Reactions of Sulfonium Salts with 2,3-Dioxopyrrolidine Derivatives: A Concise Synthesis of Spirocyclopropane

Article abstract of DOI:10.1055/s-0034-1380522

An efficient base-promoted spirocyclopropanation of 2,3-dioxopyrrolidine derivatives with sulfonium salts is described. This reaction enables a novel concise access to polysubstituted spirocyclopropane derivatives in good yields and with a trans/cis ratio of up to amp;gt;20:1 under mild conditions. amp;copy; Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0034-1380522

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
©
Georg Thieme Verlag Stuttgart · New York
2015, 47, A–I
A
special topic
Synthesis
S. Zhang et al.
Special Topic
Reactions of Sulfonium Salts with 2,3-Dioxopyrrolidine Derivatives:
A Concise Synthesis of Spirocyclopropane
Shuang Zhanga
O
Xiu-Qin Hua
Zhu-Yin Wangb
Peng-Fei Xu*a
O
O
O
O
R2
R1
N
Bn
TMG, THF
0 °C
S+
N
Bn
+
4
Br–
a
State Key Laboratory of Applied Organic Chemistry,
R1
O
R2
and College of Chemistry and Chemical Engineering,
Lanzhou University, Lanzhou 730000, P. R. of China
xupf@lzu.edu.cn
R1 = aryl
28 examples
up to 99% yield
up to >20:1 trans/cis ratio
2
R = Ot-Bu, OEt, OBn, aryl
b
College of Mechanics and Materials, Hohai University,
TMG = tetramethylguanidine
Nanjing 210098, P. R. of China
Received: 07.02.2015
Accepted after revision: 11.03.2015
Published online: 19.05.2015
Compared with the methods mentioned above, the sul-
fur ylide mediated protocol is a simple but efficient method
that has been used frequently in the synthesis of three-
membered-ring compounds.9 Since the sulfur ylide was
DOI: 10.1055/s-0034-1380522; Art ID: ss-2015-c0093-st
Abstract An efficient base-promoted spirocyclopropanation of 2,3-di-
oxopyrrolidine derivatives with sulfonium salts is described. This reac-
tion enables a novel concise access to polysubstituted spirocyclopro-
pane derivatives in good yields and with a trans/cis ratio of up to >20:1
under mild conditions.
10
first used by Corey in 1965 as a methylene transfer agent,
a variety of sulfur ylides have been developed for cycliza-
11
tion and cascade reactions. The Aggarwal group and the
Tang12 group have performed a series of elegant experi-
ments to construct three-membered-ring compounds in-
cluding epoxides, aziridines, and cyclopropanes by using
sulfur ylides. Recently, Zhou and co-workers have achieved
the synthesis of spirocyclopropane compounds via the
dearomatization of indole derivatives with sulfonium
salts.13 Apart from these formal [2+1] cycloadditions, the
Xiao group has reported several novel heterocyclic synthe-
Key words spiro compounds, spirocyclopropane, sulfur ylides, sulfo-
nium salt, 2,3-dioxopyrrolidine, heterocycles
Spirocycles, which contain a common structural pattern
present in numerous natural products and pharmaceuti-
cals, are attractive synthetic targets for chemists.1 In the
last few years, many efforts towards this goal have been
ses featuring formal [4+1] cycloadditions of sulfur
2
9g,14
made by the Carreira group. Our group has also achieved
ylides.
Moreover, some annulation processes to form
some advances in the synthesis of spirocycle compounds.3
Spirocyclopropanes and their derivatives are also widely
found in natural products and biologically active pharma-
five- and six-membered heterocyclic compounds have also
been reported.15 In further investigations, the MacMillan
group reported the first organocatalytic asymmetric cyclo-
propanation of α,β-unsaturated aldehydes with sulfur
ylides on the basis of iminium catalysis.1 Other chiral
amine derivatives also proved to be useful with α,β-unsatu-
4
ceutical agents. Due to the unique combination of their re-
6a
activities and structural properties, they often serve as im-
portant versatile building blocks of a wide range of organic
5
16b,c
16d
compounds. Therefore, a great number of synthetic meth-
rated aldehydes
or ketones.
In addition, the Xiao
ods for the construction of the spirocyclopropane skeleton
have been developed. Generally, cyclopropane can be con-
structed by the addition of a carbene to an olefin, such as in
the Lewis acid catalyzed Simmons–Smith type reactions
and metallocarbenoid-mediated cyclopropanation of diazo
group disclosed the asymmetric urea-catalyzed cyclopro-
panation of β,γ-unsaturated α-keto esters via a cooperative
effect of hydrogen-bond catalysis.17
The pyrrolin-2-one skeleton is featured in a large num-
ber of natural products and biologically active drug candi-
6
18
compounds. Furthermore, organocatalyzed Michael-initi-
ated cascade reactions using α-halo carbonyls have been
dates. Compounds which contain the pyrrolin-2-one moi-
19
ety not only have significant antiinflammatory activities,
20
used for diastereo- and enantioselective cyclopropana-
but also inhibit cyclooxygenase-2, a vascular endothelial
7
21
tions, and hypoiodite-mediated oxidative cyclopropana-
growth factor receptor (VEGF-R). However, to the best of
8
tion reactions also demonstrated good results.
our knowledge, the synthesis of polysubstituted spirocyclo-
propane compounds carrying the pyrrolin-2-one moiety
has not been reported so far. Herein, we report a convenient
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, A–I

B
Synthesis
S. Zhang et al.
Special Topic
O
O
O
R
O
1) BnNH2, EtOH
RCHO
N
Bn
N
Bn
CO2Et
2) diethyl oxalate
NaOEt
EtOH, HCl
EtO2C
Scheme 1 Synthesis of starting materials 1
synthesis of spirocyclopropane by using sulfur ylides via
Michael-initiated ring closure (MIRC) of 2,3-dioxopyrroli-
dine derivatives. 2,3-Dioxopyrrolidine derivatives can be
easily synthesized from commercially available reagents in
two steps (Scheme 1).22
ceeded smoothly for all substrates and the corresponding
products 3 were obtained in good to excellent yields, irre-
spective of the electronic properties and the positions of
the substituents on the benzene ring of 1 (entries 1–17).
However, it was observed that the reaction time was short-
er when benzene rings with electron-withdrawing groups
(entries 2–4 and 9–15) were used compared to when ben-
zene rings substituted with electron-donating groups were
used (entries 5–8 and 16–17). On the other hand, the steric
and electronic nature of the substituents had only a slight
influence on the yield of the reaction. The ortho-bromo
In our initial research, the reaction of (E)-1-benzyl-4-
benzylidenepyrrolidine-2,3-dione (1a) and sulfonium salt
2a was carried out at 40 °C in the presence of two equiva-
lents of cesium carbonate as the base and toluene as the
solvent (Table 1). To our delight, the reaction afforded spiro-
cyclopropane 3a in 84% yield and good diastereoselectivity
(
trans/cis, 8:1; entry 1). Encouraged by this result, we car-
ried out optimization of the reaction conditions to further
improve the efficiency and diastereoselectivity. A series of
bases were examined (entries 2–4); inorganic bases such as
sodium carbonate and potassium hydroxide gave moderate
yields and diastereoselectivities, while potassium tert-but-
oxide gave poor diastereoselectivity. These results indicated
that the base plays an important role in this reaction, since
it promotes the participation of sulfonium salts in the nuc-
leophilic reaction. Some organic bases were then tested.
Triethylamine and 1,4-diazabicyclo[2.2.2]octane gave no
better results than other bases (entries 5 and 6), but the re-
actions promoted by 1,8-diazabicyclo[5.4.0]undec-7-ene
and 1,1,3,3-tetramethylguanidine (TMG) afforded high
yields and good diastereoselectivities (entries 7 and 8).
Table 1 Optimizing the Conditions for the Reaction of (E)-1-Benzyl-4-
benzylidenepyrrolidine-2,3-dione (1a) with Sulfonium Salt 2aa
O
O
O
O
t-Bu
base
solvent
O
O
N
Bn
Ph
N
Bn
+
S+
Br–
40 °C
2a
O
Ph
O
1a
t-Bu
3
a
b
c
Entry
Base
Solvent
Time (h)
R
a
t
i
o
t
r
a
n
s
/
c
i
s
Y
i
e
l
d
(
%
)
1
2
3
4
5
6
7d
8
9
Cs
Na
KOH
t-BuOK
Et
2
CO
3
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
THF
10
48
10
12
48
12
2
8:1
8:1
84
64
58
58
29
56
86
97
98
82
99
92
99
75
99
1,1,3,3-Tetramethylguanidine was chosen as the optimal
2
CO
3
base for the reaction, giving a better yield (97%) than 1,8-
diazabicyclo[5.4.0]undec-7-ene (86%). Next, several com-
mon solvents were examined in the reaction. It was found
that the reaction worked well in tetrahydrofuran, dichloro-
methane, xylene, chloroform, and 1,2-dichloroethane (en-
tries 9–13). In the polar solvent acetonitrile, in contrast,
product 3a was obtained in moderate yield with poor dia-
stereoselectivity (75% yield, trans/cis, 4:1; entry 14), and
therefore tetrahydrofuran was selected as the optimal sol-
vent for this reaction. In attempts to further improve the di-
astereoselectivity, the reaction temperature was decreased
to 0 °C (entry 15); this gave similar results as at 40 °C, but
prolonged the reaction time. Therefore, in summary, the
optimized reaction conditions include the use of 1,1,3,3-te-
tramethylguanidine as the base, tetrahydrofuran as solvent,
and a temperature of 40 °C.
10:1
1.4:1
3
N
–
DABCO
DBU
9:1
11:1
9:1
TMG
TMG
TMG
TMG
TMG
TMG
TMG
TMG
2
3
13:1
9:1
10
11
12
13
CH
2
Cl
2
16
3
xylene
12:1
7:1
CHCl
DCE
3
3
4
7:1
14
MeCN
THF
4
4:1
5e
1
12
13:1
a
Reaction conditions (unless noted otherwise): 1a (0.2 mmol), 2a (0.2
Having established the optimal conditions for the reac-
tion, we then explored the reaction scope by using a variety
of 2,3-dioxopyrrolidine derivatives 1 and sulfonium salts 2
as shown in Table 2. Generally speaking, the reactions pro-
mmol), base (2 equiv), solvent (2 mL), 40 °C.
Determined by H NMR spectroscopy.
b
c
1
Isolated yields.
Reaction was carried out at room temperature.
Reaction was carried out at 0 °C.
d
e
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, A–I

C
Synthesis
S. Zhang et al.
Special Topic
substrates (entries 2 and 15) gave lower yields, probably
due to steric effects. Next, various kinds of sulfonium salts 2
were also tested, and good yields and excellent diastereose-
lectivities were also obtained for these reactions (entries
Table 2 Scope of the Reaction of 1 with Sulfonium Salts 2a
O
O
O
O
TMG
THF
O
R2
R1
N
Bn
18–28). Using different ester groups in the sulfonium salts
S+
N
Bn
+
2
decreased the yield of 3 (entries 18 and 19). Sulfonium
40 °C
Br–
salts synthesized from 2-halo-1-phenylethanones also
worked well and gave the corresponding products in good
yields and excellent diastereoselectivities (entries 20–28).
Notably, electron-donating-group-substituted substrates
such as methyl-substituted (entries 21–23) and methoxy-
substituted ones (entry 24) were well tolerated in this
transformation when the reaction time was sufficient. Sul-
fonium salts with phenyl groups carrying electron-
withdrawing substituents (entries 25–28) gave lower yields
than those with electron-donating substituents or without
substituents.
R1
2
R2
O
1
3
Entry Ar
R
Time Ratio
3
Yield
(%)c
(
h)
trans/cisb
1
2
3
4
5
6
7
8
9
Ph
Ot-Bu
Ot-Bu
Ot-Bu
Ot-Bu
Ot-Bu
Ot-Bu
Ot-Bu
Ot-Bu
Ot-Bu
Ot-Bu
Ot-Bu
Ot-Bu
Ot-Bu
Ot-Bu
Ot-Bu
3
2
2
2
4
2
4
5
2
2
1
1
1
1
13:1
>20:1
17:1
3a
3b
3c
3d
3e
3f
98
88
99
98
93
99
88
98
95
94
95
93
98
96
88
2-BrC
3-BrC
4-BrC
6
6
6
H
H
H
4
4
4
>20:1
8:1
2-MeC
6
H
4
4
4
The structures of products 3 were established by their
3-MeC H
17:1
6
1
13
H NMR, C NMR, IR, and HRMS spectra, and the configura-
tion of product 3d was determined by single-crystal X-ray
4-MeC
6
H
17:1
3g
3h
3i
3,4-Me
2
C
6
H
3
19:1
23
diffraction analysis (Figure 1).
2-ClC
4-ClC
6
6
H
4
4
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
1
0
1
2
3
4
5
H
3j
1
1
1
1
1
3,4-Cl
4-NCC
2-FC
4-F CC
2
C
6
H
3
3k
3l
6
H
4
6
H
4
3m
3n
3o
3
6 4
H
2-Br-4-FC
6
H
3
0.5
1
6
7
Ot-Bu
Ot-Bu
8
16:1
3p
3q
96
92
O
O
1
10
>20:1
Figure 1 X-ray crystal structure of compound 3d
1
1
2
2
8
9
0
1
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
OEt
1
1
2
4
2
4
2
2
2
3
2
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
20:1
3r
88
82
99
99
92
97
92
72
81
75
80
In summary, we have successfully developed a concise
and efficient method for the synthesis of spirocyclopropane
compounds under mild basic conditions. The reaction of
OBn
3s
Ph
3t
2-MeC
3-MeC
6
6
H
4
3u
3v
3w
3x
3y
3z
2,3-dioxopyrrolidine derivatives and sulfonium salts fea-
tures high yields and diastereoselectivities (72–99% yields,
up to >20:1 trans/cis ratio).
22
23
H
4
2,4-Me C H
2
6
3
24
25
26
4-MeOC
6
H
4
2-BrC
4-BrC
6
6
H
4
All glassware was thoroughly oven-dried. Chemicals and solvents
were either used as purchased from commercial suppliers or purified
H
4
1
13
by standard techniques. H NMR and C NMR spectra were recorded
on a Bruker AM-400 (400 MHz) spectrometer; the solvent was CDCl3
and TMS was used as internal standard. IR spectra were recorded on a
Nicolet NEXUS 670 FT-IR instrument. HRMS measurements (ESI)
were carried out on a Bruker Apex II mass instrument.
27
2-FC H
3aa
3ab
6
4
28
4-ClC
6
H
4
>20:1
a
Reaction conditions: 1 (0.2 mmol), 2 (0.2 mmol), TMG (2 equiv), THF (2
mL), 40 °C.
b
1
Determined by H NMR spectroscopy.
Isolated yields.
c
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, A–I

D
Synthesis
S. Zhang et al.
Special Topic
Spirocyclopropanes 3; General Procedure
,3-Dioxopyrrolidine derivative 1 (0.2 mmol) and sulfonium salt 2
0.2 mmol) in anhydrous THF (2.0 mL) were placed in a 10 mL Schlenk
IR (KBr): 3400, 2926, 1753, 1720, 1494, 1453, 1369, 1323, 1245, 1151,
–1
1074, 1012, 836, 734, 698 cm .
2
(
1
H NMR (400 MHz, CDCl ): δ = 7.41–7.09 (m, 7 H), 7.08 (d, J = 8.4 Hz, 2
3
tube equipped with a magnetic stirring bar. The mixture was stirred
and heated with an oil bath at 40 °C. Then TMG (0.4 mmol, 2.0 equiv)
was introduced directly, and the stirring was continued at the same
temperature. The reaction was monitored by TLC analysis. After the
reaction was completed, the mixture was subjected directly to flash
column chromatography to yield the corresponding products.
H), 4.75 (d, J = 14.4 Hz, 1 H), 4.70 (d, J = 14.4 Hz, 1 H), 3.74 (d, J = 12.0
Hz, 1 H), 3.67 (d, J = 12.0 Hz, 1 H), 3.22 (d, J = 7.4 Hz, 1 H), 3.06 (d, J =
7.4 Hz, 1 H), 1.43 (s, 9 H).
13
C NMR (100 MHz, CDCl ): δ = 193.1, 167.9, 159.0, 134.4, 131.3,
3
1
3
30.6, 130.4, 129.0, 128.5, 128.3, 121.9, 83.0, 48.5, 47.1, 41.5, 37.7,
4.9, 27.9.
HRMS (ESI): m/z [M + NH4]+ calcd for C24H28N O : 487.1227; found:
2
4
tert-Butyl 5-Benzyl-6,7-dioxo-2-phenyl-5-azaspiro[2.4]heptane-1-
carboxylate (3a)
487.1222.
Yield: 77 mg (98%); white solid; mp 146.6–147.7 °C.
tert-Butyl 5-Benzyl-6,7-dioxo-2-(o-tolyl)-5-azaspiro[2.4]heptane-
-carboxylate (3e)
IR (KBr): 3411, 2926, 2371, 1752, 1720, 1455, 1438, 1369, 1323, 1241,
1
–1
1
151, 1096, 735, 700 cm .
Yield: 75 mg (93%); white solid; mp 121.2–122.5 °C.
1
H NMR (400 MHz, CDCl ): δ = 7.40–7.19 (m, 10 H), 4.74 (s, 2 H), 3.75
3
IR (KBr): 3416, 2954, 2926, 2374, 1753, 1720, 1456, 1369, 1323, 1243,
(d, J = 12.0 Hz, 1 H), 3.69 (d, J = 12.0 Hz, 1 H), 3.28 (d, J = 7.2 Hz, 1 H),
–1
1150, 736, 702 cm
.
3.12 (d, J = 7.2 Hz, 1 H), 1.43 (s, 9 H).
1
H NMR (400 MHz, CDCl ): δ = 7.40–7.32 (m, 5 H), 7.22–7.06 (m, 4 H),
3
13
C NMR (100 MHz, CDCl ): δ = 193.1, 168.3, 159.2, 134.6, 131.3,
3
4.99 (d, J = 14.4 Hz, 1 H), 4.54 (d, J = 14.4 Hz, 1 H), 3.77 (s, 2 H), 3.12 (d,
1
3
29.0, 128.9, 128.5, 128.3, 128.2, 127.9, 82.8, 48.6, 47.3, 42.6, 38.0,
4.9, 28.0.
J = 7.6 Hz, 1 H), 3.08 (d, J = 7.6 Hz, 1 H), 1.96 (s, 3 H), 1.46 (s, 9 H).
13
C NMR (100 MHz, CDCl ): δ = 192.5, 168.5, 159.2, 137.0, 134.6,
3
HRMS (ESI): m/z [M + H]+ calcd for C24H26NO : 392.1856; found:
4
1
4
30.1, 130.0, 129.0, 128.9, 128.6, 128.4, 128.1, 125.8, 82.9, 48.5, 46.9,
1.3, 37.3, 34.6, 28.0, 19.4.
392.1852.
HRMS (ESI): m/z [M + H]+ calcd for C25H28NO : 406.2013; found:
4
tert-Butyl 5-Benzyl-2-(2-bromophenyl)-6,7-dioxo-5-
azaspiro[2.4]heptane-1-carboxylate (3b)
406.2008.
Yield: 83 mg (88%); white solid; mp 171.0–172.0 °C.
tert-Butyl 5-Benzyl-6,7-dioxo-2-(m-tolyl)-5-azaspiro[2.4]heptane-
-carboxylate (3f)
IR (KBr): 3394, 2924, 2371, 1720, 1603, 1438, 1240, 1152, 1124, 1029,
1
–1
7
40, 701 cm .
Yield: 80 mg (99%); white solid; mp 114.7–116.4 °C.
1
H NMR (400 MHz, CDCl ): δ = 7.45–7.32 (m, 8 H), 7.14 (s, 1 H), 5.03
3
IR (KBr): 3418, 2977, 2926, 2869, 1753, 1719, 1607, 1438, 1322, 1227,
(d, J = 14.0 Hz, 1 H), 4.48 (d, J = 14.0 Hz, 1 H), 3.87 (d, J = 11.6 Hz, 1 H),
–1
1150, 1088, 736, 701 cm
.
3.74 (d, J = 11.6 Hz, 1 H), 3.06 (d, J = 8.8 Hz, 2 H), 1.47 (s, 9 H).
1
H NMR (400 MHz, CDCl ): δ = 7.40–7.31 (m, 5 H), 7.19–6.98 (m, 4 H),
3
13
C NMR (100 MHz, CDCl ): δ = 192.6, 167.9, 159.2, 134.5, 132.3,
3
4.77 (d, J = 14.4 Hz, 1 H), 4.72 (d, J = 14.4 Hz, 1 H), 3.74 (d, J = 12.0 Hz,
1
3
32.1, 130.9, 129.5, 128.9, 128.4, 127.2, 125.8, 83.0, 48.5, 46.5, 42.4,
6.8, 35.1, 28.0.
1
H), 3.68 (d, J = 12.0 Hz, 1 H), 3.25 (d, J = 7.2 Hz, 1 H), 3.11 (d, J = 7.2
Hz, 1 H), 2.31 (s, 3 H), 1.43 (s, 9 H).
HRMS (ESI): m/z [M + H]+ calcd for C24H25BrNO : 470.0961; found:
4
13
C NMR (100 MHz, CDCl ): δ = 193.1, 168.4, 159.3, 137.9, 134.6,
3
470.0956.
1
4
31.2, 129.6, 129.0, 128.8, 128.5, 128.3, 128.1, 126.0, 82.8, 48.6, 47.4,
2.7, 38.0, 34.9, 28.0, 21.3.
tert-Butyl 5-Benzyl-2-(3-bromophenyl)-6,7-dioxo-5-
azaspiro[2.4]heptane-1-carboxylate (3c)
HRMS (ESI): m/z [M + H]+ calcd for C25H28NO : 406.2013; found:
4
406.2008.
Yield: 93 mg (99%); white solid; mp 121.2–122.5 °C.
IR (KBr): 3418, 2978, 2929, 1753, 1720, 1567, 1440, 1369, 1323, 1241,
tert-Butyl 5-Benzyl-6,7-dioxo-2-(p-tolyl)-5-azaspiro[2.4]heptane-
-carboxylate (3g)
–1
1151, 1084, 841, 736, 701 cm .
1
1
H NMR (400 MHz, CDCl ): δ = 7.41–7.30 (m, 7 H), 7.17–7.10 (m, 2 H),
Yield: 71 mg (88%); white solid; mp 150.9–152.8 °C.
3
4
1
.77 (d, J = 14.4 Hz, 1 H), 4.71 (d, J = 14.4 Hz, 1 H), 3.74 (d, J = 12.0 Hz,
H), 3.67 (d, J = 12.0 Hz, 1 H), 3.23 (d, J = 7.2 Hz, 1 H), 3.07 (d, J = 7.2
IR (KBr): 3397, 2973, 2925, 2869, 1752, 1720, 1453, 1439, 1369, 1323,
–1
1150, 1089, 841, 735, 704 cm
.
Hz, 1 H), 1.43 (s, 9 H).
1
H NMR (400 MHz, CDCl ): δ = 7.40–7.30 (m, 5 H), 7.08 (s, 4 H), 4.74
3
13
C NMR (100 MHz, CDCl ): δ = 193.0, 167.9, 159.0, 134.4, 133.6,
3
(s, 2 H), 3.74 (d, J = 11.8 Hz, 1 H), 3.68 (d, J = 11.8 Hz, 1 H), 3.25 (d, J =
1
4
32.0, 131.1, 129.7, 129.0, 128.5, 128.4, 127.6, 122.2, 83.1, 48.6, 47.1,
1.3, 37.7, 34.8, 27.9.
7.4 Hz, 1 H), 3.10 (d, J = 7.4 Hz, 1 H), 2.29 (s, 3 H), 1.43 (s, 9 H).
13
C NMR (100 MHz, CDCl ): δ = 193.1, 168.4, 159.3, 137.7, 134.6,
3
HRMS (ESI): m/z [M + NH4]+ calcd for C24H28N O : 487.1227; found:
2
4
1
3
29.0, 128.9, 128.8, 128.5, 128.3, 128.3, 82.8, 48.5, 47.4, 42.6, 38.1,
4.9, 28.0, 21.0.
487.1222.
HRMS (ESI): m/z [M + H]+ calcd for C25H28NO : 406.2013; found:
4
tert-Butyl 5-Benzyl-2-(4-bromophenyl)-6,7-dioxo-5-
azaspiro[2.4]heptane-1-carboxylate (3d)
406.2011.
Yield: 92 mg (98%); white solid; mp 178.2–180.0 °C.
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, A–I

E
Synthesis
S. Zhang et al.
Special Topic
+
tert-Butyl 5-Benzyl-2-(3,4-dimethylphenyl)-6,7-dioxo-5-
HRMS (ESI): m/z [M + NH ] calcd for C24H27Cl N O : 477.1342; found:
4 2 2 4
azaspiro[2.4]heptane-1-carboxylate (3h)
477.1336.
Yield: 82 mg (98%); white solid; mp 136.2–137.7 °C.
tert-Butyl 5-Benzyl-2-(4-cyanophenyl)-6,7-dioxo-5-
azaspiro[2.4]heptane-1-carboxylate (3l)
IR (KBr): 3413, 2974, 2926, 2374, 1752, 1720, 1439, 1369, 1322, 1228,
152, 1093, 736, 702 cm–1
1
.
1
Yield: 77 mg (93%); white solid; mp 167.8–169.0 °C.
H NMR (400 MHz, CDCl ): δ = 7.40–7.30 (m, 5 H), 7.04–6.91 (m, 3 H),
3
4
1
.77 (d, J = 14.4 Hz, 1 H), 4.72 (d, J = 14.4 Hz, 1 H), 3.73 (d, J = 12.0 Hz,
H), 3.68 (d, J = 12.0 Hz, 1 H), 3.23 (d, J = 7.4 Hz, 1 H), 3.10 (d, J = 7.4
IR (KBr): 3410, 2974, 2926, 2371, 2228, 1720, 1439, 1369, 1241, 1153,
1091, 740, 702 cm .
–1
Hz, 1 H), 2.22 (s, 3 H), 2.20 (s, 3 H), 1.43 (s, 9 H).
1
H NMR (400 MHz, CDCl ): δ = 7.57 (d, J = 8.4 Hz, 2 H), 7.41–7.30 (m, 7
3
13
C NMR (100 MHz, CDCl ): δ = 193.1, 168.4, 159.3, 136.4, 136.4,
H), 4.76 (d, J = 14.4 Hz, 1 H), 4.71 (d, J = 14.4 Hz, 1 H), 3.77 (d, J = 12.0
Hz, 1 H), 3.69 (d, J = 12.0 Hz, 1 H), 3.29 (d, J = 7.2 Hz, 1 H), 3.10 (d, J =
7.2 Hz, 1 H), 1.44 (s, 9 H).
3
1
4
34.6, 130.9, 129.4, 129.0, 128.6, 128.5, 128.3, 126.3, 82.7, 48.5, 47.4,
2.7, 38.1, 34.9, 28.0, 19.7, 19.4.
HRMS (ESI): m/z [M + H]+ calcd for C26H30NO : 420.2169; found:
13C NMR (100 MHz, CDCl
131.9, 129.8, 129.0, 128.6, 128.4, 118.3, 111.8, 83.4, 48.6, 47.0, 41.2,
7.8, 34.9, 27.9.
HRMS (ESI): m/z [M + H]+ calcd for C25H25ClN O : 417.1809; found:
): δ = 193.1, 167.6, 158.8, 136.8, 134.3,
3
4
420.2171.
3
tert-Butyl 5-Benzyl-2-(2-chlorophenyl)-6,7-dioxo-5-
2
4
azaspiro[2.4]heptane-1-carboxylate (3i)
417.1804.
Yield: 81 mg (95%); white solid; mp 151.6–152.8 °C.
tert-Butyl 5-Benzyl-2-(2-fluorophenyl)-6,7-dioxo-5-
azaspiro[2.4]heptane-1-carboxylate (3m)
IR (KBr): 3420, 3060, 2978, 2927, 1754, 1721, 1441, 1325, 1239, 1152,
–1
1093, 841, 739, 702 cm .
1
Yield: 80 mg (98%); white solid; mp 29.0–30.1 °C.
H NMR (400 MHz, CDCl ): δ = 7.37–7.20 (m, 9 H), 5.00 (d, J = 14.4 Hz,
3
1
H), 4.53 (d, J = 14.4 Hz, 1 H), 3.83 (d, J = 12.0 Hz, 1 H), 3.73 (d, J = 12.0
IR (KBr): 3414, 2955, 2926, 1755, 1721, 1496, 1455, 1369, 1326, 1229,
–1
Hz, 1 H), 3.12 (d, J = 7.4 Hz, 1 H), 3.04 (d, J = 7.4 Hz, 1 H), 1.46 (s, 9 H).
1151, 759, 702 cm
.
13
1H NMR (400 MHz, CDCl
C NMR (100 MHz, CDCl ): δ = 192.6, 167.9, 159.1, 135.0, 134.5,
3
): δ = 7.40–7.23 (m, 7 H), 7.14 (t, J = 7.2 Hz, 1
3
1
4
30.6, 130.3, 129.3, 129.1, 128.9, 128.6, 128.3, 126.7, 82.9, 48.4, 46.6,
0.0, 36.8, 34.8, 28.0.
H), 6.97 (t, J = 8.6 Hz, 1 H), 4.88 (d, J = 14.4 Hz, 1 H), 4.69 (d, J = 14.4
Hz, 1 H), 3.79 (d, J = 11.8 Hz, 1 H), 3.69 (d, J = 11.8 Hz, 1 H), 3.18 (d, J =
7.4 Hz, 1 H), 3.00 (d, J = 7.4 Hz, 1 H), 1.44 (s, 9 H).
HRMS (ESI): m/z [M + H]+ calcd for C24H25ClNO : 426.1461; found:
4
13C NMR (100 MHz, CDCl
): δ = 193.0, 168.0, 162.5, 160.1, 159.2,
34.5, 130.5, 130.5, 129.9, 129.8, 129.0, 128.9, 128.7, 128.3, 128.2,
426.1463.
3
1
1
3
24.0, 123.9, 119.5, 119.4, 115.3, 115.1, 83.0, 48.4, 46.8, 36.6, 35.6,
5.5, 34.2, 28.0.
tert-Butyl 5-Benzyl-2-(4-chlorophenyl)-6,7-dioxo-5-
azaspiro[2.4]heptane-1-carboxylate (3j)
HRMS (ESI): m/z [M + H]+ calcd for C24H25FNO : 410.1762; found:
Yield: 80 mg (94%); white solid; mp 176.9–178.0 °C.
4
410.1764.
IR (KBr): 3414, 2926, 2371, 1752, 1719, 1496, 1439, 1323, 1242, 1152,
–1
1091, 1015, 738, 702 cm .
tert-Butyl 5-Benzyl-6,7-dioxo-2-[4-(trifluoromethyl)phenyl]-5-
azaspiro[2.4]heptane-1-carboxylate (3n)
1
H NMR (400 MHz, CDCl ): δ = 7.38–7.24 (m, 7 H), 7.37 (d, J = 8.0 Hz, 2
3
H), 4.73 (t, J = 14.8 Hz, 2 H), 3.74 (d, J = 12.0 Hz, 1 H), 3.67 (d, J = 12.0
Hz, 1 H), 3.23 (d, J = 7.2 Hz, 1 H), 3.07 (d, J = 7.2 Hz, 1 H), 1.43 (s, 9 H).
Yield: 88 mg (96%); white solid; mp 164.0–166.2 °C.
1
3
IR (KBr): 3411, 2924, 2857, 2368, 1750, 1715, 1619, 1449, 1153, 1121,
C NMR (100 MHz, CDCl ): δ = 193.1, 168.0, 159.1, 134.5, 133.9,
3
–1
843, 734, 701 cm .
1
3
30.3, 129.9, 129.0, 128.5, 128.4, 128.4, 83.1, 48.6, 47.2, 41.2, 37.8,
5.0, 28.0.
1H NMR (400 MHz, CDCl3): δ = 7.55–7.32 (m, 9 H), 4.75 (s, 2 H), 3.77
(d, J = 12.0 Hz, 1 H), 3.69 (d, J = 12.0 Hz, 1 H), 3.30 (d, J = 7.2 Hz, 1 H),
HRMS (ESI): m/z [M + H]+ calcd for C24H25ClNO : 426.1461; found:
4
4
3.13 (d, J = 7.2 Hz, 1 H), 1.44 (s, 9 H).
26.1456.
13
C NMR (100 MHz, CDCl ): δ = 193.2, 167.9, 159.0, 135.4, 134.4,
3
1
3
29.4, 129.1, 128.6, 128.5, 125.2, 125.2, 83.3, 48.7, 47.1, 41.4, 37.8,
4.9, 28.0.
tert-Butyl 5-Benzyl-2-(3,4-dichlorophenyl)-6,7-dioxo-5-
azaspiro[2.4]heptane-1-carboxylate (3k)
HRMS (ESI): m/z [M + H]+ calcd for C25H25F NO : 460.1730; found:
Yield: 87 mg (95%); white solid; mp 161.2–162.8 °C.
3
4
460.1734.
IR (KBr): 3415, 2979, 2929, 1752, 1715, 1478, 1439, 1369, 1323, 1241,
–1
1
152, 1092, 1031, 737, 702 cm .
tert-Butyl 5-Benzyl-2-(2-bromo-4-fluorophenyl)-6,7-dioxo-5-
azaspiro[2.4]heptane-1-carboxylate (3o)
1
H NMR (400 MHz, CDCl ): δ = 7.40–7.30 (m, 7 H), 7.05–7.03 (m, 1 H),
3
4.77 (d, J = 14.2 Hz, 1 H), 4.70 (d, J = 14.2 Hz, 1 H), 3.74 (d, J = 12.2 Hz,
Yield: 86 mg (88%); white solid; mp 161.1–162.7 °C.
1
H), 3.66 (d, J = 12.2 Hz, 1 H), 3.21 (d, J = 7.2 Hz, 1 H), 3.04 (d, J = 7.2
Hz, 1 H), 1.43 (s, 9 H).
IR (KBr): 3418, 2975, 2927, 1754, 1721, 1599, 1492, 1434, 1369, 1326,
–1
13
1224, 1151, 1092, 857, 738, 702 cm
1H NMR (400 MHz, CDCl
): δ = 7.36–7.28 (m, 6 H), 7.21–7.18 (m, 1 H),
7.05–7.00 (m, 1 H), 5.05 (d, J = 14.2 Hz, 1 H), 4.47 (d, J = 14.2 Hz, 1 H),
.85 (d, J = 12.0 Hz, 1 H), 3.74 (d, J = 12.0 Hz, 1 H), 3.04 (d, J = 7.2 Hz, 1
H), 3.00 (d, J = 7.2 Hz, 1 H), 1.47 (s, 9 H).
.
C NMR (100 MHz, CDCl ): δ = 193.1, 167.7, 158.9, 134.4, 132.3,
3
1
4
32.1, 131.6, 130.9, 130.1, 129.0, 128.6, 128.4, 128.3, 83.3, 48.6, 47.0,
0.6, 37.6, 35.0, 27.9.
3
3
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, A–I

F
Synthesis
S. Zhang et al.
Special Topic
13
1
C NMR (100 MHz, CDCl ): δ = 192.7, 167.8, 163.1, 160.6, 159.1,
H NMR (400 MHz, CDCl ): δ = 7.37–7.17 (m, 15 H), 5.18 (d, J = 12.0
3
3
1
1
34.5, 131.9, 131.8, 128.9, 128.4, 128.2, 128.1, 125.9, 125.8, 119.9,
19.6, 114.6, 114.4, 83.2, 48.6, 46.5, 41.6, 36.8, 35.3, 28.0.
Hz, 1 H), 5.13 (d, J = 12.0 Hz, 1 H), 4.74 (d, J = 14.4 Hz, 1 H), 4.69 (d, J =
14.4 Hz, 1 H), 3.77 (d, J = 12.0 Hz, 1 H), 3.70 (d, J = 12.0 Hz, 1 H), 3.35
(d, J = 7.4 Hz, 1 H), 3.25 (d, J = 7.4 Hz, 1 H).
HRMS (ESI): m/z [M + H]+ calcd for C24H24BrFNO : 488.0867; found:
4
13
488.0864.
C NMR (100 MHz, CDCl ): δ = 192.7, 169.3, 159.1, 134.9, 134.5,
3
1
6
31.0, 129.1, 128.9, 128.7, 128.7, 128.6, 128.4, 128.4, 128.3, 128.1,
7.6, 48.6, 47.5, 43.0, 38.2, 33.4.
tert-Butyl 5-Benzyl-2-(2-naphthyl)-6,7-dioxo-5-azaspiro[2.4]hep-
tane-1-carboxylate (3p)
HRMS (ESI): m/z [M + NH4]+ calcd for C27H27N O : 443.1965; found:
2
4
Yield: 85 mg (96%); white solid; mp 176.9–178.1 °C.
443.1967.
IR (KBr): 3411, 2972, 2923, 1752, 1720, 1437, 1368, 1322, 1236, 1149,
–1
1-Benzoyl-5-benzyl-2-phenyl-5-azaspiro[2.4]heptane-6,7-dione
3t)
811, 745, 702 cm .
(
1
H NMR (400 MHz, CDCl ): δ = 7.75–7.70 (m, 4 H), 7.47–7.25 (m, 8 H),
3
Yield: 79 mg (99%); white solid; mp 173.1–174.9 °C.
4.77 (d, J = 14.4 HZ, 1 H), 4.73 (d, J = 14.4 Hz, 1 H), 3.81 (d, J = 12.0 Hz,
1
H), 3.72 (d, J = 12.0 Hz, 1 H), 3.44 (d, J = 7.4 Hz, 1 H), 3.26 (d, J = 7.4
IR (KBr): 3396, 2924, 2370, 1752, 1719, 1669, 1450, 1298, 1237, 1155,
1028, 740, 699 cm .
–1
Hz, 1 H), 1.45 (s, 9 H).
13
1
C NMR (100 MHz, CDCl ): δ = 193.1, 168.3, 159.2, 134.6, 132.9,
H NMR (400 MHz, CDCl ): δ = 8.00 (d, J = 7.6 Hz, 2 H), 7.64 (t, J = 7.4
3
3
1
1
32.8, 129.0, 128.7, 128.6, 128.4, 128.1, 128.0, 127.8, 127.6, 126.6,
26.3, 126.2, 82.9, 48.6, 47.4, 42.7, 38.1, 35.1, 28.0.
Hz, 1 H), 7.50 (t, J = 7.6 Hz, 2 H), 7.35–7.24 (m, 10 H), 4.78 (d, J = 14.4
Hz, 1 H), 4.68 (d, J = 14.4 Hz, 1 H), 4.21 (d, J = 7.2 Hz, 1 H), 3.88 (d, J =
12.0 Hz, 1 H), 3.68 (d, J = 12.0 Hz, 1 H), 3.57 (d, J = 6.8 Hz, 1 H).
HRMS (ESI): m/z [M + NH4]+ calcd for C28H31N O : 459.2278; found:
2
4
13
459.2274.
C NMR (100 MHz, CDCl ): δ = 194.8, 193.4, 159.2, 136.6, 134.5,
3
1
4
34.1, 131.7, 129.0, 128.9, 128.9, 128.5, 128.4, 128.3, 128.0, 48.6, 47.3,
4.2, 41.0, 36.6.
tert-Butyl 2-(Benzo[d][1,3]dioxol-5-yl)-5-benzyl-6,7-dioxo-5-
azaspiro[2.4]heptane-1-carboxylate (3q)
HRMS (ESI): m/z [M + H]+ calcd for C26H22NO : 396.1594; found:
3
Yield: 80 mg (92%); white solid; mp 174.2–175.3 °C.
396.1950.
IR (KBr): 3410, 1751, 1719, 1493, 1446, 1368, 1321, 1233, 1151, 1040,
–1
5-Benzyl-1-(2-methylbenzoyl)-2-phenyl-5-azaspiro[2.4]heptane-
931, 737, 702 cm .
6,7-dione (3u)
1
H NMR (400 MHz, CDCl ): δ = 7.40–7.30 (m, 5 H), 6.72–6.66 (m, 3 H),
3
Yield: 88 mg (99%); white solid; mp 116.2–117.4 °C.
5.93 (m, 2 H), 4.75 (s, 2 H), 3.72 (d, J = 11.8 Hz, 1 H), 3.66 (d, J = 11.8
Hz, 1 H), 3.22 (d, J = 7.2 Hz, 1 H), 3.05 (d, J = 7.2 Hz, 1 H), 1.43 (s, 9 H).
IR (KBr): 3413, 3061, 2926, 1751, 1716, 1673, 1601, 1455, 1434, 1321,
1234, 1094, 1061, 1010, 748, 699 cm .
–1
13
C NMR (100 MHz, CDCl ): δ = 193.1, 168.2, 159.3, 147.6, 147.4,
3
1
1
4
34.6, 129.0, 128.5, 128.4, 125.0, 122.6, 109.3, 108.0, 101.2, 82.9, 48.6,
7.3, 42.6, 38.1, 35.1, 28.0.
H NMR (400 MHz, CDCl ): δ = 7.72 (d, J = 8.0 Hz, 1 H), 7.45–7.24 (m,
3
13 H), 4.78 (d, J = 14.0 Hz, 1 H), 4.71 (d, J = 14.4 Hz, 1 H), 4.06 (d, J = 7.2
Hz, 1 H), 3.88 (d, J = 12.4 Hz, 1 H), 3.70 (d, J = 12.4 Hz, 1 H), 3.57 (d, J =
HRMS (ESI): m/z [M + H]+ calcd for C25H26NO : 436.1755; found:
6
7
.2 Hz, 1 H), 2.45 (s, 3 H).
436.1753.
13
C NMR (100 MHz, CDCl ): δ = 198.1, 193.3, 159.2, 138.4, 137.2,
3
1
4
34.5, 132.5, 132.1, 131.6, 129.0, 128.9, 128.5, 128.4, 128.0, 126.1,
8.6, 47.3, 44.3, 41.3, 39.5, 21.1.
Ethyl 5-Benzyl-6,7-dioxo-2-phenyl-5-azaspiro[2.4]heptane-1-car-
boxylate (3r)
HRMS (ESI): m/z [M + H]+ calcd for C27
H24NO : 410.1751; found:
Yield: 64 mg (88%); white solid; mp 116.5–118.7 °C.
3
4
10.1746.
IR (KBr): 3417, 2924, 1753, 1720, 1439, 1320, 1266, 1233, 1194, 1162,
–1
1096, 1027, 736, 699 cm .
5
6
-Benzyl-1-(3-methylbenzoyl)-2-phenyl-5-azaspiro[2.4]heptane-
,7-dione (3v)
1
H NMR (400 MHz, CDCl ): δ = 7.41–7.18 (m, 10 H), 4.74 (s, 2 H),
3
4.22–4.15 (m, 2 H), 3.80 (d, J = 12.0 Hz, 1 H), 3.73 (d, J = 12.0 Hz, 1 H),
Yield: 75 mg (92%); white solid; mp 179.2–181.2 °C.
3.33 (d, J = 7.2 Hz, 1 H), 3.20 (d, J = 12.0 Hz, 1 H), 1.27 (t, J = 7.0 Hz, 3
H).
IR (KBr): 3400, 2923, 2372, 1752, 1717, 1666, 1603, 1436, 1323, 1256,
1160, 1094, 752, 698 cm .
–1
13
C NMR (100 MHz, CDCl ): δ = 192.9, 169.3, 159.1, 134.6, 131.1,
3
1
1
3
29.0, 128.9, 128.5, 128.3, 128.3, 128.0, 61.8, 48.6, 47.4, 42.9, 38.1,
3.5, 14.0.
H NMR (400 MHz, CDCl ): δ = 7.81 (d, J = 6.8 Hz, 2 H), 7.46–7.24 (m,
3
12 H), 4.79 (d, J = 14.4 Hz, 1 H), 4.69 (d, J = 14.4 Hz, 1 H), 4.22 (d, J = 7.2
Hz, 1 H), 3.88 (d, J = 12.4 Hz, 1 H), 3.66 (d, J = 12.0 Hz, 1 H), 3.59 (d, J =
HRMS (ESI): m/z [M + H]+ calcd for C22H22NO : 364.1543; found:
4
7
.2 Hz, 1 H), 2.43 (s, 3 H).
364.1547.
13
C NMR (100 MHz, CDCl ): δ = 195.0, 193.5, 159.2, 138.9, 136.7,
3
1
1
35.0, 134.5, 131.8, 129.0, 129.0, 128.9, 128.8, 128.6, 128.4, 128.4,
28.0, 125.6, 48.7, 47.3, 44.2, 41.1, 36.7, 21.3.
Benzyl 5-Benzyl-6,7-dioxo-2-phenyl-5-azaspiro[2.4]heptane-1-
carboxylate (3s)
]+ calcd for C27
H N O : 427.2016; found:
Yield: 70 mg (82%); white solid; mp 150.0–153.4 °C.
HRMS (ESI): m/z [M + NH
27.2011.
4 27 2 3
4
IR (KBr): 3406, 3058, 2924, 1959, 1752, 1721, 1455, 1319, 1265, 1190,
–1
1
158, 967, 739, 699 cm .
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, A–I

G
Synthesis
S. Zhang et al.
Special Topic
5-Benzyl-1-(2,4-dimethylbenzoyl)-2-phenyl-5-azaspiro[2.4]hep-
HRMS (ESI): m/z [M + H]+ calcd for C26H21BrNO : 474.0699; found:
3
tane-6,7-dione (3w)
474.0706.
Yield: 82 mg (97%); white solid; mp 174.4–176.6 °C.
5
-Benzyl-1-(2-fluorobenzoyl)-2-phenyl-5-azaspiro[2.4]heptane-
IR (KBr): 3321, 2957, 2925, 1751, 1716, 1668, 1611, 1453, 1321, 1231,
095, 1060, 1030, 735, 699 cm–1
6,7-dione (3aa)
1
.
1
Yield: 62 mg (75%); white solid; mp 143.6–144.8 °C.
H NMR (400 MHz, CDCl ): δ = 7.67 (d, J = 8.0 Hz, 1 H), 7.38–7.23 (m,
3
1
1
0 H), 7.11–7.07 (m, 2 H), 4.78 (d, J = 14.4 Hz, 1 H), 4.68 (d, J = 14.4 Hz,
H), 4.06 (d, J = 7.2 Hz, 1 H), 3.87 (d, J = 12.4 Hz, 1 H), 3.68 (d, J = 12.0
IR (KBr): 3415, 3062, 2926, 2854, 1751, 1714, 1673, 1609, 1454, 1324,
1272, 1229, 1105, 1016, 736, 699 cm .
–1
Hz, 1 H), 3.56 (d, J = 7.2 Hz, 1 H), 2.43 (s, 3 H), 2.36 (s, 3 H).
1
H NMR (400 MHz, CDCl ): δ = 7.76–7.71 (m, 1 H), 7.61–7.55 (m, 1 H),
3
13
C NMR (100 MHz, CDCl ): δ = 197.1, 193.4, 159.2, 143.4, 138.9,
7.39–7.16 (m, 12 H), 4.78 (d, J = 14.4 Hz, 1 H), 4.72 (d, J = 14.4 Hz, 1 H),
4.22 (dd, J = 7.2 Hz, J = 2.2 Hz, 1 H), 3.88 (d, J = 12.0 Hz, 1 H), 3.69 (d,
J = 12.0 Hz, 1 H), 3.58 (d, J = 7.2 Hz, 1 H).
3
1
1
34.5, 134.3, 133.0, 131.8, 129.5, 129.0, 128.9, 128.4, 128.3, 128.3,
27.9, 126.7, 48.6, 47.3, 44.1, 41.2, 39.3, 21.4, 21.2.
HRMS (ESI): m/z [M + H]+ calcd for C28H26NO : 424.1907; found:
13C NMR (100 MHz, CDCl
159.2, 135.6, 135.5, 134.5, 131.6, 130.4, 130.3, 129.0, 129.0, 128.8,
): δ = 193.9, 193.9, 192.9, 163.1, 160.6,
3
3
424.1902.
1
4
28.5, 128.3, 128.0, 126.0, 125.8, 124.8, 124.7, 117.1, 116.8, 48.6, 47.3,
4.4, 41.1, 40.6, 40.5.
5
-Benzyl-1-(4-methoxybenzoyl)-2-phenyl-5-azaspiro[2.4]hep-
tane-6,7-dione (3x)
HRMS (ESI): m/z [M + Na]+ calcd for C26H20FNO : 436.1319; found:
3
436.1317.
Yield: 78 mg (92%); white solid; mp 202.4–203.9 °C.
IR (KBr): 3407, 2926, 2852, 1747, 1709, 1657, 1600, 1456, 1325, 1243,
–1
5-Benzyl-1-(4-chlorobenzoyl)-2-phenyl-5-azaspiro[2.4]heptane-
,7-dione (3ab)
1171, 1028, 850, 737, 699 cm .
6
1
H NMR (400 MHz, CDCl ): δ = 8.01–7.98 (m, 2 H), 7.38–7.24 (m, 10
3
Yield: 69 mg (80%); white solid; mp 197.8–199.1 °C.
H), 6.99–6.95 (m, 2 H), 4.79 (d, J = 14.4 Hz, 1 H), 4.67 (d, J = 14.4 Hz, 1
H), 4.17 (d, J = 7.2 Hz, 1 H), 3.87 (d, J = 12.0 Hz, 1 H), 3.86 (s, 3 H), 3.68
IR (KBr): 3318, 2923, 2371, 1751, 1714, 1668, 1589, 1433, 1325, 1240,
–1
(d, J = 12.0 Hz, 1 H), 3.57 (d, J = 7.2 Hz, 1 H).
1092, 1010, 757, 698 cm
1H NMR (400 MHz, CDCl
): δ = 7.94 (d, J = 8.8 Hz, 2 H), 7.46 (d, J = 8.4
3
.
13
C NMR (100 MHz, CDCl ): δ = 193.7, 192.9, 164.4, 159.3, 134.6,
3
1
5
31.9, 130.8, 129.7, 129.0, 129.0, 128.5, 128.4, 128.3, 128.0, 114.2,
5.6, 48.7, 47.4, 44.0, 40.8, 36.4.
Hz, 2 H), 7.38–7.23 (m, 10 H), 4.76 (d, J = 14.4 Hz, 1 H), 4.69 (d, J = 14.4
Hz, 1 H), 4.15 (d, J = 7.2 Hz, 1 H), 3.87 (d, J = 12.0 Hz, 1 H), 3.67 (d, J =
12.0 Hz, 1 H), 3.56 (d, J = 7.2 Hz, 1 H).
HRMS (ESI): m/z [M + H]+ calcd for C27H24NO : 426.1700; found:
4
13C NMR (100 MHz, CDCl
1
4
): δ = 193.7, 193.4, 159.1, 140.8, 134.8,
34.5, 131.5, 129.7, 129.3, 129.0, 128.9, 128.5, 128.4, 128.3, 128.1,
8.6, 47.2, 44.3, 41.1, 36.4.
426.1695.
3
5
6
-Benzyl-1-(2-bromobenzoyl)-2-phenyl-5-azaspiro[2.4]heptane-
,7-dione (3y)
HRMS (ESI): m/z [M + H]+ calcd for C26H21ClNO : 430.1199; found:
3
430.1204.
Yield: 68 mg (72%); white solid; mp 163.9–165.0 °C.
IR (KBr): 3397, 2923, 2373, 1752, 1716, 1676, 1587, 1431, 1321, 1228,
–1
1
095, 1062, 751, 699 cm .
Acknowledgment
1
H NMR (400 MHz, CDCl ): δ = 7.62 (d, J = 7.2 Hz, 1 H), 7.60–7.24 (m,
3
1
3 H), 4.81 (d, J = 14.4 Hz, 1 H), 4.70 (d, J = 14.4 Hz, 1 H), 4.04 (d, J = 7.2
We are grateful to the NSFC (21172097, 21202070, 21302075, and
Hz, 1 H), 3.88 (d, J = 12.0 Hz, 1 H), 3.72 (d, J = 12.0 Hz, 1 H), 3.65 (d, J =
7
21372105), the International S&T Cooperation Program of China
.2 Hz, 1 H).
(2013DFR70580), the National Natural Science Foundation from Gan-
13
C NMR (100 MHz, CDCl ): δ = 198.5, 192.9, 159.2, 140.7, 134.5,
su Province of China (no. 1204WCGA015), and the ‘111’ program from
MOE of the P. R. of China.
3
1
1
33.8, 132.8, 131.3, 129.2, 129.0, 128.9, 128.5, 128.4, 128.3, 128.1,
27.8, 119.4, 48.6, 47.1, 44.5, 42.0, 41.3.
HRMS (ESI): m/z [M + Na]+ calcd for C26H20BrNO : 496.0519; found:
3
Supporting Information
496.0524.
Supporting information for this article is available online at
5
6
-Benzyl-1-(4-bromobenzoyl)-2-phenyl-5-azaspiro[2.4]heptane-
,7-dione (3z)
http://dx.doi.org/10.1055/s-0034-1380522.
S
u
p
p
o
nrtIo
i
g
f
rm oaitn
S
u
p
p
ortioIgnfmr oaitn
Yield: 77 mg (81%); white solid; mp 202.3–204.5 °C.
References
IR (KBr): 3374, 2923, 2372, 1594, 1384, 1294, 1235, 1155, 1117, 1036,
–1
7
43, 702 cm .
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©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, A–I

I
Synthesis
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Special Topic
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www.ccdc.cam.ac.uk/data_request/cif.
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, A–I