Asymmetric [3 + 2] Cycloaddition of Methyleneindolinones with N,N′-Cyclic Azomethine Imines Catalyzed by a N,N′-Dioxide-Mg(OTf)2 Complex

Article abstract of DOI:10.1021/acs.joc.5b01760

A highly efficient chiral N,N′-dioxide-Mg(OTf)₂ catalyst system has been developed for the asymmetric 1,3-dipolar cycloaddition between methyleneindolinones and N,N′-cyclic azomethine imines. The desired pyrazolidine products with contiguous qu

Full text of DOI:10.1021/acs.joc.5b01760

Article
pubs.acs.org/joc
Asymmetric [3 + 2] Cycloaddition of Methyleneindolinones with
N,N′‑Cyclic Azomethine Imines Catalyzed by a N,N′‑Dioxide−
Mg(OTf)2 Complex
Chengkai Yin,† Lili Lin,† Dong Zhang,† Juhua Feng,† Xiaohua Liu,† and Xiaoming Feng*,†,‡
†Key Laboratory of Green Chemistry & Technology, Ministry of Education, College of Chemistry, Sichuan University, Chengdu
610064, People’s Republic of China
‡Collaborative Innovation Center of Chemical Science and Engineering, Tianjin 300072, People’s Republic of China
S
* Supporting Information
ABSTRACT: A highly efficient chiral N,N′-dioxide−Mg-
(OTf)2 catalyst system has been developed for the asymmetric
1,3-dipolar cycloaddition between methyleneindolinones and
N,N′-cyclic azomethine imines. The desired pyrazolidine
products with contiguous quaternary−tertiary stereocenters
were obtained in up to 99% yields with up to 99% ee and >19:1
dr under mild reaction conditions.
in developing a highly efficient chiral N,N′-dioxide−alkaline
earth metal complex, the L-PiPr2 - Mg(OTf)2,12 for the
asymmetric 1,3-DC reaction between methyleneindolinones
and N,N′-cyclic azomethine imines, affording products with
both spirooxindole and pyrazolidine structures and contiguous
quaternary−tertiary stereocenters in up to 99% yield, >19:1 dr,
and >99% ee.
INTRODUCTION
■
1,3-Dipolar cycloadditions (1,3-DCs) are among the most
powerful tools for the construction of five-membered hetero-
cycles.1 Up to now, many 1,3-dipoles, such as nitrones,2
azomethine ylides,3 nitrile imines4 and nitrile oxides,5 have
been developed for the cycloadditions. Among them, N,N′-
cyclic azomethine imines, which were first reported in 1968,
can afford useful pyrazolidine motifs by reacting with alkynes or
olefins.6,7 On the other hand, methyleneindolinones are useful
structures in synthesizing spirooxindoles, which are valuable for
accessing natural products and have attracted considerable
attention.8 The 1,3-DCs of N,N′-cyclic azomethine imines with
methyleneindolinones can afford products with pyrazolide and
spirooxindole structures, both of which are useful structural
units in organic synthesis and may have practical use in
pharmaceutical field.9 In 2013, Wang developed a new chiral
bis-phosphoric acid bearing triple axial chirality for the
enantioselective 1,3-dipolar cycloaddition of N,N′-cyclic
azomethine imines and methyleneindolinones, creating chiral
spiro[pyrazolidin-3,3-oxindoles] in excellent yields and selecti-
vities.7q Since the attractive structure might be beneficial for
drug discovery, developing new efficient catalysts for this 1,3-
dipolar cycloaddition is still helpful.
RESULTS AND DISSCUSION
■
Initially, the 1,3-DC of (E)-tert-butyl 3-(2-methoxy-2-oxoethy-
lidene)-2-oxoindoline-1-carboxylate (1a) with N,N′-cyclic
azomethine imine (2a) was selected as model reaction to
optimize the reaction conditions and the representative results
are summarized in Table 1. At first, several alkaline metal salts
complexing with L-PiPr2 derived from (S)-pipecolic acid were
examined in CH2Cl2. The complexes of Ca(OTf)2 and
Ba(ClO4)2 both gave high dr values, but moderate yields and
ee values (Table 1, entries 1−2). Excitingly, the complex of
Mg(OTf)2 could offer only one isomer in nearly quantitative
yield (Table 1, entry 3). The anions of Mg(II) had no obvious
effect on the reaction since the complex of Mg(NTf2)2 gave
similar results with that of Mg(OTf)2 (Table 1, entry 4). Then,
the structure of ligand was tested. The chiral backbone of ligand
had little effect on dr and ee and relatively obvious effect on
yield. Both L-proline derived L-PrPr2 and L-ramipril derived L-
RaPr2 gave lower yields (Table 1, entry 3 vs entries 5 and 6).
On the contrary, the steric hindrance of the amide moiety
affected the reaction greatly. Decreasing the steric hindrance
Chiral metal complex catalysts have shown promising
catalytic abilities and potential applications in lab and industry
synthesis. Alkaline earth metals are abundant, less toxic and less
harmful to human beings, making them competitive to form
chiral catalysts.10,11 On the other hand, N,N′-dioxides are
proved to have good ability in complexing with alkaline earth
metals and have shown a promising ability in the field of
catalytic asymmetric synthesis. Herein, we described our effort
Received: July 30, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.5b01760
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The Journal of Organic Chemistry
Article
the amide was changed to ethyl ester group, the enantiose-
lectivity was decreased to 80% ee (Scheme 1, 3aa). The (E)-
benzyl 3-(2-(tert-butoxy)-2-oxoethylidene)-2-oxoindoline-1-
carboxylate, which is protected by -Cbz group, was also tested
in the reaction system, and the desired product can be obtained
with excellent yield (99%) and moderate enantioselectivity
(49%) (Scheme 2, 3ac). We think if the protecting group on
the amide of the methyleneindolinones replaced from Boc to
ethyl ester group or Cbz group, the steric hindrance of the
proposed transition state would decrease when the methyl-
eneindolinones coordinated with the catalyst to react with the
N,N′-cyclic azomethine imine. The absolute configuration of 3t
was determined to be (1′R,2′R,3′R) by X-ray crystallographic
analysis, and the others were assigned to be the same by
comparing the Cotton effect of the CD spectra with that of 3t
(see Supporting Information).
Table 1. Optimization of the Reaction Conditions
a
b
c
entry
metal
ligand
yield (%)
dr
ee (%)
1
2
3
4
5
6
7
Ca(OTf)2
Ba(ClO4)2
Mg(OTf)2
Mg(NTf2)2
Mg(OTf)2
Mg(OTf)2
Mg(OTf)2
Mg(OTf)2
Mg(OTf)2
L-PiPr2
L-PiPr2
L-PiPr2
L-PiPr2
L-PrPr2
L-RaPr2
L-PiPh
L-PiPr2
L-PiPr2
45
38
99
99
90
91
76
99
74
15:1
66
63
>99
99
99
98
75
99
98
19:1
To show the prospect of the methodology in synthesis, a
gram-scale synthesis of 3a was carried out (Scheme 2). 2.5
mmol of 1a and 2a were treated in the optimized reaction
conditions, and the product 3a was obtained in >99% yield
(1.19g) with >19:1 dr and 98% ee.
>19:1
19:1
>19:1
>19:1
19:1
To gain insight into the reaction mechanism, operando IR
experiment of methyleneindolinone (1a) and N,N′-cyclic
azomethine imine (2a) catalyzed by the L-PiPr2-Mg(OTf)2
was carried out (Scheme 3A, see Supporting Information for
detail). The results clearly demonstrated that the amount of
product increased with the consuming of starting materials.
Since no intermediates were observed, the reaction may
proceed in a concerted way. Besides, the operando IR
experiment also gave some information about the interaction
between the catalyst and the substrate 1a. As shown in Scheme
3B, when Mg(OTf)2 was added to the solution of ligand L-
PiPr2, the peak at 1674 cm−1, which was caused by the ligand,
decreased. Meanwhile, a peak at 1660 cm−1 appeared. This
change indicated the complexation between the ligand and
Mg(OTf)2. After the addition of substrate 1a (caused peak at
1640 cm−1), a new peak at about 1635 cm−1 was formed
gradually with disappearance of the catalyst (peak at 1660
cm−1) and substrate 1a (peak at 1640 cm−1). This change
indicated that there was an interaction between the catalyst and
the substrate.
A nonlinear effect (NLE) experiment was investigated for the
reaction system, by varying the ee value of the chiral ligand L-
PiPr2 (Scheme 4). The relationship between the enantiomeric
excess of the product 3a and L-PiPr2 showed a weak negative
nonlinear effect, which suggested that both monomeric and
oligomeric species of the catalyst may exist in the reaction
system, but the monomeric complex might function as the
more active and effective catalyst.
d
8
>19:1
19:1
e
9
a
Unless otherwise noted, the reactions were carried out with 1a (0.1
mmol) and 2a (0.1 mmol) in 1.0 mL of CH2Cl2, 10 mol % catalyst
b
c
loading in N2, at 30 °C for 48 h. Isolated yield. Determined by
d
e
HPLC. With 5 mol % catalyst loading. With 1 mol % catalyst
loading.
from isopropyl to hydrogen led to a dramatic decrease of yield
and enantioselectivity (Table 1, entry 7). Delightedly, the
catalyst loading could be decreased to 5 mol %, and the results
were maintained (Table 1, entry 8). Further the yield decreased
to 74%, when the catalyst loading were lowed to 1 mol %
(Table 1, entry 9). Thus, the optimized experimental
conditions were as follows: 5 mol % L-PiPr2- Mg(OTf)2
(1:1) in CH2Cl2 at 30 °C.
Under the optimal conditions, the scope of the reaction was
examined and the results were summarized in Table 2. First, the
scope of 2 was examined. Aryl R2 with electron-donating or
electron-withdrawing groups at meta- or para- positons on the
N,N′-cyclic azomethine imines gave the corresponding
products in excellent yields with high enantioselectivities
(Table 2, entries 2−9). But R2 with a substituent at the
ortho- position gave lower yield and decreased enantioselectivity
(Table 2, entry 10), which might be caused by the steric
hindrance of the ortho- substituent with the catalyst. When R2
were ring-fused naphthyl group, heteroaromatic thiophene
group as well as furan group, the desired products could also be
obtained in 71% to 99% yields with 10:1 to >19:1 dr and 90%
to 99% ee (Table 2, entries 11−13).
Then, the scope of methyleneindolinones was determined.
Substituent R1 at different positions of the phenyl groups had
little influence on the selectivity. All products were obtained in
90% to 99% ee (7:1 to >19:1 dr, Table 2, entries 14 to 23). To
our delight, when R2 equaled aliphatic cyclopentyl was also
tolerant in the reaction system, giving desired 3ab in 46% yield
with 6:1 dr and 99% ee (Table 2, entry 24). At last, the ester
group and the N-protecting group of methyleneindolinones
were tested (Scheme 1). The results showed that the bulkier
ester groups did not affect the dr and ee, but caused a decrease
of yield. When the protecting group on the nitrogen atom of
The catalytic composition between substrate and the catalyst
were also investigated by ESI-MS (Scheme 5). A mixture of
ligand L-PiPr2, Mg(OTf)2 and 1a (1:1:1) in CH2Cl2, displayed
an ion at m/z 821.4166 ([L-PiPr2 + Mg2+ + OTf−]+ m/z calcd
821.3985), this result suggested that the L-PiPr2 coordinated
with the Mg(OTf)2 in a 1:1 ratio (see Supporting Information
for detail). Another characteristic signal of [L-PiPr2 + Mg2+
+
OTf− + 1a]+ at m/z 1124.5394 (m/z calcd 1124.5092) was also
observed, which suggested that the catalyst coordinated with 1a
in a 1:1 ratio.
On the basis of the operando IR, NLE and ESI-MS analysis,
as well as our previous work12d,e and the absolute configuration
of the products,13 a possible transition-state model was
proposed. As shown in Scheme 6, the ligand and the oxygen
B
DOI: 10.1021/acs.joc.5b01760
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Table 2. Substrate Scope in the Asymmetric [3 + 2] Cycloaddition
a
Unless otherwise noted, the reactions were carried out with 1 (0.1 mmol) and 2 (0.1 mmol) in 1.0 mL of CH2Cl2, 5 mol % catalyst loading in N2, at
b
c
d
e
30 °C for 48 h. Isolated yield. The diastereoselectivities of the products were detected by 1H NMR. Determined by HPLC. Reaction time is 36 h.
f
The absolute configuration was determined by X-ray crystallographic analysis.
atoms of both amide and the N-Boc of the methyleneindoli-
none coordinated with the Mg(II) to form an octahedral
complex (in Scheme 3B, the new peak at 1635 cm−1 may
represent a feature peak of this complex). The Si face of the
C
DOI: 10.1021/acs.joc.5b01760
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The Journal of Organic Chemistry
Article
Scheme 1. Substrate Scope of Other Methyleneindolinones
Scheme 4. Nonlinear Effect Experiment of 1a and 2a
(1′R,2′R,3′R) configuration, which was same with the result of
the X-ray crystallographic analysis (Scheme 6).
CONCLUSIONS
■
We have developed a highly efficient chiral N,N′-dioxide−
Mg(OTf)2 complex for the catalytic asymmetric 1,3-dipolar
cycloaddition of methyleneindolinones with N,N′-cyclic
azomethine imines. With less than 5 mol % catalyst loading,
pyrazolidinyl spirooxindole products with contiguous quater-
nary−tertiary stereocenter were obtained in up to 99% yield,
>19:1 dr and >99% ee.
Scheme 2. Gram Scale Synthesis of 3a
EXPERIMENTAL SECTION
■
General Remarks. 1H NMR spectra were recorded on commercial
instruments (400 MHz). Chemical shifts were reported in ppm from
tetramethylsilane with the solvent resonance as the internal standard
(CDCl3, δ = 7.26; DMSO, δ = 2.49). Spectra were reported as follows:
chemical shift (δ ppm), multiplicity (s = singlet, d = doublet, t =
triplet, q = quartet, m = multiplet), coupling constants (Hz),
integration and assignment. 13C NMR spectra were collected on
commercial instruments (100 MHz) with complete proton decou-
pling. Chemical shifts are reported in ppm from the tetramethylsilane
with the solvent resonance as internal standard (CDCl3, δ = 77.0;
DMSO, δ = 39.6). Enantiomeric excesses (ee) were determined by
HPLC analysis using the corresponding commercial chiralpak column
as stated in the experimental procedures at 25 °C. Optical rotations
Scheme 3. Operando IR Experiments of Standard Reaction
were reported as follows: [a]T (c g/100 mL, in solvent). HRMS was
D
recorded on a commercial apparatus (ESI Source). All reagents and
solvents were obtained from commercial suppliers and used without
further purification except as indicated below. All catalytic reactions
were run in dried glassware. CH2Cl2 was distilled over CaH2.
General Procedure for Chiral N,N′-Dioxide Preparation. The
N,N′-dioxides were prepared according to the methods reported in the
literature.12a
General Procedure to Prepare the Substrates. Methacrylate
(3.6 mL) was added to the solution of hydrazine hydrate (2 mL) in 10
mL ethanol which was cooled in an ice bath. After addition, the
mixture was heated to reflux for 8 h. Then the solvent and the volatile
components were removed under reduced pressure. The thick
colorless oil, crude pyrazolidin-3-one, was obtained in 80% yield. By
subjecting pyrazolidin-3-one (1.1 equiv) to various aromatic aldehydes
(1.0 equiv) in methanol (20 mmol in 15 mL of methanol) at room
temperature, the crude products of the desired 3-oxo-1,2-pyrazolidi-
nium ylides were formed. After removing the solvent methanol, the
crude product was recrystallized in ethanol. Washed by ethyl acetate
and dried under a vacuum, the pure product was obtained.
General Procedure to Prepare the Substrates 1ab.
Pyrazolidin-3-one (1.1 equiv) was added into the cyclopentanecarbal-
dehyde (1.0 equiv) in methanol (20 mmol in 15 mL of methanol) at
room temperature, the crude products of the desired 3-oxo-1,2-
methyleneindolinone was shielded by the 2,6-diisopropylphenyl
group of the ligand, therefore, the N,N′-cyclic azomethine
imine attacked from the Re face to afford the product with
D
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Scheme 5. HRMS of the N,N′-Dioxide, Mg2+, OTf−, and 1a
PrOH; 90/10, 1.0 mL/min, λ = 254 nm) tR(major) = 8.95 min, tR(minor)
=
Scheme 6. Possible Transition-State Model
1
11.77 min; H NMR (400 MHz, CDCl3) δ 7.62−7.50 (m, 2H), 7.15
(t, J = 7.6 Hz, 1H), 7.05 (t, J = 7.6 Hz, 1H), 6.90−6.88(m, 4H), 5.19
(s, 1H), 4.21 (s, 1H), 3.76−3.73 (m, 1H), 3.22 (s, 3H), 3.10−3.01 (m,
1H), 3.00−2.89 (m, 1H), 2.87−2.76 (m, 1H), 2.17 (s, 3H), 1.63 (s,
9H). 13C NMR (100 MHz, CDCl3) δ 173.8, 173.0, 166.9, 148.5, 139.4,
138.5, 129.3, 128.9, 128.1, 127.1, 126.0, 123.9, 114.4, 84.9, 78.4, 77.4,
77.3, 77.1, 76.7, 65.1, 63.6, 52.2, 47.0, 31.6, 28.0, 21.1. HRMS (ESI-
TOF) calcd for C27H29N3NaO6 [M + Na]+ 514.1954, found 514.1953.
1-tert-Butyl 3′-methyl 2,5′-dioxo-1′-(3-(trifluoromethyl)phenyl)-
3′,5′,6′,7′-tetrahydro-1′H-spiro[indoline-3,2′-pyrazolo[1,2-a]-
pyrazole]-1,3′-dicarboxylate (3c). Yield 54.2 mg; 99%, yellow oil;
99% ee, 7:1 dr; [α]21 = −13.9 (c = 0.74 in CHCl3); HPLC (Daicel
D
chiralcel IA, n-hexane/i-PrOH 80/20, 1.0 mL/min, λ = 254 nm) tR1
=
12.18 min, tR2 = 20.27 min; 1H NMR (400 MHz, CDCl3) δ 7.53 (dd, J
= 12.8, 4.8 Hz, 2H), 7.37 (d, J = 7.4 Hz, 1H), 7.31 (s, 1H), 7.23−
7.19(m, 2H), 7.14 (td, J = 8.0, 1.4 Hz, 1H), 7.05 (td, J = 7.6, 0.8 Hz,
1H), 5.24 (s, 1H), 4.28 (s, 1H), 3.82−3.78 (m, 1H), 3.25 (s, 3H),
3.15−3.02 (m, 1H), 2.96−2.93 (m, 1H), 2.92−2.75 (m, 1H), 1.63 (s,
9H). 13C NMR (100 MHz, CDCl3) δ 173.7, 172.5, 171.2, 166.7, 148.3,
139.1, 132.6, 130.8, 130.4, 129.7, 128.7, 125.7, 125.6, 125.5, 124.1,
124.0, 123.9, 123.2, 114.5, 85.3, 77.9, 77.4, 77.1, 76.7, 65.3, 63.2, 60.4,
52.4, 47.1, 31.5, 27.9, 21.1, 14.2, 0.0. HRMS (ESI-TOF) calcd for
C27H26F3N3NaO6 [M + Na]+ 568.1671, found 568.1674.
pyrazolidinium ylide was formed. After removing the solvent
methanol, the crude product was recrystallized in ethanol. Washed
by ethyl acetate and dried under a vacuum, the pure product was
obtained in 50% yield, white powder.
General Procedure of the Catalytic Reactions. A mixture of
N,N′-dioxide L-PiPr2 (3.3 mg, 0.005 mmol), Mg(OTf)2 (1.6 mg,
0.005 mmol), 1a (30.3 mg, 0.1 mmol), was stirred in dry CH2Cl2 (1
mL) at 30 °C in the N2 for 30 min. Then, N,N′-cyclic azomethine
imine (2a) (17.4 mg, 0.1 mmol) was added. The reaction mixture was
stirred at 30 °C for 48 h. After complete consumption of the starting
materials, the mixture was directly purified by column chromatography
on silica gel (petroleum ether: ethyl acetate = 2:1) to afford 3a (47.2
mg, 99% yield) as a light yellow powder.
1-tert-Butyl 3′-methyl 1′-(3-bromophenyl)-2,5′-dioxo-3′,5′,6′,7′-
tetrahydro-1′H-spiro[indoline-3,2′-pyrazolo[1,2-a]pyrazole]-1,3′-di-
carboxylate (3d). Yield 45.2 mg, 82%; yellow oil; 99% ee, >19:1 dr;
[α]25 = −20.2 (c = 0.61 in CHCl3); HPLC (Daicel chiralcel IA, n-
D
hexane/i-PrOH 90/10, 1.0 mL/min, λ = 254 nm) tR(major) = 22.93 min,
1-tert-Butyl 3′-methyl 2,5′-dioxo-1′-phenyl-3′,5′,6′,7′-tetrahydro-
1′H-spiro[indoline-3,2′-pyrazolo[1,2-a]pyrazole]-1,3′-dicarboxylate
(3a). Yield 47.2 mg, 99%; yellow powder, mp 90−92 °C; 99% ee,
>19:1 dr; [α]21D = −25.7 (c = 0.68 in CHCl3); HPLC (Daicel chiralcel
IA, n-hexane/i-PrOH; 80/20, 1.0 mL/min, λ = 254 nm) tR(major) = 9.52
1
tR(minor) = 38.30 min; H NMR (400 MHz, CDCl3) δ 7.54 (t, J = 8.6
Hz, 2H), 7.26−7.13 (m, 3H), 7.08 (t, J = 7.4 Hz, 1H), 6.96−6.92 (m,
2H), 5.20 (s, 1H), 4.18 (s, 1H), 3.80−3.76 (m, 1H), 3.24 (s, 3H),
3.11−2.92 (m, 2H), 2.90−2.76 (m, 1H), 1.64 (s, 9H). 13C NMR (100
MHz, CDCl3) δ 173.7, 172.6, 166.8, 148.3, 139.2, 133.7, 131.9, 130.2,
129.7, 129.7, 125.8, 125.7, 124.0, 123.3, 122.3, 114.5, 85.2, 77.7, 77.4,
77.3, 77.1, 76.7, 65.2, 63.3, 52.3, 47.1, 31.5, 28.0. HRMS (ESI-TOF)
calcd for C26H2678.9183BrN3NaO6 [M + Na]+ 578.0903, found
578.0912. C26H2680.9163BrN3NaO6 [M + Na]+ 580.0882, found
580.0900.
1
min, tR(minor) = 14.16 min; H NMR (400 MHz, CDCl3) δ 7.53−7.50
(m, 2H), 7.16−7.00 (m, 7H), 5.21 (s, 1H), 4.24 (s, 1H), 3.79−3.75
(m, 1H), 3.23 (s, 3H), 3.12−3.02 (m, 1H), 2.95−2.93 (m, 1H), 2.88−
2.75 (m, 1H), 1.63 (s, 9H). 13C NMR (100 MHz, CDCl3) δ 173.9,
172.9, 166.9, 148.5, 139.3, 131.3, 129.4, 128.7, 128.2, 127.2, 125.9,
123.9, 123.8, 114.4, 84.9, 78.5, 77.4, 77.0, 76.7, 65.2, 63.5, 52.3, 47.0,
31.6, 28.0, 0.0. HRMS (ESI-TOF) calcd for C26H27N3NaO6 [M +
Na]+ 500.1798, found 500.1793.
1-tert-Butyl 3′-methyl 1′-(3,4-dimethylphenyl)-2,5′-dioxo-
3′,5′,6′,7′-tetrahydro-1′H-spiro[indoline-3,2′-pyrazolo[1,2-a]-
pyrazole]-1,3′-dicarboxylate (3e). Yield 27.2 mg, 54%; yellow oil;
1-tert-Butyl 3′-methyl 2,5′-dioxo-1′-(p-tolyl)-3′,5′,6′,7′-tetrahy-
99% ee, 10:1 dr; [α]21 = −16.8 (c = 0.12 in CHCl3); HPLC (Daicel
dro-1′H-spiro[indoline-3,2′-pyrazolo[1,2-a]pyrazole]-1,3′-dicarbox-
D
ylate (3b). Yield 48.7 mg, 99%; yellow oil; 97% ee, >19:1 dr; [α]21
=
chiralcel IA, n-hexane/i-PrOH 80/20, 1.0 mL/min, λ = 254 nm)
D
−22.5 (c = 0.75 in CHCl3); HPLC (Daicel chiralcel IA, n-hexane/i-
tR(major) = 9.20 min, tR(minor) = 13.46 min; 1H NMR (400 MHz, CDCl3)
E
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1
δ 7.48−7.45 (m, 2H), 7.07 (t, J = 7.6 Hz, 1H), 6.98 (t, J = 7.6 Hz, 1H),
6.72 (q, J = 7.6 Hz, 3H), 5.12 (s, 1H), 4.09 (s, 1H), 3.69−3.65 (m,
1H), 3.15 (s, 3H), 3.02−2.81 (m, 2H), 2.78−2.64 (m, 1H), 2.00 (s,
3H), 1.98 (s, 3H), 1.56 (s, 9H). 13C NMR (100 MHz, CDCl3) δ
173.7, 173.0, 167.0, 148.6, 139.4, 137.1, 136.5, 129.4, 129.3, 128.5,
128.4, 126.0, 124.7, 124.0, 123.8, 114.4, 84.8, 78.5, 77.4, 77.0, 76.7,
65.2, 63.5, 52.2, 47.1, 31.7, 28.1, 19.5, 19.4. HRMS (ESI-TOF) calcd
for C28H31N3NaO6 [M + Na]+ 528.2111, found 528.2117.
tR(minor) = 13.22 min; H NMR (400 MHz, CDCl3) δ 7.56 (d, J = 8.2
Hz, 1H), 7.27−7.20(m, 2H), 7.04−7.00(m, 2H), 6.92−6.65 (m, 3H),
5.21 (s, 1H), 4.43 (s, 1H), 3.77−3.72(m, 1H), 3.14 (s, 3H), 3.10−2.99
(m, 1H), 2.80−2.75(m, 2H), 1.58 (s, 9H). 13C NMR (100 MHz,
CDCl3) δ 173.4, 171.8, 166.0, 160.8, 158.3, 147.7, 138.6, 129.0, 128.9,
128.3, 128.2, 128.1, 124.4, 123.0, 122.9, 122.8, 122.7, 118.8, 118.6,
114.1, 113.9, 113.6, 83.7, 76.3, 76.0, 75.7, 70.8, 63.1, 62.8, 51.2, 45.6,
29.8, 27.0, −0.0. HRMS (ESI-TOF) calcd for C26H26FN3NaO6 [M +
Na]+ 518.1703, found 518.1712.
1-tert-Butyl 3′-methyl 1′-(4-bromophenyl)-2,5′-dioxo-3′,5′,6′,7′-
tetrahydro-1′H-spiro[indoline-3,2′-pyrazolo[1,2-a]pyrazole]-1,3′-di-
carboxylate (3f). Yield 49.0 mg, 88%; yellow oil; 99% ee, >19:1 dr;
[α]21D = −15.5 (c = 0.91 in CHCl3); HPLC (Daicel chiralcel ODH, n-
hexane/i-PrOH, 1.0 mL/min, λ = 254 nm) tR(major) = 27.28 min,
1-tert-Butyl 3′-methyl 1′-(naphthalen-1-yl)-2,5′-dioxo-3′,5′,6′,7′-
tetrahydro-1′H-spiro[indoline-3,2′-pyrazolo[1,2-a]pyrazole]-1,3′-di-
carboxylate (3k). Yield 45.3 mg, 86%; yellow solid, mp 86−88 °C;
>99% ee, >19:1 dr; [α]20 = −187.1 (c = 0.87 in CHCl3); HPLC
D
1
tR(minor) = 39.19 min; H NMR (400 MHz, CDCl3) δ 7.55 (t, J = 7.4
(Daicel chiralcel IA, n-hexane/i-PrOH 80/20, 1.0 mL/min, λ = 254
1
Hz, 2H), 7.27 (s, 1H), 7.20−7.16(m, 2H), 7.06 (t, J = 7.6 Hz, 1H),
6.94 (d, J = 8.4 Hz, 2H), 5.19 (s, 1H), 4.20 (s, 1H), 3.85−3.68 (m,
1H), 3.22 (s, 3H), 3.10−2.89 (m, 2H), 2.89−2.72 (m, 1H), 1.64 (s,
9H). 13C NMR (100 MHz, CDCl3) δ 173.7, 172.8, 166.7, 148.3, 139.3,
131.5, 130.4, 129.7, 128.9, 125.9, 124.0, 123.4, 122.9, 114.7, 85.2, 77.8,
77.4, 77.3, 77.1, 76.7, 65.0, 63.6, 52.3, 47.1, 31.6, 28.0, 0.0. HRMS
(ESI-TOF) calcd for C26H2678.9183BrN3NaO6 [M + Na]+ 578.0903,
found 578.0907. C26H2680.9163BrN3NaO6 [M + Na]+ 580.0882, found
580.0886.
nm) tR(major) = 7.71 min, tR(minor) = 13.77 min; H NMR (400 MHz,
CDCl3) δ 7.90 (d, J = 8.4 Hz, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.62−7.51
(m, 3H), 7.45−7.41 (m, 3H), 7.38−7.28 (m, 2H), 7.18 (t, J = 7.6 Hz,
1H), 7.07−6.97 (m, 2H), 5.41 (s, 1H), 5.01 (s, 1H), 3.88−3.71 (m,
1H), 3.22 (s, 3H), 3.09−3.01 (m, 1H), 2.96−2.77 (m, 2H), 1.50 (s,
9H). 13C NMR (101 MHz, CDCl3) δ 207.1, 174.3, 173.8, 167.2, 148.1,
139.2, 133.3, 132.0, 131.2, 129.2, 129.0, 128.9, 128.7, 128.3, 127.1,
127.0, 126.6, 125.9, 125.6, 124.6, 124.1, 123.8, 122.4, 114.5, 84.6, 77.4,
77.3, 77.1, 76.8, 74.2, 64.9, 64.0, 52.2, 46.6, 31.0, 31.0, 27.9. HRMS
(ESI-TOF) calcd for C30H29N3NaO6 [M + Na]+ 550.1954, found
550.1953.
1-tert-Butyl 3′-methyl 1′-(4-fluorophenyl)-2,5′-dioxo-3′,5′,6′,7′-
tetrahydro-1′H-spiro[indoline-3,2′-pyrazolo[1,2-a]pyrazole]-1,3′-di-
carboxylate (3g). Yield 45.5 mg, 91%; yellow solid, mp 62−64 °C;
1-tert-Butyl 3′-methyl 2,5′-dioxo-1′-(thiophen-2-yl)-3′,5′,6′,7′-
tetrahydro-1′H-spiro[indoline-3,2′-pyrazolo[1,2-a]pyrazole]-1,3′-di-
carboxylate (3l). Yield 43.6 mg, 90%; yellow oil; 94% ee, 10:1 dr;
>99% ee, >19:1 dr; [α]21 = −22.9 (c = 0.73 in CHCl3); HPLC
D
(Daicel chiralcel IA, n-hexane/i-PrOH 80/20, 1.0 mL/min, λ = 254
1
nm) tR(major) = 10.28 min, tR(minor) = 15.35 min; H NMR (400 MHz,
[α]20 = −1.63(c = 0.046 in CHCl3); HPLC (Daicel chiralcel IA, n-
D
CDCl3) δ 7.62−7.50 (m, 2H), 7.17 (t, J = 8.0 Hz, 1H), 7.09−7.00 (m,
3H), 6.78 (t, J = 8.4 Hz, 2H), 5.20 (s, 1H), 4.22 (s, 1H), 3.84−3.70
(m, 1H), 3.23 (s, 3H), 3.09−2.91 (m, 2H), 2.88−2.74 (m, 1H), 1.63
(s, 9H). 13C NMR (100 MHz, CDCl3) δ 173.8, 172.8, 166.8, 163.9,
161.5, 148.4, 139.3, 129.6, 129.0, 128.9, 127.1, 127.0, 125.8, 124.0,
123.6, 115.4, 115.2, 114.6, 85.1, 77.8, 77.4, 77.3, 77.1, 76.7, 65.1, 63.4,
52.3, 47.0, 31.6, 28.0, 0.0. HRMS (ESI-TOF) calcd for
C26H26FN3NaO6 [M + Na]+ 518.1703, found 518.1707.
1-tert-Butyl 3′-methyl 1′-(4-methoxyphenyl)-2,5′-dioxo-
3′,5′,6′,7′-tetrahydro-1′H-spiro[indoline-3,2′-pyrazolo[1,2-a]-
pyrazole]-1,3′-dicarboxylate (3h). Yield 46.4 mg, 91%; yellow oil;
94% ee, >19:1 dr; [α]21D = −18.7 (c = 0.93 in CHCl3); HPLC (Daicel
chiralcel IA, n-hexane/i-PrOH 80/20, 1.0 mL/min, λ = 254 nm)
tR(major) = 11.50 min, tR(minor) = 16.80 min; 1H NMR (400 MHz,
CDCl3) δ 7.54−7.42 (m, 2H), 7.09−7.07(m, 1H), 6.99 (t, J = 7.6 Hz,
1H), 6.90 (d, J = 8.7 Hz, 2H), 6.53 (d, J = 8.7 Hz, 2H), 5.23 (s, 1H),
5.12 (s, 1H), 4.12 (s, 1H), 3.75−3.63 (m, 1H), 3.60 (s, 3H), 3.13 (d, J
= 13.2 Hz, 3H), 3.02−2.93 (m, 1H), 2.92−2.82 (m, 1H), 2.82−2.67
(m, 1H), 1.56 (s, 8H). 13C NMR (100 MHz, CDCl3) δ 173.8, 173.0,
167.0, 159.7, 148.5, 139.3, 129.4, 128.5, 125.9, 123.9, 123.8, 123.0,
114.5, 113.6, 84.9, 78.3, 77.4, 77.1, 76.8, 65.1, 63.5, 55.1, 53.5, 52.3,
47.0, 31.6, 28.0, 1.0. HRMS (ESI-TOF) calcd for C27H29N3NaO7 [M
+ Na]+ 530.1903, found 530.1904.
hexane/i-PrOH 80/20, 1.0 mL/min, λ = 254 nm) tR(minor) = 7.85 min,
1
tR(major) = 10.31 min; H NMR (400 MHz, CDCl3) δ 7.63 (t, J = 8.0
Hz, 2H), 7.24 (d, J = 8.0 Hz, 1H), 7.12−7.08(m, 2H), 6.88−6.71 (m,
2H), 5.17 (s, 1H), 4.50 (s, 1H), 3.78−3.76(m, 1H), 3.24 (s, 3H),
3.14−3.08 (m, 1H), 2.94−2.90(m, 1H), 2.86−2.78 (m, 1H), 1.63 (s,
8H). 13C NMR (100 MHz, CDCl3) δ 173.8, 129.8, 127.1, 126.4, 124.1,
114.6, 85.1, 77.3, 77.0, 76.7, 75.0, 64.8, 63.6, 52.3, 47.0, 31.4, 28.0.
HRMS (ESI-TOF) calcd for C24H25N3NaO6S [M + Na]+ 506.1362,
found 506.1366.
1-tert-Butyl 3′-methyl 1′-(furan-3-yl)-2,5′-dioxo-3′,5′,6′,7′-tetra-
hydro-1′H-spiro[indoline-3,2′-pyrazolo[1,2-a]pyrazole]-1,3′-dicar-
boxylate (3m). Yield 38.6 mg, 83%; yellow solid, mp 116−118 °C;
95% ee, 15:1 dr; [α]20D = −13.38 (c = 0.16 in CHCl3); HPLC (Daicel
chiralcel IA, n-hexane/i-PrOH 80/20, 1.0 mL/min, λ = 254 nm)
tR(major) = 10.77 min, tR(minor) = 15.08 min; 1H NMR (400 MHz,
CDCl3) δ 7.68 (d, J = 8.1 Hz, 1H), 7.58 (d, J = 6.8 Hz, 1H), 7.25−7.05
(m, 5H), 5.13 (s, 1H), 4.12 (s, 1H), 3.26−3.20 (m, 3H), 3.17 (dd, J =
4.2, 1.6 Hz, 1H), 3.13−3.05 (m, 1H), 2.94−2.87 (m, 1H), 2.86−2.78
(m, 1H), 1.63 (s, 9H). 13C NMR (101 MHz, CDCl3) δ 173.9, 172.7,
166.8, 148.5, 143.4, 141.4, 139.7, 129.7, 129.0, 128.2, 125.8, 125.3,
124.3, 124.1, 116.3, 114.7, 109.0, 100.0, 85.2, 77.4, 77.0, 76.7, 71.6,
64.2, 63.6, 53.5, 52.3, 46.8, 31.5, 28.0, 21.5. HRMS (ESI-TOF) calcd
for C24H25N3NaO7 [M + Na]+ 490.1590, found 490.1586.
1-tert-Butyl 3′-methyl 1′-(4-chlorophenyl)-2,5′-dioxo-3′,5′,6′,7′-
tetrahydro-1′H-spiro[indoline-3,2′-pyrazolo[1,2-a]pyrazole]-1,3′-di-
carboxylate (3i). Yield 38.6 mg, 75%; yellow oil; >99% ee, >19:1 dr;
1-tert-Butyl 3′-methyl 5-chloro-2,5′-dioxo-1′-phenyl-3′,5′,6′,7′-
tetrahydro-1′H-spiro[indoline-3,2′-pyrazolo[1,2-a]pyrazole]-1,3′-di-
carboxylate (3n). Yield 41.9 mg, 82%; yellow solid, 76−78 °C; 95%
[α]21 = −19.6 (c = 0.57 in CHCl3); HPLC (Daicel chiralcel IA, n-
ee, >19:1 dr; [α]25 = −62.5 (c = 0.64 in CHCl3); HPLC (Daicel
D
D
hexane/i-PrOH 80/20, 1.0 mL/min, λ = 254 nm) tR(major) = 10.56 min,
chiralcel IA, n-hexane/i-PrOH 80/20, 1.0 mL/min, λ = 254 nm)
tR(major) = 10.06 min, tR(minor) = 14.64 min; 1H NMR (400 MHz,
CDCl3) δ 7.58 (d, J = 2.0 Hz, 1H), 7.47 (d, J = 8.8 Hz, 1H), 7.20−6.98
(m, 6H), 5.20 (s, 1H), 4.24 (s, 1H), 3.90−3.76 (m, 1H), 3.33 (s, 3H),
3.10−3.07(m, 1H), 2.97−2.94(m, 1H), 2.89−2.75 (m, 1H), 1.62 (s,
9H). 13C NMR (100 MHz, CDCl3) δ 174.1, 172.2, 166.7, 148.2, 137.8,
130.9, 129.5, 129.4, 128.9, 128.4, 127.0, 125.9, 125.6, 115.7, 85.3, 78.3,
77.4, 77.1, 76.8, 65.1, 63.3, 60.4, 52.5, 46.8, 31.4, 28.0, 21.1, 14.2, −0.2.
HRMS (ESI-TOF) calcd for C26H2634.9689ClN3NaO6 [M + Na]+
534.1408, found 534.1417. C26H2636.9659ClN3NaO6 [M + Na]+
536.1378, found 536.1390.
1
tR(minor) = 16.02 min; H NMR (400 MHz, CDCl3) δ 7.55−7.53(m,
2H), 7.18 (t, J = 7.8 Hz, 1H), 7.06 (t, J = 7.6 Hz, 3H), 7.00 (d, J = 8.4
Hz, 2H), 5.19 (s, 1H), 4.21 (s, 1H), 3.83−3.69 (m, 1H), 3.22 (s, 3H),
3.10−2.91 (m, 2H), 2.88−2.77 (m, 1H), 1.64 (s, 9H). 13C NMR (100
MHz, CDCl3) δ 173.7, 172.8, 166.8, 148.3, 139.3, 134.6, 129.9, 129.7,
128.6, 128.5, 125.9, 124.0, 123.4, 114.6, 85.2, 77.7, 77.4, 77.3, 77.0,
76.7, 65.0, 63.6, 52.3, 47.1, 31.6, 28.1, 0.0. HRMS (ESI-TOF) calcd for
C26H2634.9689ClN3NaO6 [M + Na]+ 534.1408, found 534.1416.
C26H2636.9659ClN3NaO6 [M + Na]+ 536.1378, found 536.1376.
1-tert-Butyl 3′-methyl 1′-(2-fluorophenyl)-2,5′-dioxo-3′,5′,6′,7′-
tetrahydro-1′H-spiro[indoline-3,2′-pyrazolo[1,2-a]pyrazole]-1,3′-di-
carboxylate (3j). Yield 31.9 mg, 64%; yellow oil; 50% ee, 10:1 dr;
1-tert-Butyl 3′-methyl 5-fluoro-2,5′-dioxo-1′-phenyl-3′,5′,6′,7′-
tetrahydro-1′H-spiro[indoline-3,2′-pyrazolo[1,2-a]pyrazole]-1,3′-di-
carboxylate (3o). Yield 43.7 mg, 88%; yellow oil; 96% ee, >19:1 dr;
[α]20 = −6.2 (c = 0.13 in CHCl3); HPLC (Daicel chiralcel IA, n-
D
hexane/i-PrOH 80/20, 1.0 mL/min, λ = 254 nm) tR(major) = 8.10 min,
[α]20 = −23.8 (c = 0.61 in CHCl3); HPLC (Daicel chiralcel IA, n-
D
F
DOI: 10.1021/acs.joc.5b01760
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
hexane/i-PrOH 80/20, 1.0 mL/min, λ = 254 nm) tR(major) = 8.99 min,
tR(minor) = 17.49 min; 1H NMR (400 MHz, CDCl3) δ 7.51 (dd, J = 9.0,
4.5 Hz, 1H), 7.33 (dd, J = 8.0, 2.8 Hz, 1H), 7.19−7.07 (m, 3H), 7.05
(dd, J = 7.6, 1.8 Hz, 2H), 6.86−6.81(m, 1H), 5.21 (s, 1H), 4.25 (s,
1H), 3.89−3.73 (m, 1H), 3.32 (s, 3H), 3.10−3.07(m, 1H), 2.98−
2.94(m, 1H), 2.89−2.75 (m, 1H), 1.63 (s, 9H). 13C NMR (100 MHz,
CDCl3) δ 174.2, 172.4, 166.8, 160.3, 157.9, 148.4, 135.4, 135.3, 131.0,
128.9, 128.4, 127.0, 125.7, 125.6, 116.1, 115.8, 115.7, 113.5, 113.3,
85.2, 78.3, 77.4, 77.1, 76.8, 65.3, 65.2, 63.3, 60.4, 52.5, 46.8, 31.4, 28.0,
21.1, 14.2, −0.2. HRMS (ESI-TOF) calcd for C26H26FN3NaO6 [M +
Na]+ 518.1703, found 518.1705.
pyrazole]-1,3′-dicarboxylate (3t). Yield 44.9 mg, 88%; white solid,
mp 166−168 °C; 99% ee, >19:1 dr; [α]25 = −67.0 (c = 0.10 in
D
CHCl3); HPLC (Daicel chiralcel IA, n-hexane/i-PrOH 80/20, 1.0
mL/min, λ = 254 nm) tR1 = 9.34 min, tR2 = 10.38 min, tR3 = 11.31 min,
1
tR4 = 31.56 min; H NMR (400 MHz, CDCl3) δ 7.42 (d, J = 8.8 Hz,
1H), 7.09−6.99(m, 6H), 6.66−6.64(m, 1H), 5.21 (s, 1H), 4.24 (s,
1H), 3.87−3.67 (m, 4H), 3.27 (s, 3H), 3.09−2.97(m, 1H), 2.95−
2.93(m, 1H), 2.87−2.75 (m, 1H), 1.62 (s, 9H). 13C NMR (100 MHz,
CDCl3) δ 174.0, 173.0, 167.0, 156.2, 148.5, 132.7, 131.3, 128.7, 128.3,
127.1, 124.9, 115.4, 115.0, 111.5, 84.7, 78.4, 77.4, 77.0, 76.7, 65.5, 63.5,
55.9, 52.4, 46.9, 31.5, 28.0. HRMS (ESI-TOF) calcd for
C27H29N3NaO7 [M + Na]+ 530.1903, found 530.1910.
1-tert-Butyl 3′-methyl 5-bromo-2,5′-dioxo-1′-phenyl-3′,5′,6′,7′-
tetrahydro-1′H-spiro[indoline-3,2′-pyrazolo[1,2-a]pyrazole]-1,3′-di-
carboxylate (3p). Yield 50.5 mg, 91%; white solid, mp 132−134 °C;
97% ee, >19:1 dr; [α]22D = −72.0 (c = 0.76 in CHCl3); HPLC (Daicel
1-tert-Butyl 3′-methyl 6-chloro-2,5′-dioxo-1′-phenyl-3′,5′,6′,7′-
tetrahydro-1′H-spiro[indoline-3,2′-pyrazolo[1,2-a]pyrazole]-1,3′-di-
carboxylate (3u). Yield 43.9 mg, 86%; yellow oil; 99% ee, >19:1 dr;
chiralcel IA, n-hexane/i-PrOH 80/20, 1.0 mL/min, λ = 254 nm) tR1
=
[α]20 = −31.5 (c = 0.71 in CHCl3); HPLC (Daicel chiralcel IA, n-
D
3.51 min, tR2 = 4.02 min tR3 = 10.18 tR4 = 14.04; 1H NMR (400 MHz,
CDCl3) δ 7.72 (d, J = 2.0 Hz, 1H), 7.42 (d, J = 8.8 Hz, 1H), 7.26 (dd,
J = 8.8, 2.4 Hz, 1H), 7.18−6.97 (m, 5H), 5.20 (s, 1H), 4.24 (s, 1H),
3.89−3.75 (m, 1H), 3.34 (s, 3H), 3.10−3.07(m, 1H), 2.99−2.94(m,
1H), 2.90−2.73 (m, 1H), 1.63 (d, J = 3.2 Hz, 9H). 13C NMR (100
MHz, CDCl3) δ 174.1, 172.0, 166.8, 148.2, 138.4, 132.3, 131.0, 129.0,
128.7, 128.4, 128.2, 127.2, 127.0, 126.0, 116.9, 116.1, 85.4, 78.3, 77.4,
77.1, 76.8, 65.1, 63.3, 60.4, 52.5, 46.7, 31.4, 28.0, 21.1, 14.2, 0.0. HRMS
(ESI-TOF) calcd for C26H2678.9183BrN3NaO6 [M + Na]+ 578.0903,
found 578.0908. C26H2680.9163BrN3NaO6 [M + Na]+ 580.0882, found
580.0886.
hexane/i-PrOH 90/10, 1.0 mL/min, λ = 254 nm) tR1 = 15.531 min, tR2
1
= 17.75 min, tR3 = 19.47 min, tR4 = 29.67 min; H NMR (400 MHz,
CDCl3) δ 7.60 (d, J = 1.6 Hz, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.16−7.09
(m, 3H), 7.04−7.01(m, 3H), 5.19 (s, 1H), 4.23 (s, 1H), 3.79−3.75(m,
1H), 3.29 (s, 3H), 3.13−3.04 (m, 1H), 3.00−2.90 (m, 1H), 2.87−2.77
(m, 1H), 1.63 (s, 9H). 13C NMR (100 MHz, CDCl3) δ 174.1, 172.5,
166.8, 148.2, 140.2, 135.2, 131.0, 129.0, 128.4, 127.0, 126.8, 124.0,
122.2, 115.3, 85.5, 78.3, 77.4, 77.3, 77.1, 76.7, 64.9, 63.4, 52.5, 46.8,
31.4, 28.0. HRMS (ESI-TOF) calcd for C26H2634.9689ClN3NaO6 [M +
Na]+ 534.1408, found 534.1416. C26H2636.9659ClN3NaO6 [M + Na]+
536.1378, found 536.1403.
1-tert-Butyl 3′-methyl 6-bromo-2,5′-dioxo-1′-phenyl-3′,5′,6′,7′-
tetrahydro-1′H-spiro[indoline-3,2′-pyrazolo[1,2-a]pyrazole]-1,3′-di-
carboxylate (3q). Yield 39.7 mg, 71%; white solid, mp 133−135 °C;
1-tert-Butyl 3′-methyl 2,5′-dioxo-1′-phenyl-5-(trifluoromethoxy)-
3′,5′,6′,7′-tetrahydro-1′H-spiro[indoline-3,2′-pyrazolo[1,2-a]-
pyrazole]-1,3′-dicarboxylate (3v). Yield 57.2 mg, 99%; yellow oil;
95% ee, >19:1 dr; [α]25D = −31.3 (c = 0.91 in CHCl3); HPLC (Daicel
chiralcel IA, n-hexane/i-PrOH, 1.0 mL/min, λ = 254 nm) tR1 = 14.23
min, tR2 = 16.84 min, tR3 = 19.34 min, tR4 = 23.79 min, tR5 = 25.12 min,
98% ee, 7:1 dr; [α]21 = −31.2 (c = 0.49 in CHCl3); HPLC (Daicel
D
chiralcel IA, n-hexane/i-PrOH 80/20, 1.0 mL/min, λ = 254 nm)
tR(major) = 8.31 min, tR(minor) = 12.34 min; 1H NMR (400 MHz, CDCl3)
δ 7.76 (d, J = 1.6 Hz, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.20 (dd, J = 8.0,
1.6 Hz, 1H), 7.18−7.06 (m, 3H), 7.07−6.97 (m, 2H), 5.19 (s, 1H),
4.23 (s, 1H), 3.89−3.70 (m, 1H), 3.29 (s, 3H), 3.08−3.06(m, 1H),
2.95−2.92(m, 1H), 2.86−2.75 (m, 1H), 1.63 (s, 9H). 13C NMR (100
MHz, CDCl3) δ 174.1, 172.4, 166.8, 148.2, 140.3, 131.0, 129.0, 128.5,
127.0, 127.0, 123.2, 122.8, 118.0, 85.6, 78.2, 77.4, 77.1, 76.74, 65.0,
63.4, 52.5, 46.8, 31.4, 28.0, 0.0. HRMS (ESI-TOF) calcd for
C26H2678.9183BrN3NaO6 [M + Na]+ 578.0903, found 578.0910.
C26H2680.9163BrN3NaO6 [M + Na]+580.0882, found 580.0886.
1
tR6 = 44.28 min; H NMR (400 MHz, CDCl3) δ 7.57 (d, J = 8.8 Hz,
1H), 7.49 (d, J = 1.6 Hz, 1H), 7.15−7.06 (m, 3H), 7.01−6.99(m, 3H),
5.22 (s, 1H), 4.25 (s, 1H), 3.90−3.74 (m, 1H), 3.31 (s, 3H), 3.19−
3.03 (m, 1H), 3.01−2.76 (m, 2H), 1.63 (s, 9H). 13C NMR (100 MHz,
CDCl3) δ 174.4, 172.3, 166.8, 148.2, 145.0, 138.0, 130.9, 129.0, 128.4,
127.0, 125.6, 122.6, 119.5, 119.2, 115.6, 85.5, 78.3, 77.4, 77.3, 77.0,
76.7, 65.2, 63.3, 52.4, 46.5, 31.2, 28.0. HRMS (ESI-TOF) calcd for
C27H26F3N3NaO7 [M + Na]+ 584.1621, found 584.1625.
1-tert-Butyl 3′-methyl 7-bromo-2,5′-dioxo-1′-phenyl-3′,5′,6′,7′-
tetrahydro-1′H-spiro[indoline-3,2′-pyrazolo[1,2-a]pyrazole]-1,3′-di-
carboxylate (3w). Yield 45.3 mg, 81%; white solid, mp 88−90 °C;
1-tert-Butyl 3′-methyl 5,7-dimethyl-2,5′-dioxo-1′-phenyl-
3′,5′,6′,7′-tetrahydro-1′H-spiro[indoline-3,2′-pyrazolo[1,2-a]-
pyrazole]-1,3′-dicarboxylate (3r). Yield 43.8 mg, 87%; yellow solid,
90% ee, 15:1 dr; [α]21 = −16.5 (c = 0.70 in CHCl3); HPLC (Daicel
D
mp 150−152 °C; 99% ee, >19:1 dr; [α]21 = −51.0 (c = 0.67 in
chiralcel IA, n-hexane/i-PrOH 80/20, 1.0 mL/min, λ = 254 nm)
tR(major) = 10.58 min, tR(minor) = 13.52 min; 1H NMR (400 MHz,
CDCl3) δ 7.53 (d, J = 7.6 Hz, 1H), 7.37−7.26 (m, 2H), 7.21−6.99 (m,
5H), 6.91 (t, J = 8.0 Hz, 1H), 5.18 (s, 1H), 4.27 (s, 1H), 3.81−3.77(m,
1H), 3.23 (s, 3H), 3.18−3.03 (m, 1H), 2.89 (m, 2H), 1.62 (s, 9H). 13C
NMR (100 MHz, CDCl3) δ 174.2, 173.1, 166.6, 146.9, 138.5, 134.0,
131.0, 128.9, 128.4, 127.5, 127.1, 125.1, 124.9, 106.2, 85.9, 77.9, 77.4,
77.3, 77.0, 76.7, 65.7, 63.5, 52.3, 46.9, 31.4, 27.7. HRMS (ESI-TOF)
calcd for C26H2678.9183BrN3NaO6 [M + Na]+ 578.0903, found
578.0901. C26H2680.9163BrN3NaO6 [M + Na]+ 580.0882, found
580.0883.
D
CHCl3); HPLC (Daicel chiralcel IA, n-hexane/i-PrOH 80/20, 1.0
1
mL/min, λ = 254 nm) tR(major) = 8.50 min, tR(minor) = 10.43 min; H
NMR (400 MHz, CDCl3) δ 7.22 (s, 1H), 7.15−6.99 (m, 5H), 6.73 (s,
1H), 5.17 (s, 1H), 4.23 (s, 1H), 3.87−3.73 (m, 1H), 3.21 (s, 3H),
3.14−3.03 (m, 1H), 3.02−2.91 (m, 1H), 2.88−2.73 (m, 1H), 2.25 (s,
3H), 1.98 (s, 3H), 1.60 (s, 9H). 13C NMR (100 MHz, CDCl3) δ
173.9, 173.8, 166.8, 148.3, 135.7, 133.5, 132.6, 131.5, 128.6, 128.1,
127.2, 124.8, 124.1, 123.0, 84.8, 78.2, 77.4, 77.1, 76.8, 65.5, 63.5, 52.2,
47.3, 31.8, 27.8, 20.9, 19.2, 0.0. HRMS (ESI-TOF) calcd for
C28H31N3NaO6 [M + Na]+ 528.2111, found 528.2119.
1-tert-Butyl 3′-methyl 5-methyl-2,5′-dioxo-1′-phenyl-3′,5′,6′,7′-
tetrahydro-1′H-spiro[indoline-3,2′-pyrazolo[1,2-a]pyrazole]-1,3′-di-
carboxylate (3s). Yield 44.9 mg, 91%; yellow oil; 99% ee, >19:1 dr;
Di-tert-butyl 2,5′-dioxo-1′-phenyl-3′,5′,6′,7′-tetrahydro-1′H-
spiro[indoline-3,2′-pyrazolo[1,2-a]pyrazole]-1,3′-dicarboxylate
(3x). Yield 43.0 mg, 85%; yellow oil; >99% ee, >19:1 dr; [α]22
=
D
[α]21 = −42.6 (c = 0.80 in CHCl3); HPLC (Daicel chiralcel IA, n-
−28.7 (c = 0.99 in CHCl3); HPLC (Daicel chiralcel IA, n-hexane/i-
PrOH 80/20, 1.0 mL/min, λ = 254 nm) tR(major) = 12.29 min, tR(minor)
= 20.37 min; 1H NMR (400 MHz, CDCl3) δ 7.69 (d, J = 7.6 Hz, 1H),
7.53 (d, J = 8.0 Hz, 1H), 7.21−6.98 (m, 7H), 5.08 (s, 1H), 4.27 (s,
1H), 3.86−3.69 (m, 1H), 3.13−2.91 (m, 2H), 2.88−2.68 (m, 1H),
1.62 (s, 9H), 0.92 (s, 9H). 13C NMR (100 MHz, CDCl3) δ 173.8,
173.0, 164.7, 148.5, 139.7, 131.5, 129.3, 128.6, 128.2, 127.3, 126.8,
124.1, 124.0, 114.3, 84.9, 82.7, 77.9, 77.4, 77.3, 77.1, 76.8, 64.9, 64.1,
47.3, 32.0, 28.0, 27.1. HRMS (ESI-TOF) calcd for C29H33N3NaO6 [M
+ Na]+ 542.2267, found 542.2267.
D
hexane/i-PrOH 80/20, 1.0 mL/min, λ = 254 nm) tR(major) = 9.39 min,
1
tR(minor) = 12.78 min; H NMR (400 MHz, CDCl3) δ 7.44−7.32 (m,
2H), 7.16−7.00 (m, 5H), 6.92 (d, J = 8.4 Hz, 1H), 5.20 (s, 1H), 4.24
(s, 1H), 3.84−3.70 (m, 1H), 3.24 (s, 3H), 3.13−2.94 (m, 2H), 2.89−
2.78 (m, 1H), 2.29 (s, 3H), 1.62 (s, 9H). 13C NMR (100 MHz,
CDCl3) δ 173.7, 173.1, 166.9, 148.50, 136.9, 133.5, 131.4, 129.7,
128.7, 128.2, 127.2, 126.4, 123.6, 114.2, 84.8, 78.4, 77.4, 77.3, 77.1,
76.7, 65.2, 63.5, 52.2, 47.2, 31.7, 28.0, 21.0. HRMS (ESI-TOF) calcd
for C27H29N3NaO6 [M + Na]+ 514.1954, found 514.1959.
1-tert-Butyl 3′-methyl 5-methoxy-2,5′-dioxo-1′-phenyl-
1-tert-Butyl 3′-isopropyl 2,5′-dioxo-1′-phenyl-3′,5′,6′,7′-tetrahy-
3′,5′,6′,7′-tetrahydro-1′H-spiro[indoline-3,2′-pyrazolo[1,2-a]-
dro-1′H-spiro[indoline-3,2′-pyrazolo[1,2-a]pyrazole]-1,3′-dicarbox-
G
DOI: 10.1021/acs.joc.5b01760
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
ylate (3y). Yield 39.3 mg, 78%; yellow oil; >99% ee, >19:1 dr; [α]22
=
D
−31.9 (c = 0.73 in CHCl3); HPLC (Daicel chiralcel IA, n-hexane/i-
PrOH 80/20, 1.0 mL/min, λ = 254 nm) tR(major) = 10.05 min, tR(minor)
= 15.14 min; 1H NMR (400 MHz, CDCl3) δ 7.61−7.57 (m, 2H), 7.48
(d, J = 8.0 Hz, 1H), 7.32−7.30 (m, 1H), 7.22−6.95 (m, 8H), 5.15 (s,
1H), 4.58−4.54 (m, 1H), 4.26 (s, 1H), 3.83−3.71 (m, 1H), 3.10−2.93
(m, 2H), 2.87−2.73 (m, 2H), 1.63 (s, 9H), 1.02 (d, J = 6.4 Hz, 3H),
0.35 (d, J = 6.0 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 173.7, 173.0,
165.6, 148.4, 139.6, 131.3, 129.3, 129.0, 128.7, 128.2, 127.2, 126.5,
124.0, 123.8, 119.5, 114.4, 84.9, 78.3, 77.4, 77.3, 77.1, 76.7, 69.6, 65.1,
63.5, 60.5, 47.3, 45.6, 31.9, 29.7, 28.0, 26.0, 23.8, 21.6, 20.2. HRMS
(ESI-TOF) calcd for C28H31N3NaO6 [M + Na]+528.2111, found
528.2114.
1
White solid. H NMR (400 MHz, CDCl3) δ 6.54 (d, J = 7.8 Hz,
1H), 2.16−2.05 (m, 2H), 1.89−1.78 (m, 2H), 1.71−1.67 (m, 3H),
1.66−1.57 (m, 3H), 1.53−1.41 (m, 3H). 13C NMR (100 MHz,
CDCl3) δ 183.5, 144.2, 77.4, 77.1, 76.7, 56.0, 41.8, 39.6, 33.4, 31.3,
30.8, 30.7, 30.3, 26.5, 25.8, 25.5, −0.0.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.5b01760.
■
1-tert-Butyl 3′-phenyl 2,5′-dioxo-1′-phenyl-3′,5′,6′,7′-tetrahydro-
1′H-spiro[indoline-3,2′-pyrazolo[1,2-a]pyrazole]-1,3′-dicarboxylate
(3z). Yield 49.1 mg, 91%; yellow solid, mp 96−98 °C; 99% ee, >19:1
dr; [α]22D = −48.5 (c = 1.01 in CHCl3); HPLC (Daicel chiralcel IA, n-
hexane/i-PrOH 80/20, 1.0 mL/min, λ = 254 nm) tR(major) = 9.32 min,
S
Optimization detail, H and 13C NMR spectra, HPLC
data. (PDF)
Crystal data. (CIF)
1
1
tR(minor) = 16.79 min; H NMR (400 MHz, CDCl3) δ 7.69 (d, J = 7.4
Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.22 (t, J = 8.0 Hz, 1H), 7.17−7.05
(m, 9H), 6.22 (d, J = 7.8 Hz, 2H), 5.46 (s, 1H), 4.32 (s, 1H), 3.90−
3.73 (m, 1H), 3.20−3.06 (m, 1H), 3.05−2.74 (m, 2H), 1.60 (s, 10H).
13C NMR (100 MHz, CDCl3) δ 174.7, 172.8, 165.0, 149.5, 148.4,
139.7, 131.2, 129.6, 129.2, 128.8, 128.2, 127.2, 126.5, 126.1, 124.2,
123.7, 120.9, 114.7, 85.0, 78.6, 77.4, 77.3, 77.1, 76.8, 65.2, 63.4, 46.6,
31.3, 28.0. HRMS (ESI-TOF) calcd for C31H29N3NaO6 [M + Na]+
562.1954, found 562.1956.
AUTHOR INFORMATION
Corresponding Author
*E-mail: xmfeng@scu.edu.cn.
■
Notes
The authors declare no competing financial interest.
1-Ethyl 3′-methyl 2,5′-dioxo-1′-phenyl-3′,5′,6′,7′-tetrahydro-1′H-
spiro[indoline-3,2′-pyrazolo[1,2-a]pyrazole]-1,3′-dicarboxylate
(3aa). Yield 41.2 mg, 92%; yellow oil; 80% ee, 15:1 dr; [α]20
=
D
ACKNOWLEDGMENTS
■
−21.74 (c = 0.20 in CHCl3); HPLC (Daicel chiralcel IA, n-hexane/i-
PrOH 80/20, 1.0 mL/min, λ = 254 nm) tR1 = 10.25 min, tR2 = 13.81
min, tR3 = 15.97 min, tR4 = 25.38 min; 1H NMR (400 MHz, CDCl3) δ
7.52 (d, J = 8.0 Hz, 2H), 7.09−7.07(m, 1H), 7.05−6.95 (m, 6H), 5.13
(s, 1H), 4.40 (q, J = 7.2 Hz, 2H), 4.19 (s, 1H), 3.78−3.66 (m, 1H),
3.14 (s, 3H), 3.06−2.97 (m, 1H), 2.96−2.84 (m, 1H), 2.83−2.71 (m,
1H), 1.39 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 172.7,
171.8, 165.8, 149.1, 138.0, 130.2, 128.5, 127.7, 127.3, 126.2, 125.1,
123.2, 122.8, 113.4, 77.4, 76.3, 76.2, 76.0, 75.7, 64.1, 62.8, 62.7, 51.3,
46.1, 30.6, 13.2, −0.0. HRMS (ESI-TOF) calcd for C24H23N3NaO6 [M
+ Na]+ 472.1485, found 472.1493.
We thank the National Natural Science Foundation of China
(Nos. 21172151, 21321061 and 21432006) for financial
support.
REFERENCES
■
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Pearson, W. H. Synthetic Applications of 1,3-Dipolar Cycloaddition
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1-tert-Butyl 3′-methyl 1′-cyclopentyl-2,5′-dioxo-3′,5′,6′,7′-tetra-
hydro-1′H-spiro[indoline-3,2′-pyrazolo[1,2-a]pyrazole]-1,3′-dicar-
boxylate (3ab). Yield 21.6 mg, 46%; 99% ee, 6:1 dr, yellow solid, mp:
64−66 °C; this product is not stable; [α]20 = +7.8 (c = 0.41 in
D
CHCl3); HPLC (Daicel chiralcel IA, n-hexane/i-PrOH 80/20, 1.0
mL/min) tR(1) = 6.92 min, tR(2) = 7.85 min, tR(3) = 8.38 min, tR(4)
=
1
10.77 min; H NMR (400 MHz, CDCl3) δ 7.84 (d, J = 8.0 Hz, 1H),
7.54 (d, J = 7.6 Hz, 1H), 7.37 (t, J = 8.0 Hz, 1H), 7.17 (t, J = 7.6 Hz,
1H), 4.93 (s, 1H), 3.81 (dd, J = 8.0, 6.2 Hz, 1H), 3.16 (s, 3H), 3.10
(dd, J = 9.1, 4.9 Hz, 2H), 3.02 (d, J = 9.8 Hz, 1H), 2.79−2.66 (m, 1H),
1.87−1.76 (m, 1H), 1.66 (s, 9H), 1.59−1.48 (m, 2H), 1.47−1.35 (m,
2H), 1.19−1.10(m, 2H), 0.98−0.84(m, 2H). 13C NMR (100 MHz,
CDCl3) δ 173.5, 166.5, 166.0, 148.8, 140.0, 129.7, 126.3, 124. 3, 124.2,
114.8, 85.1, 79.9, 77.4, 77.3, 77.1, 76.7, 63.7, 62.6, 53.8, 52.2, 40.1,
35.1, 32.1, 29.7, 28.1, 27.6, 25.2, 23.9. HRMS (ESI-TOF) calcd for:
C25H31N3NaO6 [M + Na]+: 492.2111, found 492.2121.
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́
era, C.; Sansano, J. M. Curr. Org.
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R. K. J. Org. Chem. 1980, 45, 3916. (b) Mukaiyama, T.; Hoshino, T. J.
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1-Benzyl 3′-tert-butyl 2,5′-dioxo-1′-phenyl-3′,5′,6′,7′-tetrahydro-
1′H-spiro[indoline-3,2′-pyrazolo[1,2-a]pyrazole]-1,3′-dicarboxylate
(3ac). Yield 55.0 mg, 99%; 49% ee, yellow oil; [α]20 = −11.4 (c =
D
1.06, in CHCl3); HPLC (Daicel chiralcel IE, n-hexane/i-PrOH 80/20,
1.0 mL/min) tR(1) = 20.03 min, tR(2) = 23.87 min. 1H NMR (400 MHz,
CDCl3) δ 7.70 (d, J = 7.6 Hz, 1H), 7.65−7.55 (m, 1H), 7.52−7.44 (m,
2H), 7.44−7.26 (m, 5H), 7.16 (td, J = 8.0, 1.2 Hz, 1H), 7.10−7.04 (m,
2H), 7.03−6.91 (m, 2H), 5.43 (s, 2H), 5.09 (s, 1H), 4.28 (s, 1H),
3.78−3.76(m, 1H), 3.11−2.92 (m, 2H), 2.86−2.76 (m, 1H), 0.86 (s,
9H). 13C NMR (100 MHz, CDCl3) δ 173.8, 172.7, 164.6, 150.1, 139.2,
134.8, 131.3, 129.4, 128.7, 128.7, 128.6, 128.3, 128.3, 128.0, 127.8,
127.3, 127.2, 126.8, 124.4, 124.2, 114.4, 82.8, 78.1, 77.4, 77.1, 76.8,
68.8, 65.0, 64.1, 53.5, 47.3, 31.9, 28.0, 27.1, 27.0. ESI-HRMS calcd for
[C32H31N3NaO6+]: 576.2111, found 576.2119.
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Org. Chem. 2011, 47, 547. (f) Pezdirc, L.; Bevk, D.; Groselj, U.;
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H
DOI: 10.1021/acs.joc.5b01760
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Article
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́
Chem. Soc. 2003, 125, 10778. (i) Suarez, A.; Downey, C. W.; Fu, G. C.
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(13) CCDC 1055204 (3t). For more data see Supporting
Information.
I
DOI: 10.1021/acs.joc.5b01760
J. Org. Chem. XXXX, XXX, XXX−XXX