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3c, a white solid, 0.088 g, 76% yield. mp: 114−115 °C; H NMR (400 MHz,
CDCl3): δ 7.82−7.80 (m, 1H), 7.65 (d, J = 6.4 Hz, 1H), 7.53−7.51 (m, 1H), 7.39−7.37
(m, 3H), 7.32−7.26 (m, 3H), 7.13−7.08 (m, 3H), 6.97 (t, J = 7.2 Hz, 1H), 6.68 (d, J =
8.0 Hz, 2H), 6.51−6.46 (m, 4H), 6.14 (d, J = 16.0 Hz, 1H), 5.54−5.47 (m, 1H), 4.27 (s,
1H), 4.20−4.08 (m, 2H), 1.60−1.56 (m, 1H), 1.52−1.46 (m, 1H), 1.43−1.37 (m, 1H),
0.97−0.91 (m, 1H); 13C NMR (100 MHz, CDCl3): δ 168.3, 157.9, 152.0, 145.0, 142.2,
141.5, 141.1, 140.7, 136.1, 133.5, 129.3, 129.2, 128.8, 128.4, 128.0, 127.9, 127.0,
126.9, 126.5, 124.5, 122.3, 122.1, 120.0, 119.4, 119.0, 118.8, 117.6, 81.6, 64.8, 63.3,
61.2, 12.7, 9.0; IR (thin film) 3030, 2940, 1738, 1488, 1230, 1158, 965, 838, 739 cm−1;
HRMS (ESI) m/z calcd for C39H32NO4 (M+H)+ 578.2331, found 578.2319.
3d, a white solid, 0.079 g, 79% yield. mp: 92−93 °C; 1H NMR (500 MHz, CDCl3):
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δ 7.82 (d, J = 5.0 Hz, 1H), 7.66 (d, J = 6.0 Hz, 1H), 7.52−7.51 (m, 1H), 7.37−7.36 (m,
3H), 7.30−7.27 (m, 2H), 7.24−7.22 (m, 1H), 7.18 (d, J = 7.5 Hz, 2H), 7.12−7.09 (m,
2H), 6.61 (d, J = 8.5 Hz, 2H), 6.39 (d, J = 8.5 Hz, 2H), 6.12 (d, J = 16.0 Hz, 1H),
5.53−5.47 (m, 1H), 4.26 (s, 1H), 4.15−4.07 (m, 2H), 2.00 (s, 3H), 1.56−1.53 (m, 1H),
1.50−1.45 (m, 1H), 1.42−1.37 (m, 1H), 0.92−0.89 (m, 1H); 13C NMR (100 MHz,
CDCl3): δ 168.3, 145.2, 143.7, 141.7, 141.1, 140.7, 136.1, 133.5, 132.1, 129.1, 128.7,
128.3, 128.1, 127.9, 127.8, 127.1, 127.0, 126.5, 124.5, 122.2, 119.9, 119.3, 117.4,
81.3, 64.7, 63.1, 61.6, 20.5, 12.6, 9.1; IR (thin film) 3026, 2923, 2864, 1741, 1447,
1182, 967, 822, 737 cm−1; HRMS (ESI) m/z calcd for C34H30NO3 (M+H)+ 500.2226,
found 500.2208.
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3e, a white solid, 0.091 g, 86% yield. mp: 105−106 °C; H NMR (500 MHz,
CDCl3): δ 7.79 (d, J = 6.0 Hz, 1H), 7.64 (d, J = 6.0 Hz, 1H), 7.55 (d, J = 7.0 Hz, 1H),
7.40−7.35 (m, 3H), 7.31 (t, J = 7.0 Hz, 2H), 7.25−7.23 (m, 1H), 7.20 (d, J = 7.5 Hz,
2H), 7.13−7.08 (m, 2H), 6.68 (d, J = 8.0 Hz, 2H), 6.40 (d, J = 8.0 Hz, 2H), 6.14 (d, J
= 16.0 Hz, 1H), 5.55−5.49 (m, 1H), 4.24 (s, 1H), 4.12−4.10 (m, 2H), 2.61−2.56 (m,
1H), 1.55−1.52 (m, 1H), 1.50−1.45 (m, 1H), 1.40−1.35 (m, 1H), 1.00 (d, J = 7.0 Hz,
6H), 0.93−0.86 (m, 1H); 13C NMR (125 MHz, CDCl3): δ 168.4, 145.4, 144.0, 143.0,
141.8, 141.0, 140.7, 136.1, 133.4, 129.0, 128.7, 128.4, 127.9, 127.8, 127.0, 126.9,
126.5, 125.5, 124.5, 122.2, 119.9, 119.4, 117.2, 81.1, 64.7, 63.1, 61.8, 33.1, 23.8, 23.7,
12.6, 9.1; IR (thin film) 3022, 2949, 2866, 1733, 1448, 1164, 963, 832, 747 cm−1;
HRMS (ESI) m/z calcd for C36H34NO3 (M+H)+ 528.2539, found 528.2529.
1
3f, a white solid, 0.092 g, 82% yield. mp: 119−120 °C; H NMR (400 MHz,
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CDCl3): δ 7.78 (d, J = 6.4 Hz, 1H), 7.59 (d, J = 7.6 Hz, 1H), 7.55 (d, J = 6.8 Hz, 1H),
7.41−7.35 (m, 3H), 7.31−7.26 (m, 3H), 7.19 (d, J = 7.2 Hz, 2H), 7.15−7.07 (m, 2H),
6.92 (d, J = 8.8 Hz, 2H), 6.34 (d, J = 8.8 Hz, 2H), 6.13 (d, J = 15.6 Hz, 1H),
5.53−5.46 (m, 1H), 4.23 (s, 1H), 4.15−4.08 (m, 2H), 1.58−1.53 (m, 1H), 1.53−1.45
(m, 1H), 1.41−1.37 (m, 1H), 0.96−0.90 (m, 1H); 13C NMR (100 MHz, CDCl3): δ
168.0, 145.5, 145.0, 141.3, 140.9, 140.6, 136.0, 133.6, 130.5, 129.3, 129.0, 128.3,
128.1, 127.9, 127.2, 126.6, 126.5, 124.3, 122.0, 120.1, 119.5, 118.6, 115.3, 81.1, 64.8,
63.3, 61.5, 12.4, 9.0; IR (thin film) 3026, 2936, 2877, 1738, 1480, 1172, 963, 830,
741 cm−1; HRMS (ESI) m/z calcd for C33H27BrNO3 (M+H)+ 564.1174, found
564.1153.
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3g, a white solid, 0.072 g, 73% yield. mp: 117−118 °C; H NMR (500 MHz,
CDCl3): δ 7.82−7.80 (m, 1H), 7.64 (d, J = 7.5 Hz, 1H), 7.53 (d, J = 8.0 Hz, 1H),
7.40−7.36 (m, 3H), 7.31 (t, J = 7.5 Hz, 2H), 7.25−7.23 (m, 1H), 7.18 (d, J = 7.0 Hz,
2H), 7.13−7.08 (m, 2H), 6.52−6.49 (m, 2H), 6.47−6.44 (m, 2H), 6.12 (d, J = 15.5 Hz,
1H), 5.53−5.47 (m, 1H), 4.27 (s, 1H), 4.18−4.08 (m, 2H), 1.59−1.56 (m, 1H),
1.49−1.45 (m, 1H), 1.41−1.37 (m, 1H), 0.95−0.92 (m, 1H); 13C NMR (125 MHz,
CDCl3): δ 168.2, 159.7 (d, J = 239.2 Hz), 144.8, 142.1 (d, J = 2.5 Hz), 141.2, 141.1,
140.6, 136.1, 133.5, 129.3, 128.9, 128.3, 128.0, 127.9, 127.0 (d, J = 15.5 Hz), 126.5,
124.4, 122.1, 120.0, 119.5, 119.2, 119.1, 114.3 (d, J = 22.7 Hz), 81.6, 64.8, 63.3, 61.2,
12.7, 9.0; IR (thin film) 3027, 2941, 2875, 1743, 1501, 964, 834, 742 cm−1; HRMS
(ESI) m/z calcd for C33H27FNO3 (M+H)+ 504.1975, found 504.1957.
1
3h, a white solid, 0.051 g, 62% yield. mp: 133−134 °C; H NMR (500 MHz,
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CDCl3): δ 7.72 (d, J = 7.0 Hz, 1H), 7.60 (d, J = 7.0 Hz, 1H), 7.53 (d, J = 8.5 Hz, 3H),
7.46 (d, J = 7.5 Hz, 1H), 7.43−7.40 (m, 1H), 7.37−7.34 (m, 1H), 7.32 (t, J = 7.0 Hz,
2H), 7.25−7.23 (m, 1H), 7.20 (d, J = 7.0 Hz, 2H), 7.15−7.12 (m, 1H), 7.08 (t, J = 7.0
Hz, 1H), 6.42 (d, J = 8.5 Hz, 2H), 6.16 (d, J = 16.0 Hz, 1H), 5.55−5.49 (m, 1H), 4.20
(s, 1H), 4.13−4.12 (m, 2H), 3.72 (s, 3H), 1.59−1.54 (m, 1H), 1.53−1.48 (m, 1H),
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1.43−1.41 (m, 1H), 0.99−0.96 (m, 1H); C NMR (125 MHz, CDCl3): δ 167.9, 166.8,
150.6, 145.6, 141.7, 140.7, 136.1, 133.7, 129.7, 129.4, 129.1, 128.5, 128.4, 128.3,
127.9, 127.4, 126.5, 126.3, 124.1, 123.1, 122.0, 120.2, 119.6, 115.2, 80.6, 64.9, 63.6,
61.9, 51.5, 11.9, 9.1; IR (thin film) 3024, 2950, 2856, 1716, 1445, 1276, 1175, 964,
741 cm−1; HRMS (ESI) m/z calcd for C35H30NO5 (M+H)+ 544.2124, found 544.2105.
1
3i, a white solid, 0.097 g, 94% yield. mp: 100−101 °C; H NMR (500 MHz,
CDCl3): δ 7.78 (d, J = 6.0 Hz, 1H), 7.62 (d, J = 6.5 Hz, 1H), 7.54 (d, J = 6.0 Hz, 1H),
7.39−7.37 (m, 3H), 7.31 (t, J = 7.0 Hz, 2H), 7.24−7.23 (m, 1H), 7.19 (d, J = 7.5 Hz,
2H), 7.12−7.09 (m, 2H), 6.30 (s, 1H), 6.13 (d, J = 16.0 Hz, 1H), 6.07 (s, 2H),
5.54−5.50 (m, 1H), 4.23 (s, 1H), 4.13−4.11 (m, 2H), 1.90 (s, 6H), 1.56−1.53 (m, 1H),
1.51−1.46 (m, 1H), 1.41−1.36 (m, 1H), 0.95−0.91 (m, 1H); 13C NMR (125 MHz,
CDCl3): δ 168.4, 146.2, 145.5, 141.8, 141.0, 140.7, 136.9, 136.1, 133.4, 129.0, 128.7,
128.3, 127.9, 127.8, 127.0, 126.8, 126.5, 124.4, 124.3, 122.2, 119.8, 119.2, 115.0,
81.1, 64.7, 63.1, 61.6, 21.2, 12.6, 9.1; IR (thin film) 3026, 2950, 2861, 1737, 1449,
1165, 967, 740, 688 cm−1; HRMS (ESI) m/z calcd for C35H32NO3 (M+H)+ 514.2382,
found 514.2366.
1
3j, a yellow solid, 0.097 g, 92% yield. mp: 129−130 °C; H NMR (400 MHz,
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CDCl3): δ 7.77 (d, J = 7.2 Hz, 1H), 7.60 (d, J = 7.2 Hz, 1H), 7.57 (d, J = 7.2 Hz, 1H),
7.51−7.49 (m, 2H), 7.45−7.37 (m, 3H), 7.32−7.28 (m, 2H), 7.26−7.25 (m, 1H), 7.19
(d, J = 7.2 Hz, 1H), 7.15−7.06 (m, 2H), 6.90 (t, J = 8.0 Hz, 1H), 6.47 (d, J = 7.6 Hz,
1H), 6.16 (d, J = 16.0 Hz, 1H), 5.55−5.48 (m, 1H), 4.26 (s, 1H), 4.20−4.09 (m, 2H),
1.62−1.58 (m, 1H), 1.54−1.49 (m, 1H), 1.01−0.95 (m, 1H), 0.89−0.83 (m, 1H); 13C
NMR (100 MHz, CDCl3): δ 167.8, 147.8, 147.6, 144.7, 141.0, 140.8, 140.7, 136.0,
133.8, 129.7, 129.3, 128.5, 128.4, 128.3, 127.9, 127.5, 126.5, 126.4, 124.2, 122.0,
121.9, 120.3, 119.7, 116.9, 111.6, 81.1, 64.9, 63.8, 61.4, 12.2, 9.1; IR (thin film) 3029,
2949, 2860, 1740, 1521, 1342, 1168, 966, 738, 691 cm−1; HRMS (ESI) m/z calcd for
C33H27N2O5 (M+H)+ 531.1920, found 531.1904.
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3k, a white solid, 0.053 g, 47% yield. mp: 38−39 °C; 1H NMR (400 MHz, CDCl3):
δ 7.75 (d, J = 7.2 Hz, 1H), 7.44 (d, J = 7.6 Hz, 2H), 7.38 (d, J = 7.6 Hz, 1H),
7.23−7.16 (m, 7H), 7.12 (d, J = 7.2 Hz, 2H), 7.08 (d, J = 7.6 Hz, 1H), 7.03 (t, J = 7.6
Hz, 1H), 6.90 (d, J = 7.6 Hz, 1H), 6.83 (t, J = 7.2 Hz, 1H), 6.06 (d, J = 16.0 Hz, 1H),
5.50−5.43 (m, 1H), 4.26 (s, 1H), 4.17−4.12 (m, 1H), 4.08−4.03 (m, 1H), 1.63−1.57
(m, 1H), 1.51−1.45 (m, 1H), 1.36−1.30 (m, 1H), 1.00−0.94 (m, 1H); 13C NMR (100
MHz, CDCl3): δ 167.3, 145.4, 143.3, 142.1, 141.7, 140.2, 136.0, 133.8, 132.9, 129.0,
128.8, 128.4, 127.9, 127.5, 127.1, 127.0, 126.9, 126.6, 126.5, 125.0, 123.7, 122.0,
120.6, 119.6, 119.5, 81.1, 65.1, 64.8, 58.4, 10.8, 10.3; IR (thin film) 3058, 2927, 2852,
1737, 1451, 1221, 965, 740, 692 cm−1; HRMS (ESI) m/z calcd for C33H27BrNO3
(M+H)+ 564.1174, found 564.1157.
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3l, a white solid, 0.110 g, 86% yield. mp: 143−144 °C; H NMR (400 MHz,
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CDCl3): δ 7.91 (s, 1H), 7.77 (s, 1H), 7.52 (d, J = 7.6 Hz, 1H), 7.35−7.21 (m, 6H), 7.15
(s, 2H), 6.89−6.85 (m, 2H), 6.75 (t, J = 7.2 Hz, 1H), 6.48 (d, J = 8.0 Hz, 2H), 6.22 (d,
J = 16.0 Hz, 1H), 5.63−5.56 (m, 1H), 4.32−4.27 (m, 1H), 4.22 (s, 1H), 4.16−4.11 (m,
1H), 1.53−1.47 (m, 2H), 1.42−1.36 (m, 1H), 0.98−0.92 (m, 1H); 13C NMR (100 MHz,
CDCl3): δ 167.7, 147.0, 145.7, 143.5, 139.0, 138.6, 136.0, 134.3, 132.5, 132.1, 130.0,
128.4, 128.1, 128.0, 127.9, 126.6, 123.4, 122.1, 121.7, 121.4, 121.2,120.7, 117.3, 80.9,
65.1, 63.3, 61.6, 12.6, 9.0; IR (thin film) 3023, 2926, 2867, 1752, 1595, 1184, 968,
814, 734 cm−1; HRMS (ESI) m/z calcd for C33H26Br2NO3 (M+H)+ 642.0279, found
642.0271.
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3m (dr = 1:1), a white solid, 0.105 g, 93% yield. mp: 39−40 °C; isomer 1: 1H NMR
(400 MHz, CDCl3): δ 7.93 (s, 1H), 7.79−7.76 (m, 2H), 7.38−7.18 (m, 8H), 7.12−7.09
(m, 2H), 6.86−6.82 (m, 4H), 6.20−6.12 (m, 1H), 5.64−5.56 (m, 1H), 4.32−4.26 (m,
2H), 4.21 (s, 1H), 1.52−1.46 (m, 2H), 1.42−1.37 (m, 1H), 0.96−0.93 (m, 1H); 13C
NMR (100 MHz, CDCl3): δ 167.9, 147.6, 146.1, 141.5, 140.1, 139.7, 136.1, 134.0,
132.3, 130.0, 129.0, 128.5, 128.0, 127.8, 127.5, 126.6, 124.5, 123.0, 122.0, 121.6,
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120.8, 120.1, 117.3, 81.2, 65.0, 63.3, 61.7, 12.6, 9.1; isomer 2: H NMR (400 MHz,
CDCl3): δ 7.61−7.59 (m, 1H), 7.52−7.49 (m, 2H), 7.38−7.18 (m, 8H), 6.72−6.68 (m,
2H), 6.49−6.45 (m, 4H), 6.20−6.12 (m, 1H), 5.54−5.47 (m, 1H), 1.52−1.46 (m, 2H),
1.42−1.37 (m, 1H), 0.96−0.91 (m, 1H); 13C NMR (100 MHz, CDCl3): δ 167.9, 146.0,
144.9, 143.8, 140.0, 139.6, 136.0, 133.8, 131.8, 130.0, 129.4, 128.4, 127.9, 127.7,
126.9, 126.5, 124.5, 122.9, 121.9, 121.3, 120.6, 119.5, 117.1, 81.1, 64.8, 63.2, 61.6,
12.4, 9.1; IR (thin film) 3026, 2925, 2854, 1742, 1596, 1172, 965, 744, 692 cm−1;
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HRMS (ESI) m/z calcd for C33H27BrNO3 (M+H)+ 564.1174, found 564.1168.
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3ab, a white solid, 0.075 g, 75% yield. mp: 104−105 °C; H NMR (400 MHz,
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CDCl3): δ 7.81−7.79 (m, 1H), 7.65 (d, J = 7.2 Hz, 1H), 7.55−7.53 (m, 1H), 7.44 (d, J
= 7.2 Hz, 1H), 7.37−7.35 (m, 2H), 7.31−7.27 (m, 2H), 7.21−7.12 (m, 3H), 7.09 (d, J =
7.2 Hz, 2H), 6.84−6.80 (m, 2H), 6.69 (t, J = 7.2 Hz, 1H), 7.49 (d, J = 8.0 Hz, 2H),
6.00 (s, 1H), 4.30 (s, 1H), 4.13 (d, J = 12.0 Hz, 1H), 3.87 (d, J = 12.4 Hz, 1H),
1.58−1.54 (m, 1H), 1.51−1.47 (m, 1H), 1.43−1.37 (m, 1H), 1.35 (s, 3H), 0.95−0.93
(m, 1H); 13C NMR (100 MHz, CDCl3): δ 168.3, 146.3, 145.3, 141.7, 141.0, 140.6,
136.8, 131.8, 129.1, 128.7, 128.2, 128.0, 127.9, 127.6, 127.1, 126.8, 126.6, 124.4,
122.7, 120.0, 119.4, 117.1, 81.3, 70.5, 63.2, 61.7, 15.0, 12.6, 9.1; IR (thin film) 3057,
2920, 2867, 1733, 1448, 1182, 1027, 741, 696 cm−1; HRMS (ESI) m/z calcd for
C34H30NO3 (M+H)+ 500.2226, found 500.2207.
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3ac, a white solid, 0.093 g, 96% yield. mp: 120−121 °C; H NMR (500 MHz,
CDCl3): δ 7.80 (d, J = 7.0 Hz, 1H), 7.63 (d, J = 7.5 Hz, 1H), 7.59 (d, J = 7.5 Hz, 1H),
7.47 (d, J = 7.0 Hz, 1H), 7.41−7.35 (m, 2H), 7.32−7.27 (m, 5H), 7.17 (t, J = 7.0 Hz,
1H), 7.12 (d, J = 7.0 Hz, 1H), 6.84 (t, J = 7.5 Hz, 2H), 6.69 (t, J = 7.0 Hz, 1H), 6.49
(d, J = 8.0 Hz, 2H), 4.44 (d, J = 15.5 Hz, 1H), 4.25 (s, 1H), 4.17 (d, J = 15.5 Hz, 1H),
1.52−1.49 (m, 2H), 1.43−1.41 (m, 1H), 0.99−0.94 (m, 1H); 13C NMR (125 MHz,
CDCl3): δ 168.0, 146.3, 145.2, 141.5, 140.9, 140.7, 131.8, 129.2, 128.8, 128.6, 128.1,
128.0, 127.6, 127.0, 126.8, 124.4, 122.7, 122.1, 120.1, 119.5, 117.1, 86.0, 82.2, 81.2,
63.2, 61.8, 52.5, 12.7, 9.1; IR (thin film) 3053, 2955, 2850, 1744, 1592, 1489, 1167,
744, 692 cm−1; HRMS (ESI) m/z calcd for C33H26NO3 (M+H)+ 484.1913, found
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3ad, a white solid, 0.089 g, 97% yield. mp: 93−94 °C; 1H NMR (500 MHz, CDCl3):
δ 7.78 (d, J = 7.5 Hz, 1H), 7.63 (d, J = 7.5 Hz, 1H), 7.54 (d, J = 7.0 Hz, 1H),
7.41−7.33 (m, 3H), 7.20−7.09 (m, 5H), 6.83 (t, J = 7.5 Hz, 2H), 6.74 (d, J = 7.5 Hz,
2H), 6.69 (t, J = 7.0 Hz, 1H), 6.48 (d, J = 8.0 Hz, 2H), 4.60 (d, J = 13.0 Hz, 1H), 4.38
(d, J = 13.0 Hz, 1H), 4.27 (s, 1H), 1.53−1.45 (m, 2H), 1.41−1.37 (m, 1H), 0.94−0.89
(m, 1H); 13C NMR (125 MHz, CDCl3): δ 168.3, 146.3, 145.2, 141.6, 140.9, 140.6,
134.8, 129.1, 128.8, 128.1, 128.0, 127.8, 127.7, 127.6, 127.0, 126.8, 124.4, 122.7,
120.0, 119.5, 117.2, 81.3, 66.2, 63.2, 61.6, 12.6, 9.1; IR (thin film) 3031, 2946, 2890,
1738, 1447, 1168, 1015, 742, 692 cm−1; HRMS (ESI) m/z calcd for C31H26NO3
(M+H)+ 460.1913, found 460.1895.
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3ae, a white solid, 0.069 g, 81% yield. mp: 87−88 °C; 1H NMR (400 MHz, CDCl3):
δ 7.78 (d, J = 6.8 Hz, 1H), 7.64−7.59 (m, 2H), 7.50 (d, J = 7.6 Hz, 1H), 7.42−7.34 (m,
2H), 7.22 (d, J = 7.6 Hz, 1H), 7.15 (t, J = 7.6 Hz, 1H), 6.84−6.80 (m, 2H), 6.69 (d, J =
7.2 Hz, 1H), 6.48 (d, J = 8.0 Hz, 2H), 4.23 (s, 1H), 3.49−3.46 (m, 2H), 1.56−1.52 (m,
1H), 1.48−1.37 (m, 2H), 0.97−0.87 (m, 3H), 0.85−0.78 (m, 2H), 0.66 (t, J = 6.8 Hz,
3H); 13C NMR (100 MHz, CDCl3): δ 168.5, 146.4, 145.3, 141.8, 141.0, 140.7, 129.1,
128.7, 128.0, 127.6, 127.0, 126.9, 124.4, 122.6, 119.9, 119.3, 117.1, 81.2, 64.1, 63.2,
61.5, 29.8, 18.6, 13.5, 12.4, 9.1; IR (thin film) 3042, 2957, 2871, 1730, 1450, 1187,
745, 690 cm−1; HRMS (ESI) m/z calcd for C28H28NO3 (M+H)+ 426.2069, found
426.2050.
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3af, a white solid, 0.071 g, 90% yield. mp: 116−117 °C; H NMR (400 MHz,
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CDCl3): δ 7.78 (d, J = 6.8 Hz, 1H), 7.63−7.61 (m, 2H), 7.51 (d, J = 7.6 Hz, 1H),
7.42−7.34 (m, 2H), 7.22 (d, J = 7.6 Hz, 1H), 7.14 (t, J = 7.2 Hz, 1H), 6.84−6.80 (m,
2H), 6.69 (d, J = 7.2 Hz, 1H), 6.48 (d, J = 8.0 Hz, 2H), 4.19 (s, 1H), 3.60−3.48 (m,
2H), 1.56−1.53 (m, 1H), 1.51−1.35 (m, 2H), 0.95−0.88 (m, 1H), 0.59 (t, J = 7.2 Hz,
3H); 13C NMR (100 MHz, CDCl3): δ 168.4, 146.4, 145.5, 141.9, 140.9, 140.7, 129.1,
128.7, 128.0, 127.6, 127.0, 126.8, 124.4, 122.6, 119.9, 119.3, 117.0, 81.2, 63.2, 61.6,
60.2, 13.2, 12.4, 9.0; IR (thin film) 3065, 2985, 1733, 1449, 1193, 741, 696 cm−1;
HRMS (ESI) m/z calcd for C26H24NO3 (M+H)+ 398.1756, found 398.1741.
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3ag, a white solid, 0.060 g, 71% yield. mp: 107−108 °C; H NMR (400 MHz,
CDCl3): δ 7.67 (d, J = 7.2 Hz, 1H), 7.63 (d, J = 7.6 Hz, 1H), 7.52 (d, J = 6.8 Hz, 1H),
7.44 (d, J = 7.6 Hz, 1H), 7.33−7.25 (m, 2H), 7.17−7.13 (m, 1H), 7.09 (d, J = 7.6 Hz,
1H), 6.76−6.72 (m, 2H), 6.62 (t, J = 7.2 Hz, 1H), 6.42 (d, J = 8.0 Hz, 2H), 4.17 (s,
1H), 1.68−1.66 (m, 1H), 1.40−1.30 (m, 2H), 0.85−0.78 (m, 1H), 0.70 (s, 9H); 13C
NMR (100 MHz, CDCl3): δ 167.0, 146.4, 145.2, 142.2, 141.3, 140.9, 128.9, 128.6,
127.8, 127.5, 127.2, 127.1, 124.4, 122.6, 119.7, 119.2, 117.3, 81.2, 80.7, 63.0, 60.9,
27.0, 11.9, 8.9; IR (thin film) 3054, 2974, 1730, 1451, 1151, 844, 746, 694 cm−1;
HRMS (ESI) m/z calcd for C28H28NO3 (M+H)+ 426.2069, found 426.2052.
3ah (dr = 3.5/1), a white solid, 0.058 g, 58% yield. mp: 86−87 °C; (major isomer):
1H NMR (400 MHz, CDCl3): δ 7.65 (d, J = 7.2 Hz, 1H), 7.61 (d, J = 7.2 Hz, 1H), 7.53
(d, J = 7.2 Hz, 1H), 7.42 (d, J = 7.2 Hz, 1H), 7.31−7.24 (m, 2H), 7.18−7.13 (m, 1H),
7.09−7.05 (m, 1H), 6.77−6.73 (m, 2H), 6.63−6.59 (m, 1H), 6.43 (d, J = 8.0 Hz, 2H),
4.24 (s, 1H), 4.09−4.02 (m, 1H), 1.62−1.58 (m, 2H), 1.39−1.30 (m, 6H), 1.12−1.07
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(m, 1H), 0.81−0.78 (m, 2H), 0.70−0.67 (m, 2H), 0.57−0.51 (m, 6H), 0.40 (d, J = 7.2
Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 167.6, 146.4, 145.1, 142.3, 141.4, 141.1,
129.0, 128.6, 127.8, 127.5, 127.2, 126.8, 124.4, 122.7, 119.7, 119.4, 117.4, 80.9, 74.3,
63.2, 60.4, 46.1, 38.7, 33.8, 30.7, 25.9, 23.2, 21.7, 20.4, 16.1, 11.7, 9.0; (minor
isomer): 1 H NMR (400 MHz, CDCl3): δ 7.70 (d, J = 7.2 Hz, 1H), 7.69 (d, J = 7.2 Hz,
1H), 7.49 (d, J = 7.2 Hz, 1H), 7.37 (d, J = 7.2 Hz, 1H), 7.31−7.24 (m, 2H), 7.18−7.13
(m, 1H), 7.09−7.05 (m, 1H), 6.77−6.73 (m, 2H), 6.63−6.59 (m, 1H), 6.39 (d, J = 8.0
Hz, 2H), 4.33 (s, 1H), 4.09−4.02 (m, 1H), 1.62−1.58 (m, 2H), 1.43−1.40 (m, 6H),
1.10−1.07 (m, 1H), 0.81−0.78 (m, 2H), 0.68−0.67 (m, 2H), 0.57−0.51 (m, 6H), 0.43
(d, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 167.7, 146.0, 144.0, 142.3, 141.5,
140.4, 129.2, 128.7, 127.7, 127.5, 127.4, 127.0, 124.6, 123.0, 119.8, 119.3, 117.8,
81.7, 74.6, 63.7, 61.1, 46.1, 40.4, 33.9, 31.1, 26.8, 22.5, 21.8, 20.8, 15.3, 12.5, 9.5; IR
(thin film) 3062, 2953, 2867, 1735, 1595, 1454, 1184, 747, 693 cm−1; HRMS (ESI)
m/z calcd for C34H38NO3 (M+H)+ 508.2852, found 508.2836.
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3ai, a white solid, 0.063 g, 73% yield. mp: 120−121 °C; H NMR (400 MHz,
CDCl3): δ 8.01 (d, J = 7.6 Hz, 1H), 7.47−7.45 (m, 1H), 7.41−7.39 (m, 3H), 7.21 (t, J
= 7.6 Hz, 1H), 7.12−7.10 (m, 1H), 7.00−6.98 (m, 2H), 6.96−6.90 (m, 4H), 6.83−6.80
(m, 2H), 6.67−6.64 (m, 1H), 6.48 (d, J = 8.4 Hz, 2H), 4.92 (s, 1H), 1.69−1.66 (m, 1H),
1.43−1.37 (m, 2H), 0.94−0.88 (m, 1H); 13C NMR (100 MHz, CDCl3): δ 196.0, 146.6,
146.2, 141.1, 141.0, 140.3, 137.1, 132.3, 129.2, 128.4, 128.3, 128.1, 127.7, 127.5,
127.4, 127.1, 124.5, 122.3, 120.0, 119.0, 116.7, 81.0, 64.5, 63.7, 13.5, 9.3; IR (thin
film) 3066, 2957, 2857, 1727, 1680, 1597, 1213, 746, 692 cm−1; HRMS (ESI) m/z
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calcd for C30H24NO2 (M+H)+ 430.1807, found 430.1792.
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3aj, as a white solid, 0.065 g, 92% yield. mp: 149−150 °C; H NMR (400 MHz,
CDCl3): δ 7.74 (d, J = 7.6 Hz, 1H), 7.70 (d, J = 7.2 Hz, 1H), 7.61 (d, J = 7.2 Hz, 1H),
7.56 (d, J = 7.2 Hz, 1H), 7.41−7.32 (m, 2H), 7.29−7.25 (m, 1H), 7.21−7.17 (m, 1H),
6.84−6.80 (m, 2H), 6.69 (t, J = 7.2 Hz, 1H), 6.49 (d, J = 8.0 Hz, 2H), 3.71−3.68 (m,
1H), 3.32−3.28 (m, 1H), 3.15−3.11 (m, 1H), 1.41−1.36 (m, 1H), 1.21−1.12 (m, 2H),
0.93−0.87 (m, 1H); 13C NMR (100 MHz, CDCl3): δ 146.6, 144.9, 141.7, 140.6, 140.5,
129.0, 128.6, 128.0, 127.6, 127.1, 126.8, 124.8, 122.5, 120.0, 119.9, 117.2, 80.9, 65.1,
61.0, 57.0, 10.7, 7.2; IR (thin film) 3660, 3030, 2927, 2865, 1592, 1217, 740, 691
cm−1; HRMS (ESI) m/z calcd for C24H22NO2 (M+H)+ 356.1651, found 356.1633.
Direct thermal rearrangement of 3a to 4a’ (Scheme 2-1): In a roundꢀbottle flask
was charged with 3a (0.2 mmol) and toluene (2 mL). And then, the reaction mixture
was stirred vigorously at 100 °C for 36 h until the substrate 3a disappeared
(monitored by TLC). At this time, the solvent was removed under reduced pressure
and the crude product was purified by flash chromatography (the crude residue was
dry loaded with silica gel, 1/100 to 1/10, ethyl acetate/petroleum ether) to provide 1a
(0.020 g, 35% yield), Nꢀ(9Hꢀfluorenꢀ9ꢀylidene)aniline (0.010 g, 20% yield) and 4a’
(0.010 g, 10% yield).
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Cinnamyl4'-hydroxy-1'-phenyl-5',6'-dihydro-1'H-spiro[fluorene-9,2'-pyridine]-3'-c
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arboxylate (4a’), a white solid, mp: 126−127 °C; H NMR (400 MHz, CDCl3): δ
12.90 (s, 1H), 7.48 (d, J = 7.2 Hz, 2H), 7.30−7.04 (m, 11H), 6.67−6.59 (m, 3H), 6.20
(d, J = 7.2 Hz, 2H), 5.78 (d, J = 16.0 Hz, 1H), 5.19ꢀ5.12 (m, 1H), 4.05 (d, J = 7.0 Hz,
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2H), 3.51 (t, J = 5.2 Hz, 2H), 2.79 (t, J = 5.2 Hz, 2H); 13C NMR (100 MHz, CDCl3): δ
174.0, 170.8, 149.2, 148.2, 141.2, 136.3, 132.8, 128.3, 127.8, 127.6, 127.4, 126.7,
126.4, 124.2, 124.1, 122.1, 119.1, 100.9, 70.4, 63.8, 45.4, 31.2; IR (thin film) 3442,
3040, 2954, 2847, 1725, 1640, 1247, 1072, 740, 694 cm−1; HRMS (ESI) m/z calcd for
C33H28NO3 (M+H)+ 486.2069, found 486.2059.
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General procedure B for preparation of product 4 (Table 4): In a roundꢀbottle
flask was charged with 3 (0.2 mmol) and THF (2 mL), LiAlH4 (0.4 mmol, 2.0 equiv)
was added. And then, the reaction mixture was stirred vigorously at 25 °C for 1 h until
the substrate 3 disappeared (monitored by TLC). At this time, the reaction was diluted
with H2O (10 mL) and exacted with Et2O (3 × 10 mL). The combined organic layers
were washed with brine (1 × 10 mL), dried over Na2SO4 and filtered. The solvent was
removed under reduced pressure and the crude product was used directly in the next
step.
In a Teflonꢀsealed reaction flask was charged with the above crude mixture and
MeCN (2 mL). And then, the reaction mixture was stirred vigorously at 120 °C for
18−24 h until the substrate disappeared (monitored by TLC). At this time, the solvent
was removed under reduced pressure and the crude product was purified by flash
chromatography (the crude residue was dry loaded with silica gel, 1/20 to 1/4, ethyl
acetate/petroleum ether) to provide product 4.
3'-(Hydroxymethyl)-1'-phenylspiro[fluorene-9,2'-piperidin]-4'-one (4a), a white
solid, 0.050 g, 70% yield. mp: 116−117 °C; 1H NMR (400 MHz, DMSOꢀd6): δ 7.74 (d,
J = 7.2 Hz, 2H), 7.63−7.61 (m, 1H), 7.40 (t, J = 7.2 Hz, 1H), 7.30−7.19 (m, 4H), 6.77
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(t, J = 7.6 Hz, 2H), 6.61−6.58 (m, 1H), 6.35 (d, J = 7.6 Hz, 2H), 4.29−4.27 (m, 1H),
4.13 (brs, 1H), 3.85−3.82 (m, 1H), 3.67 (d, J = 7.2 Hz, 1H), 3.10−3.01 (m, 2H),
2.90−2.82 (m, 1H), 2.10 (d, J = 5.6 Hz, 1H); 13C NMR (100 MHz, DMSOꢀd6): δ
208.9, 149.4, 147.2, 146.3, 140.1, 139.9, 129.1, 128.8, 128.2, 128.1, 127.8, 125.0,
124.9, 122.5, 122.4, 120.9, 120.2, 73.7, 57.9, 55.7, 47.3, 42.8; IR (thin film) 3657,
3030, 2927, 2865, 1739, 1592, 1217, 740, 691 cm−1; HRMS (ESI) m/z calcd for
C24H22NO2 (M+H)+ 356.1651, found 356.1635.
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3'-(Hydroxymethyl)-1'-(4-phenoxyphenyl)spiro[fluorene-9,2'-piperidin]-4'-one
(4c), a white solid, 0.077 g, 87% yield. mp: 38−39 °C; 1H NMR (500 MHz, CDCl3): δ
7.61 (d, J = 6.5 Hz, 1H), 7.54 (d, J = 7.0 Hz, 1H), 7.39−7.34 (m, 3H), 7.28−7.20 (m,
5H), 7.01 (t, J = 7.0 Hz, 1H), 6.71 (d, J = 7.5 Hz, 2H), 6.44 (t, J = 8.0 Hz, 2H), 6.41
(d, J = 8.0 Hz, 2H), 4.02−3.98 (m, 1H), 3.69−3.65 (m, 2H), 3.37−3.33 (m, 1H),
3.20−3.17 (m, 1H), 2.88 (d, J = 15.0 Hz, 1H), 2.59−2.58 (m, 1H), 2.27 (brs, 1H); 13C
NMR (125 MHz, CDCl3): δ 211.8, 157.5, 153.5, 145.4, 143.8, 143.7, 140.7, 139.7,
129.4, 128.9, 128.7, 127.7, 127.3, 127.2, 124.9, 124.6, 122.7, 120.5, 119.5, 118.3,
118.0, 73.7, 58.5, 58.3, 49.4, 42.4; IR (thin film) 3439, 3034, 2930, 2851, 1708, 1621,
1231, 869, 741, 698 cm−1; HRMS (ESI) m/z calcd for C30H26NO3 (M+H)+ 448.1913,
found 448.1905.
3'-(Hydroxymethyl)-1'-p-tolylspiro[fluorene-9,2'-piperidin]-4'-one (4d), a white
1
solid, 0.055 g, 74% yield. mp: 40−41 °C; H NMR (500 MHz, CDCl3): δ 7.61 (d, J =
7.5 Hz, 1H), 7.54 (d, J = 7.5 Hz, 1H), 7.38−7.34 (m, 3H), 7.29−7.18 (m, 3H), 6.59 (d,
J = 7.5 Hz, 2H), 6.35 (d, J = 8.0 Hz, 2H), 4.05−3.99 (m, 1H), 3.72−3.68 (m, 1H), 3.64
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(dd, J = 9.0 Hz, 3.0 Hz, 1H), 3.32−3.28 (m, 1H), 3.19−3.14 (m, 1H), 2.87 (dt, J = 15.0
Hz, 4.0 Hz, 1H), 2.56−2.54 (m, 1H), 2.25 (brs, 1H), 2.03 (s, 3H); 13C NMR (125 MHz,
CDCl3): δ 211.9, 145.7, 145.6, 144.3, 140.6, 139.6, 133.9, 128.7, 128.6, 128.3, 127.7,
127.2, 125.5, 124.9, 124.6, 120.4, 119.5, 73.5, 58.7, 58.3, 49.4, 42.5, 20.6; IR (thin
film) 3440, 3060, 2929, 2851, 1709, 1622, 1215, 820, 739, 694 cm−1; HRMS (ESI)
m/z calcd for C25H23NO2Na (M+Na)+ 392.1626, found 392.1609.
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3'-(Hydroxymethyl)-1'-(4-isopropylphenyl)spiro[fluorene-9,2'-piperidin]-4'-one
(4e), a white solid, 0.061 g, 77% yield. mp: 125−126 °C; 1H NMR (500 MHz, CDCl3):
δ 7.52 (d, J = 7.0 Hz, 1H), 7.48 (d, J = 7.5 Hz, 1H), 7.32−7.25 (m, 2H), 7.21−7.19 (m,
2H), 7.16−7.10 (m, 2H), 6.57 (d, J = 8.0 Hz, 2H), 6.29 (d, J = 8.5 Hz, 2H), 3.98−3.93
(m, 1H), 3.72−3.68 (m, 1H), 3.57−3.55 (m, 1H), 3.24−3.20 (m, 1H), 3.12−3.06 (m,
1H), 2.82 (dt, J = 15.0 Hz, 4.0 Hz, 1H), 2.55−2.49 (m, 2H), 2.17 (brs, 1H), 0.94 (d, J
= 6.5 Hz, 6H); 13C NMR (100 MHz, CDCl3): δ 211.9, 145.9, 145.7, 144.5, 140.5,
139.6, 128.7, 128.5, 127.7, 127.2, 125.6, 125.0, 124.9, 124.8, 124.5, 120.4, 119.4,
73.4, 58.8, 58.2, 49.2, 42.5, 33.1, 23.7, 23.6; IR (thin film) 3446, 3030, 2963, 2875,
1711, 1616, 1047, 739, 668 cm−1; HRMS (ESI) m/z calcd for C27H28NO2 (M+H)+
398.2120, found 398.2105.
1'-(4-Bromophenyl)-3'-(hydroxymethyl)spiro[fluorene-9,2'-piperidin]-4'-one (4f),
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a white solid, 0.041 g, 47% yield. mp: 42−43 °C; H NMR (500 MHz, CDCl3): δ
7.58−7.55 (m, 2H), 7.50−7.33 (m, 2H), 7.29−7.25 (m, 1H), 7.22−7.18 (m, 2H),
6.81−6.78 (m, 2H), 6.76−6.74 (m, 1H), 6.45 (d, J = 7.5 Hz, 2H), 4.07−4.02 (m, 1H),
3.84−3.79 (m, 1H), 3.67 (dd, J = 8.0 Hz, 2.5 Hz, 1H), 3.32−3.28 (m, 1H), 3.32−3.13
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(m, 1H), 2.92 (dt, J = 15.5 Hz, 4.5 Hz, 1H), 2.56ꢀ2.51 (m, 1H), 2.23 (brs, 1H); 13C
NMR (125 MHz, CDCl3): δ 211.7, 148.3, 145.6, 144.5, 140.4, 139.7, 128.8, 128.6,
127.7, 127.3, 125.0, 124.9, 124.8, 124.5, 124.1, 120.5, 119.5, 73.4, 58.7, 58.2, 48.8,
42.4; IR (thin film) 3415, 3059, 2927, 2877, 1715, 1593, 1486, 1035, 741, 697 cm−1;
HRMS (ESI) m/z calcd for C24H19BrNO (MꢀOH)+ 416.0650, found 416.0630.
1'-(4-Fluorophenyl)-3'-(hydroxymethyl)spiro[fluorene-9,2'-piperidin]-4'-one (4g),
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a white solid, 0.062 g, 82% yield. mp: 139−140 °C; H NMR (400 MHz, CDCl3): δ
7.62 (d, J = 7.2 Hz, 1H), 7.54 (d, J = 7.2 Hz, 1H), 7.40−7.34 (m, 3H), 7.30−7.18 (m,
3H), 6.49−6.45 (m, 2H), 6.42−6.38 (m, 2H), 4.01−3.94 (m, 1H), 3.65−3.59 (m, 2H),
3.36−3.31 (m, 1H), 3.22−3.14 (m, 1H), 2.87 (dt, J = 14.8 Hz, 3.6 Hz, 1H), 2.59−2.54
(m, 1H), 2.25 (s, 1H); 13C NMR (100 MHz, CDCl3): δ 211.6, 160.9 (d, J = 242.8 Hz),
145.2, 144.0, 143.6, 140.7, 139.6, 128.9 (d, J = 12.5 Hz), 127.8, 127.7, 127.6, 127.2,
124.9, 124.5, 120.5, 119.6, 114.4 (d, J = 21.9 Hz), 73.6, 58.5, 58.2, 49.6, 42.4; IR
(thin film) 3474, 3057, 2930, 2850, 1708, 1617, 1211, 837, 739 cm−1; HRMS (ESI)
m/z calcd for C24H21FNO2 (M+H)+ 374.1556, found 374.1544.
3'-(Hydroxymethyl)-1'-(4-(hydroxymethyl)phenyl)spiro[fluorene-9,2'-piperidin]-4
1
'-one (4h), a white solid, 0.056 g, 73% yield. mp: 47−48 °C; H NMR (500 MHz,
CDCl3): δ 7.58−7.55 (m, 2H), 7.41−7.37 (m, 2H), 7.34−7.32 (m, 1H), 7.29−7.26 (m,
1H), 7.22−7.18 (m, 2H), 6.80 (d, J = 8.0 Hz, 2H), 6.44 (d, J = 8.0 Hz, 2H), 4.37 (s,
2H), 4.05−4.02 (m, 1H), 3.82−3.80 (m, 1H), 3.75−3.74 (m, 1H), 3.66 (dd, J = 9.0 Hz,
3.0 Hz, 1H), 3.30−3.26 (m, 1H), 3.17−3.14 (m, 1H), 2.92 (dt, J = 15.5, Hz, 4.5 Hz,
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1H), 2.54−2.53 (m, 1H), 2.22 (brs 1H); C NMR (100 MHz, CDCl3): δ 211.6, 147.9,
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145.6, 144.4, 140.4, 139.6, 136.3, 128.8, 128.7, 127.8, 127.4, 126.6, 124.9, 124.8,
124.4, 120.5, 119.6, 73.4, 64.7, 58.7, 58.2, 48.8, 42.4; IR (thin film) 3419, 3054, 2926,
2862, 1712, 1611, 1509, 1261, 1028, 805, 739 cm−1; HRMS (ESI) m/z calcd for
C25H24NO3 (M+H)+ 386.1756, found 386.1739.
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1'-(3,5-Dimethylphenyl)-3'-(hydroxymethyl)spiro[fluorene-9,2'-piperidin]-4'-one
(4i), a white solid, 0.049 g, 63% yield. mp: 154−155 °C; 1H NMR (400 MHz, CDCl3):
δ 7.58 (d, J = 7.2 Hz, 1H), 7.54 (d, J = 7.6 Hz, 1H), 7.40−7.28 (m, 3H), 7.25−7.21 (m,
1H), 7.20−7.17 (m, 2H), 6.38 (s, 1H), 6.02 (s, 2H), 4.03ꢀ3.98 (m, 1H), 3.79−3.75 (m,
1H), 3.65−3.62 (m, 1H), 3.35−3.30 (m, 1H), 3.16−3.12 (m, 1H), 2.90−2.85 (m, 1H),
2.59 (d, J = 10.4 Hz, 1H), 2.23 (brs, 1H), 1.88 (s, 6H); 13C NMR (100 MHz, CDCl3):
δ 211.9, 148.1, 145.7, 144.5, 140.5, 139.7, 136.9, 128.7, 128.6, 127.6, 127.2, 125.6,
124.8, 124.5, 122.8, 120.2, 119.4, 73.4, 58.5, 58.3, 48.8, 42.5, 20.9; IR (thin film)
3432, 3045, 2928, 2854, 1711, 1614, 1045, 744 cm−1; HRMS (ESI) m/z calcd for
C26H26NO2 (M+H)+ 384.1964, found 384.1953.
3'-(Hydroxymethyl)-1'-(3-nitrophenyl)spiro[fluorene-9,2'-piperidin]-4'-one (4j), a
yellow liquid, 0.040 g, 50% yield. 1H NMR (500 MHz, CDCl3): δ 7.63 (d, J = 8.0 Hz,
1H), 7.56 (d, J = 8.0 Hz, 1H), 7.52 (d, J = 7.5 Hz, 1H), 7.51 (d, J = 7.0 Hz, 1H),
7.49−7.47 (m, 1H), 7.44−7.41 (m, 3H), 7.33−7.22 (m, 2H), 6.92 (t, J = 7.5 Hz, 1H),
6.61 (d, J = 7.0 Hz, 1H), 4.09−3.03 (m, 2H), 3.71−3.69 (m, 1H), 3.29−3.26 (m, 1H),
3.17−3.13 (m, 1H), 3.03−2.98 (m, 1H), 2.59−2.55 (m, 1H), 2.17 (s, 1H); 13C NMR
(100 MHz, CDCl3): δ 210.5, 149.3, 147.8, 144.9, 144.0, 139.9, 139.7, 129.4, 129.2,
128.8, 128.4, 128.3, 127.9, 124.4, 123.9, 120.8, 120.0, 117.6, 117.5, 73.1, 58.1, 58.0,
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