Synthesis of CF3-containing 3,3′-cyclopropyl spirooxindoles by sequential [3 + 2] cycloaddition/ring contraction of ylideneoxindoles with 2,2,2-trifluorodiazoethane

Article abstract of DOI:10.1021/jo500019a

A [3 + 2] cycloaddition/ring contraction sequence of ylideneoxindoles with in situ-generated 2,2,2-trifluorodiazoethane without the use of any transition-metal catalyst has been developed. The reaction provides efficient access to biologically important a

Full text of DOI:10.1021/jo500019a

Note
pubs.acs.org/joc
Synthesis of CF3‑Containing 3,3′-Cyclopropyl Spirooxindoles by
Sequential [3 + 2] Cycloaddition/Ring Contraction of
Ylideneoxindoles with 2,2,2-Trifluorodiazoethane
Tian-Ren Li, Shu-Wen Duan, Wei Ding, Yi-Yin Liu, Jia-Rong Chen, Liang-Qiu Lu,* and Wen-Jing Xiao*
Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University, 152
Luoyu Road, Wuhan, Hubei 430079, China
Collaborative Innovation Center of Chemical Science and Engineering, Tianjin 300072, China
S
* Supporting Information
ABSTRACT: A [3 + 2] cycloaddition/ring contraction
sequence of ylideneoxindoles with in situ-generated 2,2,2-
trifluorodiazoethane without the use of any transition-metal
catalyst has been developed. The reaction provides efficient
access to biologically important and synthetically useful CF3-
containing 3,3′-cyclopropyl spirooxindoles in high yield (74−
99%) with high diastereoselectivity (>95:5 d.r.).
pirocyclic oxindoles, especially 3,3′-cyclopropyl spiroox-
containing small-ring molecules with high reaction efficiency
(Scheme 2, eq 1). Other impressive work has come from the
Mykhailiuk group, who reported the cycloaddition of in situ-
generated CF3CHN2 with α-methylene aminocarboxylates to
prepare 1-amino-2-(trifluoromethyl)cyclopropane-1-carboxylic
esters, albeit with relatively low diastereoselectivity.9 Quite
recently, the Ma group developed the Ag2O-mediated [3 + 2]
cycloaddition reaction of in situ-generated CF3CHN2 with
terminal alkynes, which furnishes a diverse set of biologically
important 3-(trifluoromethyl)pyrazoles in good yields (Scheme
2, eq 2).10 Despite the advances being made, trisubstituted
electron-deficient alkenes still remain rarely exploited in
cycloaddition reactions with the use of CF3CHN2 as a CF3
synthon. As part of our ongoing research program on
developing new cascade reactions to construct carbo- and
heterocyclic systems,11 we have developed a highly efficient
sequential [3 + 2] cycloaddition/ring contraction reaction of
CF3CHN2 with ylideneoxindoles under metal-free conditions.
The reaction provides access to densely functionalized CF3-
containing 3,3′-cyclopropyl spirooxindoles in high yields and
stereoselectivities (Scheme 2, eq 3).
S
indoles, represent a ubiquitous class of biologically
important compounds. They can be also widely found in
various natural products and pharmaceuticals.1−3 For example,
many compounds containing the 3,3′-cyclopropyl spirooxin-
dole moiety exhibit interesting biological activities, and some
have been identified as powerful HIV-1 non-nucleoside reverse
transcriptase inhibitors (NNRTIs) as well as kinase and
arginine vasopressin inhibitors (Scheme 1).4 On the other
hand, enriching the repertoire of fluorine-containing carbo- and
heterocycles has attracted extensive research efforts from
synthetic and medical chemists over the past decade because
of the unique fluorine effect on the physiochemical properties
of pharmaceuticals and drug candidates.5 In this context, the
search for efficient and powerful methodologies for the
construction of highly substituted and functionalized carbo-
and heterocyclic rings bearing CF3 moieties has recently
become an attractive research topic, since the incorporation of
CF3 groups into drugs always leads to significant improvements
in lipophilicity, binding selectivity, and metabolic stability
compared with the parent molecules.6
Initially, ethyl (E)-2-(1-methyl-2-oxoindolin-3-ylidene)-
acetate (1a) was chosen as the model substrate to react with
CF3CHN2, which was generated in situ from CF3CH2NH2·HCl
and NaNO2 in DCM/H2O at 0 °C. To our delight, the initial
[3 + 2] cycloaddition occurred smoothly to give the
corresponding cycloadduct 3a in 87% isolated yield with
excellent regioselectivity and diasteroselectivity (Table 1, entry
1). The structure of 3a was unambiguously confirmed by single-
crystal X-ray analysis.12 Significantly, the subsequent ring
Recently, the highly reactive compound 2,2,2-trifluorodiazo-
ethane (CF3CHN2) has been identified as a robust C1 unit for
the synthesis of CF3-containing cyclopropane derivatives.7
Notably, Carreira and co-workers have demonstrated that this
type of reagent can be easily generated in situ from
commercially available CF3CH2NH2·HCl in the presence of
NaNO2.8 Accordingly, harsh reaction conditions and direct
handling of toxic, gaseous, and explosive CF3CHN2 can be
avoided by using this strategy. As a result, a wide range of
transition-metal-promoted cyclopropanations of various termi-
nal olefins and alkynes have been accomplished, providing
efficient access to the corresponding structurally diverse CF3-
Received: January 6, 2014
Published: February 7, 2014
© 2014 American Chemical Society
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Note
Scheme 1. Representative Therapeutic Agents Containing 3,3′-Cyclopropyl Spirooxindole Scaffolds
Scheme 2. Design of the [3 + 2] Cycloaddition/Ring Contraction Sequence for the Synthesis of CF3-Containing 3,3′-
Cyclopropyl Spirooxindoles
a
Table 1. Optimization of the Reaction Conditions
b
c
b
entry
T (°C)
solvent
t (h)
yield of 3a (%)
d.r. of 3a
yield of 4a (%)
1
2
3
5
6
7
0
25
40
25
25
25
25
25
DCM
72
60
48
36
48
36
36
96
87
87
81
92
83
90
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
87
d
DCM
n.d.
n.d.
n.d.
n.d.
n.d.
91
DCM
CHCl3
DCE
toluene
toluene
toluene
e
e
8
ef
,
n.d.
e
9
n.d.
84
a
b
Reaction conditions: 1a (0.2 mmol, 1.0 equiv), CF3CH2NH2·HCl (5 equiv), NaNO2 (6 equiv), solvent (3.0 mL), H2O (0.2 mL). Isolated yields
c
d
e
based on 1a. Determined by 1H NMR analysis. n.d. = not determined. The reaction mixture was directly warmed to reflux for 1 h upon complete
consumption of 1a. 2/NaNO2 (0.6/0.72 mmol, 3/3.6 equiv) were used.
f
contraction reaction of 3a also worked very well in refluxing
toluene to afford the final CF3-substituted 3,3′-cyclopropyl
spirooxindole 4a in 87% overall yield with excellent
diasteroselectivity. These results encouraged us to investigate
other reaction parameters to further improve the reaction
efficiency. It was found that the reaction at room temperature
gave a comparable yield of 3a with reduced reaction time, while
elevating the temperature to 40 °C resulted in somewhat
inferior results, probably because of the instability and volatility
of CF3CHN2 (Table 1, entry 2 vs entry 3). A brief screen of
reaction media showed that toluene was the best solvent of
choice (Table 1, entry 7). Notably, the sequential [3 + 2]
cycloaddition/ring contraction reaction could be carried out in
a one-pot fashion in toluene, affording the desired product 4a
in 91% overall yield (Table 1, entry 8). The reaction with
reduced amounts of CF3CH2NH2·HCl and NaNO2 led to a
slight drop in the overall yield (Table 1, entry 9).12
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Note
a
Scheme 3. Scope of the [3 + 2] Cycloaddition/Ring Contraction Sequence
a
1
Reaction conditions: see entry 8 of Table 1. Yields of isolated products are shown; all of the d.r. values were determined by H NMR analysis.
With the optimized conditions in hand, we then investigated
the substrate scope of this tandem reaction. As shown in
Scheme 3, a wide range of 3-ylideneoxindoles were found to be
suitable for the reaction. Both electron-donating groups (e.g.,
Me and MeO) and electron-withdrawing groups (e.g., F, Br,
NO2, CF3O, Cl, and CF3) were well-tolerated under the
reaction conditions, and the corresponding CF3-containing
3,3′-cyclopropyl spirooxindoles 4a−m were obtained in 79−
99% yield with >95:5 dr. Importantly, the above-mentioned
halo-substituted products allowed for further transformations
through transition-metal-catalyzed cross-coupling reactions.
Notably, the products bearing CF3O, CF3, and F groups on
the aromatic ring (4g, 88% yield; 4l, 79% yield; 4m, 85% yield;
Scheme 3) should also be of significant interest to medicinal
chemists because of the potential effect of fluorine on the
physiochemical properties of these molecules.
Moreover, the effects of varying the N-protecting group and
the ester moiety of the 3-ylideneoxindole were examined. As
shown in Scheme 3, 3-ylideneoxindoles with N-protecting
groups such as Ph (1o), Bn (1p), allyl (1q) or without a
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Note
Scheme 4. Sequential [3 + 2] Cycloaddition/1,3-H Shift Reaction for the Synthesis of CF3-Containing Spiropyrazoline Oxindole
5
other 3-ylideneoxindoles were prepared according to the above
procedure using the corresponding acetates and diones.
protecting group could participate in this reaction very well,
providing the corresponding products 4n−q in 74−92% yield.
t
General Procedure for the Sequential [3 + 2] Cycloaddition/
Ring Contraction Reaction of Alkylenyloxindoles with in Situ-
Generated CF3CHN2. CF3CH2NH2·HCl (135.5 mg, 1.0 mmol, 5
equiv), NaNO2 (83 mg, 1.2 mmol, 6 equiv), and H2O (0.2 mL) were
stirred in 3.0 mL of toluene at 0 °C for 1 h in a 10 mL Schlenk tube
under Ar. Then alkylenyloxindole 1 (0.20 mmol) was added, and the
reaction mixture was stirred at room temperature for 36 h. The
mixture was then heated to reflux for 1.5 h with vigorous stirring.
Upon completion of the reaction (as monitored by TLC), the reaction
mixture was cooled to room temperature and then directly subjected
to column chromatography to afford the desired product 4.
General Procedure for the Sequential [3 + 2] Cycloaddition/
1,3-H Shift Reaction for the Synthesis of CF3-Containing
Spiropyrazoline Oxindoles with in Situ-Generated CF3CHN2.
CF3CH2NH2·HCl (135.5 mg, 1.0 mmol, 5 equiv), NaNO2 (83 mg, 1.2
mmol, 6 equiv), and H2O (0.2 mL) were stirred in 3.0 mL of DCM at
0 °C for 1 h in a 10 mL Schlenk tube under Ar. Then DABCO (11.2
mg, 0.1 mmol) (0.5 equiv) was added, followed by alkylenyloxindole 1
(0.20 mmol), and the reaction mixture was stirred at room
temperature for 48 h. Upon completion of the reaction (as monitored
by TLC), the reaction mixture was cooled to room temperature and
then directly subjected to column chromatography to afford the
desired product 5.
Ethyl 1-Methyl-2-oxo-5′-(trifluoromethyl)-4′,5′-dihydrospiro-
[indoline-3,3′-pyrazole]-4′-carboxylate (3a). 48 h, white solid (59.4
mg, 87% yield), mp 120.6 °C, d.r. >95:5. 1H NMR (400 MHz,
CDCl3): δ 7.43 (t, J = 7.5 Hz, 1H), 7.04 (t, J = 7.7 Hz, 1H), 6.96 (d, J
= 7.8 Hz, 1H), 6.77 (d, J = 7.5 Hz, 1H), 5.96−5.89 (m, 1H), 3.93−
3.72 (m, 2H), 3.64 (d, J = 9.1 Hz, 1H), 3.38 (s, 3H), 0.68 (t, J = 7.1
Hz, 3H). 13C NMR (101 MHz, CDCl3): δ 170.2, 166.8, 144.4, 131.6,
124.5, 123.2, 123.0 (q, J = 277 Hz), 120.6, 108.9, 99.4, 91.8 (q, J = 28.7
Hz), 61.9, 45.0, 26.9, 13.1. 19F NMR (376 MHz, CDCl3): δ −71.06.
MS (EI): m/z 341.03 (M+). HRMS (ESI-TOF) for C15H14F3N3O3 [M
+ Na]+: calcd 364.0879, found 364.0885.
Ethyl 1′-Methyl-2′-oxo-3-(trifluoromethyl)spiro[cyclopropane-
1,3′-indoline]-2-carboxylate (4a). 48 h, colorless oil (56.9 mg, 91%
yield), d.r. >95:5. 1H NMR (600 MHz, CDCl3): δ 7.37 (t, J = 7.7 Hz,
1H), 7.33 (d, J = 7.7 Hz, 1H), 7.08 (t, J = 7.6 Hz, 1H), 6.94 (d, J = 7.7
Hz, 1H), 4.25−4.13 (m, 2H), 3.38 (d, J = 7.7 Hz, 1H), 3.33 (s, 3H),
3.20−3.14 (m, 1H), 1.25 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz,
CDCl3): δ 170.1, 166.2, 144.0, 128.9, 123.5, 123.3 (q, J = 274 Hz),
122.5, 122.4, 108.3, 62.0, 36.2, 35.3 (q, J = 41.0 Hz), 34.9 (d, J = 3
Hz), 26.8, 13.9. 19F NMR (376 MHz, CDCl3): δ −58.17. MS (EI): m/
z 313.23 (M+). HRMS (ESI-TOF) for C15H14F3NO3 [M + H]+: calcd
314.0999, found 314.1000.
Variation of the ester moiety (e.g., Me, Et, or Bu) had less
effect on both the reaction efficiency and stereoselectivity.
Remarkably, the reaction was also successfully extended to 3-
ylideneoxindoles with (hetero)aromatic carbonyl substituents.
For example, the reactions with phenyl- and 2-thiophene-
substituted carbonyl groups worked very well, producing 4t and
4u in 99% and 98% yield, respectively. Perhaps more
importantly, spirooxindole 4v, an analogue of an HIV-1
NNRTI, was successfully synthesized in one step from ethyl
(E)-2-(5-bromo-2-oxoindolin-3-ylidene)acetate by this meth-
odology, which further highlights the synthetic potential of this
transformation.4 All of these products were fully characterized
by 1H NMR, 13C NMR, and HRMS analysis. The structure and
stereochemistry of product 4c were also unambiguously
confirmed by single-crystal X-ray analysis.12
Interestingly, an alternative sequential [3 + 2] cycloaddition/
1,3-H shift reaction was also disclosed during optimization of
the reaction conditions. As shown in Scheme 4, in the case of
ethyl (E)-2-(1,5-dimethyl-2-oxoindolin-3-ylidene)acetate (1b),
the reaction formed CF3-substituted spiropyrazoline oxindole 5
with high diastereoselectivity when DABCO was used as the
base (91% yield, >95:5 d.r.; Scheme 4). It is noteworthy that
this process provides a complementary method to synthesize
compounds bearing both oxindole and pyrazoline skeletons.13
In summary, we have developed the first example of a
sequential [3 + 2] cycloaddition/ring contraction reaction of 3-
ylideneoxindoles with in situ-generated CF3CHN2 under
transition-metal-free conditions. This method provides a
straightforward approach to highly substituted and function-
alized CF3-containing 3,3′-cyclopropyl spirooxindole deriva-
tives in excellent yields with great diastereoselectivities.
Significantly, a CF3-substituted analogue of an HIV-1 NNRTI
can be synthesized in one step by this methodology. Moreover,
a sequential [3 + 2] cycloaddition/1,3-H shift reaction
promoted by DABCO was also disclosed, providing a new
access to CF3-containing spiropyrazoline oxindoles.
EXPERIMENTAL SECTION
■
General Considerations. Unless otherwise noted, materials were
purchased from commercial suppliers and used without further
purification. All of the solvents were treated according to known
methods.
Ethyl 1′,5′-Dimethyl-2′-oxo-3-(trifluoromethyl)spiro-
[cyclopropane-1,3′-indoline]-2-carboxylate (4b). 48 h, white solid
1
(57.6 mg, 88% yield), mp 107.9 °C, d.r. >95:5. H NMR (600 MHz,
General Procedure for the Synthesis of 3-Ylideneoxindoles.
To a stirred solution of ethyl 2-(triphenylphosphoranylidene)acetate
(22 mmol, 1.1 equiv) in anhydrous THF (50 mL) was added N-
methylindoline-2,3-dione (20 mmol, 1.0 equiv) at 0 °C. The mixture
was stirred at the same temperature until the reaction was complete, as
monitored by TLC analysis. The crude product was purified by flash
chromatography on silica gel (petroleum ether/ethyl acetate 5:1).
Compound 1a was obtained as a red solid (1.74 g, 86% yield). The
CDCl3): δ 7.14 (d, J = 7.9 Hz, 1H), 7.12 (s, 1H), 6.80 (d, J = 7.9 Hz,
1H), 4.24−4.10 (m, 2H), 3.34 (d, J = 7.7 Hz, 1H), 3.28 (s, 3H), 3.14−
3.09 (m, 1H), 2.33 (s, 3H), 1.23 (t, J = 7.1 Hz, 3H). 13C NMR (100
MHz, CDCl3): δ 170.0, 166.2, 141.7, 132.1, 129.1, 123.5, 123.4 (q, J =
273 Hz), 123.1, 108.1, 62.0, 36.2, 35.2 (q, J = 40.7 Hz), 34.8, 26.7,
21.1, 13.9. 19F NMR (376 MHz, CDCl3): δ −58.29. MS (EI): m/z
327.27 (M+). HRMS (ESI-TOF) for C16H16F3NO3 [M + H]+: calcd
328.1155, found 328.1155.
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Ethyl 5′-Methoxy-1′-methyl-2′-oxo-3-(trifluoromethyl)spiro-
[cyclopropane-1,3′-indoline]-2-carboxylate (4c). 48 h, yellow solid
CDCl3): δ 7.28 (t, J = 8.1 Hz, 1H), 7.04 (d, J = 8.2 Hz, 1H), 6.85 (d, J
= 7.8 Hz, 1H), 4.29−4.21 (m, 3H), 3.26 (s, 3H), 3.09−3.04 (m, 1H),
1.30 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 171.2, 165.2,
146.3, 130.0, 129.7, 124.5, 123.7 (q, J = 272 Hz), 118.9, 107.3, 61.9,
36.8, 36.5 (q, J = 41.0), 29.2, 26.9, 13.9. 19F NMR (376 MHz, CDCl3):
δ −57.71. MS (EI): m/z 347.25 (M+). HRMS (ESI-TOF) for
C15H13ClF3NO3 [M + H]+: calcd 348.0609, found 348.0608.
1
(55.6 mg, 81% yield), mp 90.9 °C, d.r. >95:5. H NMR (600 MHz,
CDCl3): δ 6.96 (d, J = 2.4 Hz, 1H), 6.87 (dd, J = 8.5 Hz, 2.5 Hz, 1H),
6.80 (d, J = 8.5 Hz, 1H), 4.23−4.11 (m, 2H), 3.78 (s, 3H), 3.35 (d, J =
7.8 Hz, 1H), 3.27 (s, 3H), 3.13−3.08 (m, 1H), 1.24 (t, J = 7.2 Hz,
3H). 13C NMR (100 MHz, CDCl3): δ 169.8, 166.1, 155.8, 137.5,
124.6, 123.3 (q, J = 273 Hz), 113.5, 109.7, 108.7, 62.1, 55.7, 36.4, 35.4
(q, J = 41.0 Hz), 34.8, 26.8, 13.9. 19F NMR (376 MHz, CDCl3): δ
−58.28. MS (EI): m/z 344.0 (M+). HRMS (ESI-TOF) for
C16H16F3NO4 [M + H]+: calcd 344.1104, found 344.1107.
Ethyl 6′-Bromo-1′-methyl-2′-oxo-3-(trifluoromethyl)spiro-
[cyclopropane-1,3′-indoline]-2-carboxylate (4j). 36 h, white solid
1
(71.5 mg, 91% yield), mp 129.5 °C, d.r. >95:5. H NMR (600 MHz,
CDCl3): δ 7.27 (d, J = 2.6 Hz, 1H), 7.18 (s, 2H), 7.06 (s, 1H), 4.23−
4.10 (m, 2H), 3.34 (d, J = 7.8 Hz, 1H), 3.28 (s, 3H), 3.14−3.10 (m,
1H), 1.24 (t, J = 6.9 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 169.9,
166.0, 145.3, 125.3, 123.8, 123.1 (q, J = 274 Hz), 122.6, 122.3, 111.8,
62.2, 35.9, 35.3 (q, J = 40.7 Hz), 34.9, 26.8, 14.0. 19F NMR (376 MHz,
CDCl3): δ −58.36. MS (EI): m/z 391.24 (M+). HRMS (ESI-TOF) for
C15H13BrF3NO3 [M + H]+: calcd 392.0104, found 392.0094.
Ethyl 5′-Fluoro-1′-methyl-2′-oxo-3-(trifluoromethyl)spiro-
[cyclopropane-1,3′-indoline]-2-carboxylate (4d). 36 h, yellow solid
1
(57.7 mg, 87% yield), mp 87.4 °C, d.r. >95:5. H NMR (600 MHz,
CDCl3): δ 7.13 (dd, J = 8.6 Hz, 2.6 Hz, 1H), 7.08−7.02 (m, 1H), 6.84
(dd, J = 8.6 Hz, 4.2 Hz, 1H), 4.27−4.13 (m, 2H), 3.37 (d, J = 7.8 Hz,
1H), 3.29 (s, 3H), 3.15−3.08 (m, 1H), 1.25 (t, J = 7.2 Hz, 3H). 13C
NMR (100 MHz, CDCl3): δ 169.8, 166.0, 158.9 (d, J = 239 Hz), 140.1
(d, J = 1 Hz), 125.0 (d, J = 10 Hz), 123.2 (q, J = 273 Hz), 115.1 (d, J =
23 Hz), 111.0 (d, J = 27 Hz), 108.8 (d, J = 8 Hz), 62.3, 36.3, 35.7 (q, J
= 41.0 Hz), 34.9 (d, J = 3 Hz), 26.9, 13.9. 19F NMR (376 MHz,
CDCl3): δ −58.35, −119.99. MS (EI): m/z 331.26 (M+). HRMS (ESI-
TOF) for C15H13F4NO3 [M + H]+: calcd 332.0904, found 332.0893.
Ethyl 5′-Bromo-1′-methyl-2′-oxo-3-(trifluoromethyl)spiro-
[cyclopropane-1,3′-indoline]-2-carboxylate (4e). 36 h, white solid
Ethyl 6′-Chloro-1′-methyl-2′-oxo-3-(trifluoromethyl)spiro-
[cyclopropane-1,3′-indoline]-2-carboxylate (4k). 48 h, yellowish
1
solid (64.8 mg, 93% yield), mp 102.5 °C, d.r. >95:5. H NMR (600
MHz, CDCl3): δ 7.22 (d, J = 7.8 Hz, 1H), 7.19 (t, J = 8.1 Hz, 1H),
6.89 (d, J = 7.2 Hz, 1H), 4.45 (d, J = 8.4 Hz, 1H), 4.30−4.21 (m, 2H),
3.25 (s, 3H), 3.06−3.01 (m, 1H), 1.30 (t, J = 7.1 Hz, 3H). 13C NMR
(100 MHz, CDCl3): δ 171.4, 165.2, 146.6, 129.9, 128.0, 123.8 (q, J =
273 Hz), 120.4, 118.1, 107.9, 62.0, 37.6, 36.8 (q, J = 41 Hz), 28.9, 26.8,
14.0. 19F NMR (376 MHz, CDCl3): δ −57.03. MS (EI): m/z 348.0
(M+). HRMS (ESI-TOF) for C15H13ClF3NO3 [M + H]+: calcd
348.0609, found 348.0599.
1
(71.4 mg, 91% yield), mp 90.0 °C, d.r. >95:5. H NMR (600 MHz,
CDCl3): δ 7.47 (d, J = 8.6 Hz, 2H), 6.79 (d, J = 8.0 Hz, 1H), 4.26−
4.15 (m, 2H), 3.36 (d, J = 7.8 Hz, 1H), 3.28 (s, 3H), 3.15−3.10 (m,
1H), 1.26 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 169.5,
165.9, 143.1, 131.7, 125.7, 125.4, 123.1 (q, J = 274 Hz), 115.1, 109.7,
62.3, 35.8, 35.6 (q, J = 39.7 Hz), 35.0, 26.8, 13.9. 19F NMR (376 MHz,
CDCl3): δ −63.01. MS (EI): m/z 391.21 (M+). HRMS (ESI-TOF) for
C15H13BrF3NO3 [M + H]+: calcd 392.0104, found 392.0090.
Ethyl 1′-Methyl-2′-oxo-3,7′-bis(trifluoromethyl)spiro-
[cyclopropane-1,3′-indoline]-2-carboxylate (4l). 36 h, red oil (60.3
1
mg, 79% yield), d.r. >95:5. H NMR (400 MHz, CDCl3): δ 7.64 (s,
1H), 7.50 (s, 1H), 7.12 (s, 1H), 4.23−4.13 (m, 2H), 3.51 (s, 3H), 3.40
(s, 1H), 3.19 (s, 1H), 1.24 (s, 3H). 13C NMR (100 MHz, CDCl3): δ
171.0, 165.8, 142.0, 126.8 (q, J = 5.7 Hz), 125.8, 125.7, 123.4 (q, J =
270 Hz), 123.1 (q, J = 274 Hz), 121.8, 112.9 (q, J = 33 Hz), 62.4, 36.1,
35.9 (q, J = 41 Hz), 35.0, 29.6 (q, J = 6.3 Hz), 14.0. 19F NMR (376
MHz, CDCl3): δ −53.64, −58.47. MS (EI): m/z 382.0 (M+). HRMS
(ESI-TOF) for C16H13F6NO3 [M + H]+: calcd 382.0872, found
382.0879.
Ethyl 1′-Methyl-5′-nitro-2′-oxo-3-(trifluoromethyl)spiro-
[cyclopropane-1,3′-indoline]-2-carboxylate (4f). 36 h, yellow solid
1
(59.4 mg, 83% yield), mp 143.1 °C, d.r. >95:5. H NMR (400 MHz,
CDCl3): δ 8.33 (d, J = 8.6 Hz, 1H), 8.28 (s, 1H), 7.01 (d, J = 8.6 Hz,
1H), 4.28−4.17 (m, 2H), 3.42 (d, J = 7.9 Hz, 1H), 3.38 (s, 3H), 3.31−
3.26 (m, 1H), 1.27 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3):
δ 170.2, 165.6, 149.4, 143.3, 125.8, 124.2, 122,9 (q, J = 275 Hz), 118.8,
108.0, 62.6, 35.9 (q, J = 41 Hz), 35.6 (d, J = 2 Hz), 35.4 (d, J = 2 Hz),
27.3, 13.9. 19F NMR (376 MHz, CDCl3): δ −58.54. MS (EI): m/z
359.15 (M+). HRMS (ESI-TOF) for C15H13F3N2O5 [M + H]+: calcd
359.0849, found 359.0856.
Ethyl 7′-Fluoro-1′-methyl-2′-oxo-3-(trifluoromethyl)spiro-
[cyclopropane-1,3′-indoline]-2-carboxylate (4m). 36 h, white solid
1
(56.4 mg, 85% yield), mp 89.0 °C, d.r. >95:5. H NMR (400 MHz,
CDCl3): δ 7.09 (s, 1H), 7.06 (d, J = 12.4 Hz, 1H), 7.03−6.92 (m, 1H),
4.26−4.10 (m, 2H), 3.51 (s, 3H), 3.36 (d, J = 7.8 Hz, 1H), 3.16−3.09
(m, 1H), 1.23 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ
169.8, 165.9, 147.7 (d, J = 242 Hz), 130.8 (d, J = 9 Hz), 126.2 (d, J = 4
Hz), 123.2 (q, J = 273 Hz), 123.0 (d, J = 6 Hz), 118.3 (q, J = 3 Hz),
116.9 (d, J = 19 Hz), 62.2, 36.2, 35.8 (q, J = 41 Hz), 35.4, 29.4, 14.0.
19F NMR (376 MHz, CDCl3): δ −58.35, −136.56. MS (EI): m/z
Ethyl 1′-Methyl-2′-oxo-5′-(trifluoromethoxy)-3-(trifluoromethyl)-
spiro[cyclopropane-1,3′-indoline]-2-carboxylate (4g). 36 h, white
1
solid (70.0 mg, 88% yield), mp 69.2 °C, d.r. >95:5. H NMR (400
MHz, CDCl3): δ 7.27 (s, 1H), 7.23 (d, J = 9.0 Hz, 1H), 6.91 (d, J = 8.5
Hz, 1H), 4.27−4.11 (m, 2H), 3.38 (d, J = 7.7 Hz, 1H), 3.31 (s, 3H),
3.20−3.12 (m, 1H), 1.24 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz,
CDCl3): δ 169.9, 165.9, 144.5, 142.8, 124.9, 123.1 (q, J = 274 Hz),
122.9 (q, J = 256 Hz), 122.1, 116.9, 108.7, 62.4, 36.0 (d, J = 2 Hz),
35.7 (q, J = 41 Hz), 35.1 (d, J = 3 Hz), 26.9, 13.9. 19F NMR (376
MHz, CDCl3): δ −58.31, −58.83. MS (EI): m/z 398.0 (M+). HRMS
(ESI-TOF) for C16H13F6NO4 [M + H]+: calcd 398.0822, found
398.0826.
331.28 (M+). HRMS (ESI-TOF) for C15H13F4NO3 [M + H]+: calcd
332.0904, found 332.0891.
Ethyl 2′-Oxo-3-(trifluoromethyl)spiro[cyclopropane-1,3′-indo-
line]-2-carboxylate (4n). 48 h, white solid (49.2 mg, 82% yield),
mp 153.1 °C, d.r. >95:5. 1H NMR (600 MHz, CDCl3): δ 8.89 (s, 1H),
7.28 (t, J = 7.3 Hz, 2H), 7.03 (t, J = 7.7 Hz, 1H), 6.97 (d, J = 7.9 Hz,
1H), 4.26−4.11 (m, 2H), 3.36 (d, J = 7.8 Hz, 1H), 3.18−3.13 (m,
1H), 1.24 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 173.0,
166.1, 141.5, 128.9, 124.0, 123.4 (q, J = 273 Hz), 122.6, 122.5, 110.5,
62.2, 36.7, 35.6 (q, J = 41.0 Hz), 35.0, 14.0. 19F NMR (376 MHz,
CDCl3): δ −58.21. MS (EI): m/z 300.1 (M+). HRMS (ESI-TOF) for
C14H12F3NO3 [M + H]+: calcd 300.0842, found 300.0846.
Ethyl 2′-Oxo-1′-phenyl-3-(trifluoromethyl)spiro[cyclopropane-
1,3′-indoline]-2-carboxylate (4o). 36 h, white solid (69.1 mg, 92%
yield), mp 90.9 °C, d.r. >95:5. 1H NMR (400 MHz, CDCl3): δ 7.53 (t,
J = 7.5 Hz, 2H), 7.45−7.39 (m, 4H), 7.26 (t, J = 7.5 Hz, 1H), 7.08 (t, J
= 7.5 Hz, 1H), 6.90 (d, J = 7.8 Hz, 1H), 4.30−4.12 (m, 2H), 3.45 (d, J
= 7.7 Hz, 1H), 3.25−3.18 (m, 1H), 1.26 (t, J = 7.1 Hz, 3H). 13C NMR
(100 MHz, CDCl3): δ 169.6, 166.2, 144.0, 134.0, 129.6, 128.8, 128.3,
126.5, 123.4, 123.3 (q, J = 274 Hz), 123.0, 122.8, 109.7, 62.2, 36.4 (d, J
= 2 Hz), 36.0 (q, J = 41.3 Hz), 35.3 (d, J = 3 Hz), 14.0. 19F NMR (376
Ethyl 4′-Bromo-1′-methyl-2′-oxo-3-(trifluoromethyl)spiro-
[cyclopropane-1,3′-indoline]-2-carboxylate (4h). 48 h, yellow solid
1
(75.3 mg, 96% yield), mp 107.2 °C, d.r. >95:5. H NMR (400 MHz,
CDCl3): δ 7.23 (d, J = 8.0 Hz, 1H), 7.20 (t, J = 7.9 Hz, 1H), 6.89 (d, J
= 7.5 Hz, 1H), 4.44 (d, J = 8.4 Hz, 1H), 4.29−4.22 (m, 2H), 3.25 (s,
3H), 3.06−3.01 (m, 1H), 1.31 (t, J = 7.1 Hz, 3H). 13C NMR (100
MHz, CDCl3): δ 171.4, 165.3, 146.6, 129.9, 128.0, 123.8 (q, J = 273
Hz), 120.4, 118.1, 107.9, 62.0, 37.7, 36.9 (q, J = 41.3 Hz), 29.0, 26.9,
14.0. 19F NMR (376 MHz, CDCl3): δ −56.99. MS (EI): m/z 391.1
(M+), 393.1 ([M + 2]+). HRMS (ESI-TOF) for C15H13BrF3NO3 [M +
H]+: calcd 392.0104, found 392.0095.
Ethyl 4′-Chloro-1′-methyl-2′-oxo-3-(trifluoromethyl)spiro-
[cyclopropane-1,3′-indoline]-2-carboxylate (4i). 48 h, yellow solid
1
(69.0 mg, 99% yield), mp 88.6 °C, d.r. >95:5. H NMR (400 MHz,
2300
dx.doi.org/10.1021/jo500019a | J. Org. Chem. 2014, 79, 2296−2302

The Journal of Organic Chemistry
Note
MHz, CDCl3): δ −58.17. MS (EI): m/z 376.1 (M+). HRMS (ESI-
TOF) for C20H16F3NO3 [M + H]+: calcd 376.1155, found 376.1158.
Ethyl 1′-Benzyl-2′-oxo-3-(trifluoromethyl)spiro[cyclopropane-
1,3′-indoline]-2-carboxylate (4p). 36 h, white solid (66.3 mg, 85%
yield), mp 108.2 °C, d.r. >95:5. 1H NMR (600 MHz, CDCl3): δ 7.37−
7.24 (m, 7H), 7.22 (t, J = 7.0 Hz, 1H), 7.01 (t, J = 7.2 Hz, 1H), 6.80
(d, J = 7.7 Hz, 1H), 5.11 (d, J = 15.6 Hz, 1H), 4.87 (d, J = 15.6 Hz,
1H), 4.26−4.11 (m, 2H), 3.46−3.43 (m, 1H), 3.19−3.17 (m, 1H),
1.25 (t, J = 8.2 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 170.4, 166.2,
143.2, 135.4, 128.8, 128.8, 127.7, 127.2, 123.6, 123.4 (q, J = 274 Hz),
122.6, 122.5, 109.3, 62.1, 44.3, 36.2 (d, J = 3 Hz), 35.7 (q, J = 40.7
Hz), 35.0 (d, J = 3 Hz), 14.0. 19F NMR (376 MHz, CDCl3): δ −58.19.
MS (EI): m/z 390.1 (M+). HRMS (ESI-TOF) for C21H18F3NO3 [M +
H]+: calcd 390.1312, found 390.1317.
Ethyl 1′-Allyl-2′-oxo-3-(trifluoromethyl)spiro[cyclopropane-1,3′-
indoline]-2-carboxylate (4q). 48 h, purple solid (50.1 mg, 74%
yield), mp 89.9 °C, d.r. >95:5. 1H NMR (600 MHz, CDCl3): δ 7.33−
7.29 (m, 2H), 7.04 (t, J = 7.6 Hz, 1H), 6.90 (d, J = 7.8 Hz, 1H), 5.89−
5.83 (m, 1H), 5.25 (s, 1H), 5.23 (d, J = 4.7 Hz, 1H), 4.48−4.36 (m,
2H), 4.25−4.10 (m, 2H), 3.38 (d, J = 7.7 Hz, 1H), 3.17−3.13 (m,
1H), 1.23 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 169.9,
166.2, 143.2, 131.0, 128.8, 123.5, 123.3 (q, J = 274 Hz), 122.5, 122.5,
117.8, 109.2, 62.1, 42.9, 36.1, 35.6 (q, J = 40.7 Hz), 34.9, 14.0. 19F
NMR (376 MHz, CDCl3): δ −58.37. MS (EI): m/z 340.1 (M+).
HRMS (ESI-TOF) for C17H16F3NO3 [M + H]+: calcd 340.1155,
found 340.1165.
Ethyl 5′-Bromo-2′-oxo-3-(trifluoromethyl)spiro[cyclopropane-
1,3′-indoline]-2-carboxylate (4v). 36 h, white solid (61.7 mg, 82%
1
yield), mp 187.8 °C, d.r. >95:5. H NMR (400 MHz, CDCl3): δ 9.90
(s, 1H), 7.45 (s, 1H), 7.41 (d, J = 8.0 Hz, 1H), 6.90 (d, J = 7.8 Hz,
1H), 4.26−4.20 (m, 2H), 3.35 (d, J = 7.2 Hz, 1H), 3.21−3.12 (m,
1H), 1.27 (t, J = 6.2 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 172.7,
165.8, 140.5, 131.8, 126.0, 125.9, 123.1 (q, J = 273 Hz), 115.2, 112.0,
62.5, 36.5, 35.9 (q, J = 41.0 Hz), 35.2 (d, J = 2 Hz), 14.0. 19F NMR
(376 MHz, CDCl3): δ −58.33. MS (EI): m/z 377.32 (M+). HRMS
(ESI-TOF) for C14H11BrF3NO3 [M + H]+: calcd 377.9947, found
377.9955.
Ethyl 1,5-Dimethyl-2-oxo-5′-(trifluoromethyl)-2′,4′-dihydrospiro-
[indoline-3,3′-pyrazole]-4′-carboxylate (5). 72 h, white solid (63.0
mg, 91% yield), mp 135.0 °C, d.r. >95:5. 1H NMR (600 MHz,
CDCl3): δ 7.17 (d, J = 7.9 Hz, 1H), 7.10 (s, 1H), 6.75 (d, J = 7.8 Hz,
1H), 6.17 (s, 1H), 4.58 (s, 1H), 3.91−3.81 (m, 2H), 3.24 (s, 3H), 2.31
(s, 3H), 0.88 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ
174.6, 165.1, 140.9, 137.2 (q, J = 38 Hz), 133.1, 131.3, 125.4, 125.1,
119.8 (q, J = 269 Hz), 108.4, 73.1, 61.6, 58.6 (d, J = 3.0 Hz), 26.7,
20.8, 13.4. 19F NMR (376 MHz, CDCl3): δ −63.45. MS (EI): m/z
355.12 (M+). HRMS (ESI-TOF) for C16H16F3N3O3 [M + Na]+: calcd
378.1036, found 378.1036.
ASSOCIATED CONTENT
* Supporting Information
■
S
Full experimental details, spectroscopic data for 4 and 5, and
CIF files for 3a and 4c. This material is available free of charge
via the Internet at http://pubs.acs.org.
Methyl 1′-Methyl-2′-oxo-3-(trifluoromethyl)spiro[cyclopropane-
1,3′-indoline]-2-carboxylate (4r). 36 h, purple solid (52.6 mg, 88%
yield), mp 94.6 °C, d.r. >95:5. 1H NMR (600 MHz, CDCl3): δ 7.35 (t,
J = 7.7 Hz, 1H), 7.30 (d, J = 7.5 Hz, 1H), 7.06 (t, J = 7.6 Hz, 1H), 6.91
(d, J = 7.8 Hz, 1H), 3.72 (s, 3H), 3.37 (d, J = 7.7 Hz, 1H), 3.30 (s,
3H), 3.18−3.13 (m, 1H). 13C NMR (100 MHz, CDCl3): δ 170.0,
166.7, 144.1, 128.9, 123.4, 123.3 (q, J = 273 Hz), 122.6, 122.4, 108.4,
52.8, 36.3 (d, J = 3 Hz), 35.3 (q, J = 40.7 Hz), 34.7 (d, J = 3 Hz), 26.8.
19F NMR (376 MHz, CDCl3): δ −58.43. MS (EI): m/z 300.0 (M+).
AUTHOR INFORMATION
Corresponding Authors
*E-mail: wxiao@mail.ccnu.edu.cn.
*E-mail: luliangqiu@mail.ccnu.edu.cn.
■
Notes
HRMS (ESI-TOF) for C14H12F3NO3 [M + H]+: calcd 300.0842,
found 300.0849.
The authors declare no competing financial interest.
tert-Butyl 1′-Methyl-2′-oxo-3-(trifluoromethyl)spiro-
ACKNOWLEDGMENTS
■
[cyclopropane-1,3′-indoline]-2-carboxylate (4s). 48 h, white solid
1
We are grateful to the National Natural Science Foundation of
China (21232003, 21202053, and 21272087) and the National
Basic Research Program of China (2011CB808603) for support
of this research.
(62.8 mg, 92% yield), mp 101.2 °C, d.r. >95:5. H NMR (600 MHz,
CDCl3): δ 7.33 (t, J = 7.7 Hz, 1H), 7.27 (d, J = 10.0 Hz, 1H), 7.03 (t, J
= 7.6 Hz, 1H), 6.91 (d, J = 7.8 Hz, 1H), 3.31 (s, 3H), 3.28 (s, 1H),
3.10−3.05 (m, 1H), 1.39 (s, 9H). 13C NMR (100 MHz, CDCl3): δ
170.4, 165.0, 144.0, 128.7, 123.6, 123.5 (q, J = 274 Hz), 122.4, 122.3,
108.3, 83.1, 35.9, 35.1 (q, J = 40.7 Hz), 27.9, 26.8. 19F NMR (376
MHz, CDCl3): δ −58.26. MS (EI): m/z 342.2 (M+). HRMS (ESI-
TOF) for C17H18F3NO3 [M + H]+: calcd 342.1312, found 342.1313.
2-Benzoyl-1′-methyl-3-(trifluoromethyl)spiro[cyclopropane-1,3′-
indolin]-2′-one (4t). 48 h, orange solid (68.7 mg, 99% yield), mp
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[cyclopropane-1,3′-indolin]-2′-one (4u). 48 h, yellow solid (68.5 mg,
1
98% yield), mp 137.3 °C, d.r. >95:5. H NMR (600 MHz, CDCl3): δ
7.78 (s, 1H), 7.68 (d, J = 3.9 Hz, 1H), 7.29 (t, J = 7.6 Hz, 1H), 7.22 (d,
J = 7.5 Hz, 1H), 7.10 (s, 1H), 7.02 (t, J = 7.5 Hz, 1H), 6.87 (d, J = 7.7
Hz, 1H), 4.17 (d, J = 7.6 Hz, 1H), 3.47−3.42 (m, 1H), 3.31 (s, 3H).
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−58.25. MS (EI): m/z 352.1 (M+). HRMS (ESI-TOF) for
C17H12F3NO2S [M + H]+: calcd 352.0614, found 352.0612.
2301
dx.doi.org/10.1021/jo500019a | J. Org. Chem. 2014, 79, 2296−2302

The Journal of Organic Chemistry
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