Synthesis of functionalized 3-spirocyclopropane-2-indolones from isomerised Baylis-Hillman adducts of isatin

Article abstract of DOI:10.1016/j.tet.2006.02.072

A facile, high yield stereoselective synthesis of functionalized diastereomeric 3-spirocyclopropane-2-indolones (10-17a,b) from the isomerised bromo derivatives of Baylis-Hillman adducts of isatin(2-9a,b) by reductive cyclization with sodium borohydride i

Full text of DOI:10.1016/j.tet.2006.02.072

Tetrahedron 62 (2006) 4342–4348
Synthesis of functionalized 3-spirocyclopropane-2-indolones
from isomerised Baylis–Hillman adducts of isatin
*
Ponnusamy Shanmugam, Vadivel Vaithiyanathan and Baby Viswambharan
Chemical Sciences and Technology Division, Regional Research Laboratory (CSIR), Thiruvananthapuram 695 019, Kerala, India
Received 6 December 2005; revised 6 February 2006; accepted 23 February 2006
Abstract—A facile, high yield stereoselective synthesis of functionalized diastereomeric 3-spirocyclopropane-2-indolones (10–17a,b) from
the isomerised bromo derivatives of Baylis–Hillman adducts of isatin(2–9a,b) by reductive cyclization with sodium borohydride is reported.
q 2006 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
The synthetic strategy of present study is depicted in
Scheme 1. Reductive cyclization of isomerised bromo
derivative of Baylis–Hillman adduct of isatin C would
provide functionalized 3-spirocyclopropane-2-indolones D.
The isomerised bromo derivative of Baylis–Hillman adduct
of isatin C could be synthesized from the Baylis–Hillman
adduct of isatin B by isomerisation reaction with 46%
aqueous HBr under microwave irradiation. In turn, adducts
B could be prepared from the corresponding substituted
isatins A.
Construction of cyclopropane ring systems is of great
interest of organic chemists due to its existence as a basic
unit in a number of natural products.1 Cyclopropane ring
systems are versatile building blocks in complex molecular
construction. In view of their importance as synthons,
numerous synthetic methods have been reported for their
synthesis.2 The synthesis of spirocycloindolones are of great
interest because they display a variety of biological
activities and many of them used as starting materials for
alkaloid synthesis.3 Different synthetic strategies are known
for the construction of 3-spirocycloalkylindolones4 but the
synthesis of 3-spirocyclopropane-2-indolones by reductive
cyclization of isomerised bromo derivative of Baylis–
Hillman adducts of isatin is unexplored to date. Amongst
various carbon–carbon bond forming reactions, the Baylis–
Hillman reaction is an important reaction giving rise to
densely functionalized molecules and is considered atom
economic. Highly functionalized Baylis–Hillman adducts
have been used as starting materials for various stereo-
selective preparations of functionalized intermediates and in
natural product synthesis.5 We have been working on novel
synthetic applications of the Baylis–Hillman adducts.6
Thus, in this paper, we wish to outline the synthesis of
3-spirocyclopropane-2-indolones by reductive cyclization
of isomerised Baylis–Hillman adducts of isatin for the first
time.
Br
R1
R1
R1
HO
O
Z
Z
O
O
N
R2
A
N
R2
B
O
N
R2
C
H
R1
Z
O
N
R2
D
Scheme 1. Retrosynthetic analysis.
The details of the study are shown in Scheme 2. Some of the
Baylis–Hillman adducts of isatin used in the present study
were prepared according to literature procedure.7 Thus, as
shown, the model substrate 1 was prepared by the treatment
of N-methyl isatin with ethyl acrylate using 10% mole
percent of DABCO in methanol at rt in good yield.
Keywords: Isatin; Spirocyclopropane; Sodium borohydride; 2-Indalones;
Baylis–Hillman adduct.
The pure adduct 1 with aqueous HBr (4 equiv) embedded on
silica gel (0.2 gm) was irradiated in a microwave oven for
*
Corresponding author. Tel.: C91 471 2515275; fax: C91 471 2491712;
e-mail: shanmu196@rediffmail.com
0040–4020/$ - see front matter q 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.02.072

P. Shanmugam et al. / Tetrahedron 62 (2006) 4342–4348
4343
adducts leads to a common enolate intermediate A, which
undergoes cyclopropanation as shown in Scheme 3.
Br
R1
R1
R1
+
HO
N
Z
a
Z
Br
Z
Characterization of the minor and major products (10a and
10b) was achieved based on the analysis of 1H NMR spectra
and coupling constant studies. In order to confirm the
projection of ester group (a or b) in isomers 13a and 13b,
95%
O
O
O
N
R2
N
R2
R2
E-Isomer
Z-Isomer
R1=H, R2=CH3, Z=CO2Et
R1
1
b
2a
98%
Z
2b
0
the chemical shift variation of aromatic protons Hd and Hd
was used as a tool. These are visualised in Figures 1 and 2.
H
R1
For example, the Hd proton appeared at d 7.51 due to
0
Z
H
O
+
anisotropic influence of ester carbonyl in 13a while the Hd
proton appeared at d 6.94 due to no influence of ester group
O
N
N
R2
R2
Minor 10a
Major 10b
Scheme 2. Cyclopropanation of isomerised BH adducts. Reagents and
condition: (a) 4 equiv 46% HBr, silica gel, mw, 750 W, 3 min; (b) 2 equiv,
NaBH4, THF, 0.5 h.
3 min to afford a 1:2 mixture of E:Z isomers of bromo
derivative 2a and 2b in 95% combined yield after
purification by silica gel column chromatography. Stereo-
selective cyclopropane formation from the mixture 2a and
2b in dry THF with 2 equiv of sodium borohydride at rt for
0.5 h afforded functionalized 3-cylopropyl-2-indolones as
diastereomeric mixture of 10a and 10b in 98% combined
yield. The ratio of the products (10a/10b) was found as 1:2
as estimated by 1H NMR. The new compounds were
characterized by spectral (IR, 1H and 13C NMR) and HRMS
data.
In order to study the selectivity in diastereomeric mixture
(10a and 10b) formation, we separated the E and Z isomers
of Baylis–Hillman bromo derivatives (2a and 2b) by
column chromatography and reduced them under optimized
reduction condition separately. To our surprise, the
separated geometrical isomers 2a and 2b provided the
same mixture and same ratio of cyclopropanes 10a and 10b
on exposure to sodium borohydride. Hence, it is understood
that both the isomers are undergoing reductive cyclopropa-
nation through a common stable intermediate. The
formation of diastereomeric mixture through a common
intermediate could be explained based on the plausible
mechanism proposed in Scheme 3. Thus, the hydride ion
attack on double bond of the isomerised Baylis–Hillman
Figure 1.
Br
Br
Hd
Hd'
OEt
O
Hc'
O
Ha'
Hb'
Hb
Ha
N
OEt
N
Hc
O
O
13a
13b
Figure 2.
H
R1
R1
Z
Z
H
Br
R1
H
Z
N
O
O
N
Br
Major
R2
Z
E
or
R2
+
R1
Br
R1
H
N
R2
O
Z
Commen intermediate A
N
R2
O
O
N
Minor
Z
R2
Scheme 3. Plausible mechanism for cyclopropanation.

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P. Shanmugam et al. / Tetrahedron 62 (2006) 4342–4348
0
in 13b. To fix the nature of protons of the cyclopropane
rings, the coupling constant and chemical shift correlation
studies were used as a tool. Thus, in compound 13a, the Ha
proton appeared at d 2.03 (dd, JgemZ4.5 Hz, JcisZ8.7 Hz),
JtransZ7.2 Hz). In contrary, in compound 13b, the Ha
proton appeared at d 1.80 (dd, JgemZ5.1 Hz, JcisZ8.7 Hz),
0
Hb proton appeared at d 2.38 (dd, JgemZ5.1 Hz, Jtrans
Z
0
8.1 Hz) and Hc proton appeared at d 2.64 (dd, JcisZ8.7 Hz,
JtransZ8.1 Hz). Hence, the structure with relative stereo-
chemistry of minor and major compounds 13a and 13b was
assigned as shown in Figure 2.
Hb proton appeared at d 2.13 (dd, JgemZ4.5 Hz, Jtrans
Z
7.2 Hz) and Hc proton appeared at d 2.71 (dd, JcisZ8.7 Hz,
HO
Ph
Ph
Br
Ph
b
a
To investigate the limitation and applicability of cyclopro-
panation reaction to the simple Baylis–Hillman adducts, the
adduct 1a derived from benzaldehyde with methyl acrylate
on isomerisation with aqueous HBr at rt to afford
corresponding isomerised product 1b as a single isomer.
The isomerised bromo derivative 1b in dry THF upon
reduction with 2 equiv of NaBH4 (optimised conditions) did
not yield the expected cyclopropane derivative 1c. Careful
repeatation and altering the reaction conditions provided
only the unreacted starting material. Thus, it is clear that
only isomerised bromo derivative of isatins are suitable
substrates for the cyclopropanation under reductive cycliza-
tion condition. The reaction is shown in Scheme 4.
CO2Me
CO2Me
1b
CO2Me
1a
1c
Scheme 4. Cyclopropanation of simple isomerised BH adduct. (a) 4 equiv
46% HBr, CH2Cl2, rt, 0.5 h; (b) 2 equiv NaBH4, THF, 0.5 h.
Br
R1
R1
R1
+
HO
N
Z
a
Z
Br
Z
O
O
O
N
R2
N
R2
R2
R1=H,Br
R2=Me,CH2Ph,Propargyl
E-Isomer
2a-9a
Z-Isomer
b
2b-9b
Encouraged by the preliminary results and to show the
generality of the reaction, the reaction of isomerised bromo
adducts of isatin 2ab–9ab under optimized conditions
afforded the corresponding functionalized 3-cylopropyl-2-
indolones 10a/10b–17a/17b in excellent yield. The reaction
is showed in Scheme 5 and the results are summarized in
Table 1. All the new compounds were thoroughly
Z=CO2Et,CN
R1
H
R1
Z
Z
H
+
O
O
N
N
R2
R2
Minor 10a-17a
Major 10b-17b
1
characterized by spectral (IR, H and 13C NMR, DEPT-
Scheme 5. Generality of the cyclopropanation. (a) 4 equiv 46% HBr, silica
gel, mw, 750 W, 3 min; (b) 2 equiv NaBH4, THF, 0.5 h.
135) and HRMS data.
Table 1. Synthesis of 3-spirocyclopropane-2-indolones
Entry
Reactant (E and Z)a
Conditionb
Productsc
Ratio
Combined
yield (%)d
Minor
Major
Br
EtO2C
H
H
CO2Et
CO2Et
2 equiv NaBH4,
THF, 0.5 h, rt
1
1:2
98
93
O
N
O
O
N
N
2a and 2b
10a
10b
Br
EtO2C
H
H
CO2Et
CO2Et
2 equiv NaBH4,
THF, 0.5 h, rt
2
1:2
O
N
O
O
N
N
Ph
Ph
Ph
3a and 3b
11a
11b
Br
EtO2C
H
Br
Br
Br
H
CO2Et
CO2Et
2 equiv NaBH4,
THF, 0.5 h, rt
O
O
O
3
1:2
95
N
N
N
Ph
Ph
Ph
4a and 4b
12a
12b
Br
EtO2C
H
Br
Br
Br
H
CO2Et
CO2Et
2 equiv NaBH4,
THF, 0.5 h, rt
O
4
1:1.5
96
O
O
N
N
N
13a
13b
5a and 5b

P. Shanmugam et al. / Tetrahedron 62 (2006) 4342–4348
4345
Table 1 (continued)
Entry
Reactant (E and Z)a
Conditionb
Productsc
Ratio
Combined
yield (%)d
Minor
Major
Br
EtO2C
H
H
CO2Et
CO2Et
2 equiv NaBH4,
THF, 0.5 h, rt
O
O
O
5
1:2
88
N
N
N
14a
14b
6a and 6b
Br
NC
H
H
CN
CN
2 equiv NaBH4,
THF, 0.5 h, rt
O
6
1:2
94
O
O
N
N
N
15a
15b
7a and 7b
Br
NC
H
H
CN
CN
2 equiv NaBH4,
THF, 0.5 h, rt
O
7
1:2.5
98
O
O
N
N
N
Ph
Ph
Ph
8a and 8b
16a
16b
Br
CN
NC
H
Br
Br
Br
H
CN
2 equiv NaBH4,
THF, 0.5 h, rt
8
1:1.5
86
O
O
O
N
N
N
Ph
Ph
Ph
17a
17b
9a and 9b
a E/Z mixture was used as starting material.
b See typical procedure.
c The isomers were separated by column chromatography.
d Estimated after column purification of the products.
3. Conclusion
Mass Spectrometer. Yields refer to quantities obtained after
chromatography. Solvents used are reagents grade and were
purified before use according to the literature procedure.8
In conclusion, we have demonstrated a short, novel and
facile method for the synthesis of functionalized diaster-
eomeric 3-spirocyclopropane-2-indolones from isomerised
bromo derivatives of Baylis–Hillman adducts of isatin by
reductive cyclopropanation methodology as a key step for
the first time. Further studies to apply this strategy for the
synthesis of natural products are underway in our
laboratory.
4.2. Typical experimental procedure for isomerisation
of Baylis–Hillman adducts
A mixture of Baylis–Hillman adduct 1 derived from isatin
(100 mg, 0.382 mmol) was added 4 equiv of 46% HBr and
silica gel (0.2 g) to make a slurry. The slurry was subjected
to microwave irradiation (750 W, 5 s pulse) over a period of
3 min. The crude mixture was cooled to rt and then
extracted with CH2Cl2 and the organic phase was washed
with water. The organic layer was separated and dried
(Na2SO4) and concentrated in vacuo. The crude mixture was
purified by silica gel column chromatography using a
gradient elution with hexane and hexane and EtOAc as
eluent to afford pure isomerised bromo derivatives 2a and
2b in 95% combined yield (118 mg).
4. Experimental
4.1. General consideration
All the experiments were carried out in oven-dried
glassware. Analytical thin-layer chromatography was
performed on silica gel TLC plates. Purification by gravity
column chromatography was carried out using silica gel
(100–200 mesh). Mixture of ethyl acetate and hexane and
pure ethyl acetate were used as eluent as required. IR spectra
were run on a Nicolet (impact 400D FT-IR) spectropho-
tometer. NMR spectra were obtained using chloroform-d as
solvent on Bruker DPX 300 MHz NMR spectrometer.
Chemical shifts are given in d scale with TMS as internal
reference. HRMS were measured at the JMS 600 JEOL
4.3. Typical experimental procedure for the synthesis
of 3-spirocyclopropane-2-indolones
A mixture of isomerised bromo derivatives of Baylis–
Hillman adducts 2a and 2b (40 mg, 0.123 mmol) in dry
tetrahydrofuran (3 mL) was added 2 equiv of sodium
borohydride (9.3 mg, 0.245 mmol). The mixture was stirred

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P. Shanmugam et al. / Tetrahedron 62 (2006) 4342–4348
at rt until complete disappearance of starting material (TLC,
ca. 0.5 h). Then, the THF was removed under reduced
pressure. The crude material was extracted with ethyl
acetate (2!30 mL) and the combined organic layer was
washed with water followed by brine. The organic layer was
separated and dried (Na2SO4) and concentrated in vacuo.
The crude mixture was purified by silica gel column
chromatography using a gradient elution with hexane and
hexane and EtOAc as eluent to afford pure cyclopropane
derivatives 10a and 10b in 98% combined yield (29 mg).
142.95, 167.23, 173.67; HRMS: Calcd for C20H19NO3:
321.1365; Found: 321.1363.
4.4.5. Spiro[cyclopropane-1,30-[3H]indole]-2-carboxylic
acid, 10,20-dihydro-10-benzyl-50-bromo-20-oxo-, ethyl
ester, 12a. IR (CH2Cl2): 2931, 2854, 1727, 1713, 1603,
1
1473 cmK1; H NMR (300.1 MHz/CDCl3): d 1.23 (t, JZ
6.9 Hz, 3H), 2.10 (dd, JZ4.5, 8.7 Hz, 1H), 2.17 (dd, JZ4.5,
7.5 Hz, 1H), 2.78 (dd, JZ7.5, 8.7 Hz, 1H), 4.18 (q, JZ
6.9 Hz, 2H), 4.99 (2d, JZ15.6 Hz, 2H), 6.65 (d, JZ8.4 Hz,
1H, Ar), 7.26–7.32 (m, 6H, Ar, Ph), 7.52 (d, JZ2.1 Hz, 1H,
Ar); 13C NMR (75.3 MHz/CDCl3): d 14.15, 21.48, 31.91,
33.24, 44.35, 61.57, 110.36, 115.14, 116.63, 125.98, 127.24
(2C), 127.82, 128.87 (2C), 130.41, 135.29, 142.36, 167.98,
175.01; HRMS: Calcd for C20H18BrNO3: 399.0470; Found:
399.0466.
4.4. Spectral data of new compounds
4.4.1. Spiro[cyclopropane-1,30-[3H]indole]-2-carboxylic
acid, 10,20-dihydro-10-methyl-20-oxo-, ethyl ester, 10a. IR
(CH2Cl2) 2968, 2925, 2863, 1746, 1722, 1617, 1468 cmK1
;
1H NMR (300.1 MHz/CDCl3): d 1.20 (t, JZ6.9 Hz, 3H),
2.01 (dd, JZ4.5, 8.7 Hz, 1H), 2.13 (dd, JZ4.5, 7.5 Hz, 1H),
2.70 (dd, JZ7.5, 8.7 Hz, 1H), 3.28 (s, 3H), 4.13 (q, JZ
6.9 Hz, 2H), 6.90 (d, JZ7.8 Hz, 1H, Ar), 7.02 (t, JZ7.8 Hz,
1H, Ar), 7.29 (t, JZ7.8 Hz, 1H, Ar), 7.36 (d, JZ7.8 Hz, 1H,
Ar); 13C NMR (75.3 MHz/CDCl3): d 14.33, 20.89, 26.87,
29.54, 32.94, 61.43, 108.21, 122.40, 122.80, 126.06, 127.86,
144.45, 169.03, 175.29; HRMS: Calcd for C14H15NO3:
245.1052; Found: 245.1045.
4.4.6. Spiro[cyclopropane-1,30-[3H]indole]-2-carboxylic
acid, 10,20-dihydro-10-benzyl-50-bromo-20-oxo-, ethyl
ester, 12b. IR (CH2Cl2): 3060, 2988, 2925, 1741, 1713,
1617, 1483 cmK1; 1H NMR (300.1 MHz/CDCl3): d 1.26 (t,
JZ7.2 Hz, 3H), 1.86 (dd, JZ5.1, 8.7 Hz, 1H), 2.25 (dd, JZ
5.1, 8.1 Hz, 1H), 2.69 (dd, JZ8.1, 8.7 Hz, 1H), 4.26 (q, JZ
7.2 Hz, 2H), 4.87 (d, JZ15.6 Hz, 1H), 5.02 (d, JZ15.6 Hz,
1H), 6.62 (d, JZ8.1 Hz, 1H, Ar), 6.95 (d, JZ2.1 Hz, 1H),
7.24–7.33 (m, 6H, Ar, Ph); 13C NMR (75.3 MHz/CDCl3): d
14.13, 19.81, 32.01, 33.85, 44.09, 61.56, 110.51, 114.96,
121.93, 127.19 (2C), 127.73, 128.80 (3C), 130.36, 131.01,
135.39, 166.58, 172.87; HRMS: Calcd for C20H18BrNO3:
399.0470; Found: 399.0464.
4.4.2. Spiro[cyclopropane-1,30-[3H]indole]-2-carboxylic
acid, 10,20-dihydro-10-methyl-20-oxo-, ethyl ester, 10b. IR
(CH2Cl2): 3057, 2963, 2937, 2852, 1739, 1709, 1611,
1
1466 cmK1; H NMR (300.1 MHz/CDCl3): d 1.21 (t, JZ
6.9 Hz, 3H), 1.72 (dd, JZ4.8, 8.4 Hz, 1H), 2.31 (dd, JZ4.8,
8.1 Hz, 1H), 2.57 (dd, JZ8.1, 8.4 Hz, 1H), 3.19 (s, 3H),
4.14 (q, JZ6.9 Hz, 2H), 6.77 (d, JZ7.2 Hz, 1H, Ar), 6.82
(d, JZ7.8 Hz, 1H, Ar), 6.98 (t, JZ7.5 Hz, 1H, Ar), 7.22 (t,
JZ7.8 Hz, 1H, Ar); 13C NMR (75.3 MHz/CDCl3): d 14.36,
20.73, 27.07, 29.42, 32.87, 61.84, 108.82, 122.67, 122.48,
126.53, 127.76, 143.56, 168.68, 174.29; HRMS: Calcd for
C14H15NO3: 245.1052; Found: 245.1043.
4.4.7. Spiro[cyclopropane-1,30-[3H]indole]-2-carboxylic
acid, 10,20-dihydro-10 -methyl-50-bromo-20-oxo-, ethyl
ester, 13a. IR (CH2Cl2): 2984, 2921 (cyclopropane), 1717
(ester, amide), 1606 (Ar), 1464 cmK1
;
1H NMR
(300.1 MHz/CDCl3): d 1.23 (t, JZ6.9 Hz, 3H), 2.03 (dd,
JZ4.5, 8.7 Hz, 1H), 2.13 (dd, JZ4.5, 7.2 Hz, 1H), 2.71 (dd,
JZ7.2, 8.7 Hz, 1H), 3.26 (s, 3H), 4.17 (q, JZ6.9 Hz, 2H),
6.76 (d, JZ8.1 Hz, 1H, Ar), 7.42 (d, JZ8.1 Hz, 1H, Ar),
7.51 (d, JZ1.8 Hz, 1H, Ar); 13C NMR (75.3 MHz/CDCl3):
d 14.15, 21.11, 26.76, 29.67, 33.06, 61.50, 108.04, 115.03,
125.86, 127.94, 130.49, 143.30, 168.46, 174.17; HRMS:
Calcd for C14H14BrNO3: 323.0157; Found: 323.0149.
4.4.3. Spiro[cyclopropane-1,30-[3H]indole]-2-carboxylic
acid, 10,20-dihydro-10-benzyl -20-oxo-, ethyl ester, 11a. IR
(CH2Cl2): 2927, 2849 (cyclopropane), 1721 (ester, amide),
1608 (Ar), 1464 (cyclopropane) cmK1
;
1H NMR
4.4.8. Spiro[cyclopropane-1,30-[3H]indole]-2-carboxylic
acid, 10,20-dihydro-10 -methyl-50-bromo-20-oxo-, ethyl
ester, 13b. IR (CH2Cl2): 2982, 1741, 1712, 1610,
(300.1 MHz/CDCl3): d 1.25 (t, JZ6.9 Hz, 3H), 2.08 (dd,
JZ4.2, 8.4 Hz, 1H), 2.18 (dd, JZ4.2, 7.5 Hz, 1H), 2.77 (dd,
JZ7.5, 8.4 Hz, 1H), 4.15 (q, JZ6.9 Hz, 2H), 5.10 (s, 2H),
6.84–7.45 (m, 9H, Ar); 13C NMR (75.3 MHz/CDCl3): d
14.35, 21.27, 32.12, 33.15, 44.52, 61.51, 109.24, 118.80,
122.73, 122.95, 124.93, 127.55, 127.79, 127.85, 128.40,
128.99, 136.03, 143.60, 168.99, 175.11; HRMS: Calcd for
C20H19NO3: 321.1363; Found: 321.1359.
1
1465 cmK1; H NMR (300.1 MHz/CDCl3): d 1.27 (t, JZ
7.2 Hz, 3H), 1.80 (dd, JZ5.1, 8.7 Hz, 1H), 2.38 (dd, JZ5.1,
8.1 Hz, 1H), 2.64 (dd, JZ8.1, 8.7 Hz, 1H), 3.24 (s, 3H),
4.20 (q, JZ7.2 Hz, 2H), 6.75 (d, JZ8.1 Hz, 1H, Ar), 6.94
(d, JZ1.8 Hz, 1H, Ar), 7.40 (dd, JZ8.1, 1.8 Hz, 1H, Ar);
13C NMR (75.3 MHz/CDCl3): d 14.13, 21.32, 26.67, 32.15,
33.39, 61.53, 109.52, 114.85, 121.85, 130.02, 131.02,
142.68, 166.67, 172.75; HRMS: Calcd for C14H14BrNO3:
323.0157; Found: 323.0142.
4.4.4. Spiro[cyclopropane-1,30-[3H]indole]-2-carboxylic
acid, 10,20-dihydro-10 -benzyl -20-oxo-, ethyl ester, 11b. IR
1
(CH2Cl2): 2983, 2927, 1735, 1705, 1613, 1466 cmK1; H
NMR (300.1 MHz/CDCl3): d 1.25 (t, JZ7.1 Hz, 3H), 1.85
(dd, JZ4.8, 8.4 Hz, 1H), 2.43 (dd, JZ4.8, 7.8 Hz, 1H), 2.68
(dd, JZ7.8, 8.4 Hz, 1H), 4.17 (q, JZ7.1 Hz, 2H), 4.89 (d,
JZ15.6 Hz, 1H), 5.04 (d, JZ15.6 Hz, 1H), 6.76–7.26 (m,
9H, Ar); 13C NMR (75.3 MHz/CDCl3): d 14.38, 21.16,
32.44, 33.79, 44.25, 61.63, 109.33, 118.39, 122.46, 127.38,
127.51, 127.77, 127.82, 128.93 (2C), 129.14, 136.14,
4.4.9. Spiro[cyclopropane-1,30-[3H]indole]-2-carboxylic
acid, 10,20-dihydro-10-propargyl-20-oxo-, ethyl ester, 14a.
IR (CH2Cl2): 3063, 2959, 2927, 2846, 1728, 1706, 1611,
1
1462 cmK1; H NMR (300.1 MHz/CDCl3): d 1.21 (t, JZ
7.1 Hz, 3H), 2.05 (m, 1H), 2.17 (m, 1H), 2.26 (t, JZ2.4 Hz,
1H), 2.74 (m, 1H), 4.11 (q, JZ7.1 Hz, 2H), 4.57–4.62

P. Shanmugam et al. / Tetrahedron 62 (2006) 4342–4348
4347
(d, JZ2.4 Hz, 2H), 6.75–7.48 (m, 4H, Ar); 13C NMR
(75.3 MHz/CDCl3): d 14.83, 21.72, 29.79, 32.76, 33.29,
47.92, 61.65, 72.54, 109.83, 119.20, 122.85, 127.94, 128.44,
142.21, 167.50, 173.13; HRMS: Calcd for C16H15NO3:
269.1052; Found: 269.1050.
(2C), 128.73, 128.86 (2C), 135.58, 143.18, 171.62; HRMS:
Calcd for C18H14N2O: 274.1106; Found: 274.1098.
4.4.15.
Spiro[cyclopropane-1,30-[3H]indole]-10,20-
dihydro-10 -benzyl-50-bromo -20-oxo-2-nitrile, 17a. IR
(CH2Cl2): 2975, 2852 (cyclopropane), 2249 (CN), 1721
4.4.10. Spiro[cyclopropane-1,30-[3H]indole]-2-carboxylic
acid, 10,20-dihydro-10-propargyl-20-oxo-, ethyl ester, 14b.
IR (CH2Cl21): 3054, 2986, 2930, 1740, 1719, 1612,
1467 cmK1; H NMR (300.1 MHz/CDCl3): d 1.26 (t, JZ
7.2 Hz, 3H), 1.82 (dd, JZ5.1, 8.7 Hz, 1H), 2.24 (t, JZ2.4 Hz,
1H), 2.39 (dd, JZ5.1, 8.1 Hz, 1H), 2.66 (dd, JZ8.1, 8.7 Hz,
1H), 4.19 (q, JZ7.2 Hz, 2H), 4.48–4.68 (d, JZ2.4 Hz, 2H),
6.86 (d, JZ7.2 Hz, 1H, Ar), 7.05–7.34 (m, 3H, Ar); 13C NMR
(75.3 MHz/CDCl3): d 14.32, 21.52, 29.70, 32.42, 33.68,
47.97, 61.62, 72.48, 109.37, 118.79, 122.83, 127.91, 128.95,
141.91, 167.04, 172.55; HRMS: Calcd for C16H15NO3:
269.1052; Found: 269.1047.
(CO), 1613 (Ar), 1479 (cyclopropane) cmK1 1H NMR
;
(300.1 MHz/CDCl3): d 1.94 (dd, JZ5.1, 7.2 Hz, 1H), 2.21
(dd, JZ5.1, 9.3 Hz, 1H), 2.55 (dd, JZ7.2, 9.3 Hz, 1H), 4.98
(s, 2H), 6.72 (d, JZ8.1 Hz, 1H, Ar), 7.27–7.40 (m, 7H, Ar,
Ph); 13C NMR (75.3 MHz/CDCl3): d 14.18, 21.01, 44.59,
31.56, 109.67, 122.92, 124.23, 127.26, 127.48, 127.87,
128.75, 128.89, 128.99, 131.68, 134.85, 135.44, 142.3,
172.60; HRMS: Calcd for C18H13BrN2O: 352.0211; Found:
352.0203.
4.4.16.
Spiro[cyclopropane-1,30-[3H]indole]-10,20-
dihydro-10-benzyl-50-bromo-20-oxo-2-nitrile, 17b. IR
(CH2Cl2): 2926, 2853, 2246, 1714, 1614, 1480 cmK1; H
1
4.4.11.
dihydro-10-methyl -20-oxo-2-nitrile, 15a. IR (CH2Cl2):
3086, 3027, 2236, 1701, 1614, 1469 cmK1 1H NMR
Spiro[cyclopropane-1,30-[3H]indole]-10,20-
NMR (300.1 MHz/CDCl3): d 2.03 (dd, JZ5.1, 9.3 Hz, 1H),
2.29 (dd, JZ5.1, 7.5 Hz, 1H), 2.37 (dd, JZ7.5, 9.3 Hz, 1H),
4.93–5.07 (2d, JZ15.6 Hz, 2H), 6.70 (d, JZ8.4 Hz, 1H,
Ar), 6.94 (s, 1H, Ar), 7.26–7.34 (m, 6H, Ar, Ph); 13C NMR
(75.3 MHz/CDCl3): d 15.34, 21.54, 31.63, 44.58, 111.05,
11.23, 121.63, 125.22, 127.26, 127.47, 128.01, 128.11,
128.95, 131.52, 131.67, 135.83, 142.16, 172.03; HRMS:
Calcd for C18H13BrN2O: 352.0211; Found: 352.0193.
;
(300.1 MHz/CDCl3): d 1.89 (dd, JZ4.8, 6.9 Hz, 1H), 2.13
(dd, JZ4.8, 9.3 Hz, 1H), 2.44 (dd, JZ6.9, 9.3 Hz, 1H), 3.30
(s, 3H), 6.97 (d, JZ7.8 Hz, 1H, Ar), 7.12–7.42 (m, 3H, Ar);
13C NMR (75.3 MHz/CDCl3): d 14.78, 21.31, 26.85, 31.70,
108.66, 116.85, 120.91, 122.89, 124.07, 128.83, 144.10,
172.97; HRMS: Calcd for C12H10N2O: 198.0793; Found:
198.0790.
5. Supplementary data
4.4.12.
Spiro[cyclopropane-1,30-[3H]indole]-10,20-
dihydro-10-methyl -20-oxo-2-nitrile, 15b. IR (CH2Cl2):
3031, 2963, 2916, 2848, 2247, 1705, 1611, 1466 cmK1; 1H
NMR (300.1 MHz/CDCl3): d 1.99 (dd, JZ5.1, 9.3 Hz, 1H),
2.19 (dd, JZ5.1, 7.2 Hz, 1H), 2.35 (dd, JZ7.2, 9.3 Hz, 1H),
3.34 (s, 3H), 6.79 (d, JZ7.1 Hz, 1H, Ar), 6.96 (d, JZ
7.1 Hz, 1H, Ar), 7.07 (t, JZ7.8 Hz, 1H), 7.35 (t, JZ7.8 Hz,
1H, Ar); 13C NMR (75.3 MHz/CDCl3): d 15.09, 21.14,
26.90, 31.83, 108.41, 115.89, 118.84, 122.56, 126.02,
128.87, 144.17, 171.49; HRMS: Calcd for C12H10N2O:
198.0793; Found: 198.0795.
1
Scanned copies of the H and 13C NMR spectra of all the
diastereomeric mixtures available as supporting data.
Acknowledgements
The authors thank Prof. T.K. Chandrashekar, Director,
RRL-T for providing infrastructure facilities. V.V and B.V
thank CSIR (New Delhi) for the award of a Junior Research
Fellowship (JRF). Thanks are due to Mrs. Viji for providing
HRMS data. The authors thank the referee of this
manuscript for critical suggestions on mechanism of
cyclopropanation.
4.4.13.
Spiro[cyclopropane-1,30-[3H]indole]-10,20-
dihydro-10 -benzyl -20-oxo-2-nitrile, 16a. IR (CH2Cl2):
3030, 2925, 2855 (cyclopropane), 2240 (CN), 1717 (amide),
1
1612 (Ar), 1465 cmK1; H NMR (300.1 MHz/CDCl3): d
1.94 (dd, JZ5.1, 6.9 Hz, 1H), 2.20 (dd, JZ5.1, 9.3 Hz, 1H),
2.52 (dd, JZ6.9, 9.3 Hz, 1H), 4.95 (s, 2H), 6.87 (d, JZ
7.8 Hz, 1H, Ar), 6.96 (d, JZ7.1 Hz, 1H, Ar), 7.07 (t, JZ
7.8 Hz, 1H), 7.05–7.34 (m, 8H, Ar, Ph); 13C NMR
(75.3 MHz/CDCl3): 15.00, 21.58, 30.91, 44.50, 109.67,
116.84, 121.00, 122.92, 124.08, 127.34 (2C), 127.88,
128.76, 128.89 (2C), 135.32, 143.27, 173.16; HRMS:
Calcd for C18H14N2O: 274.1106; Found: 274.1103.
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