Synthesis of spiroindolone scaffolds by Pictet-Spengler spirocyclisation using β-cyclodextrin-SO3H as a recyclable catalyst

Article abstract of DOI:10.1016/j.tet.2017.05.089

A recyclable catalyst, β-cyclodextrin-SO₃H in aqueous medium was used effectively for the synthesis of spiroindolones (tetrahydrospiro-β-carbolines as well as tetrahydrospiro-γ-carbolines) in a Pictet-Spengler spirocyclisation. The products wer

Full text of DOI:10.1016/j.tet.2017.05.089

Accepted Manuscript
Synthesis of spiroindolone scaffolds by Pictet-Spengler spirocyclisation using β-
cyclodextrin-SO H as a recyclable catalyst
3
Tukaram D. Urmode, Monali A. Dawange, Vaishali S. Shinde, Radhika S. Kusurkar
PII:
S0040-4020(17)30598-7
10.1016/j.tet.2017.05.089
TET 28755
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 10 March 2017
Revised Date: 29 May 2017
Accepted Date: 30 May 2017
Please cite this article as: Urmode TD, Dawange MA, Shinde VS, Kusurkar RS, Synthesis of
spiroindolone scaffolds by Pictet-Spengler spirocyclisation using β-cyclodextrin-SO H as a recyclable
3
catalyst, Tetrahedron (2017), doi: 10.1016/j.tet.2017.05.089.
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ACCEPTED MANUSCRIPT
Graphical Abstract
Synthesis of Spiroindolone scaffolds by Pictet-Spengler Spirocyclisation using
β
-cyclodextrin-SO H as a recyclable catalyst
3
a
Tukaram D. Urmode, Monali A. Dawange, Vaishali S. Shinde and Radhika S. Kusurkar *
a
Department of Chemistry, Savitribai Phule Pune University, Pune-411007, Maharashtra, India.
rsk@chem.unipune.ac.in
Using a recyclable catalyst, β-cyclodextrin-SO H in aqueous medium in a Pictet-Spengler
3
spirocyclisation, the synthesis of spiroindolones
(tetrahydrospiro-β-carbolines as well as
tetrahydrospiro-γ-carbolines) was demonstrated. The products were obtained in good yield in an
environmental friendly procedure.
1

ACCEPTED MANUSCRIPT
Synthesis of Spiroindolone scaffolds by Pictet-Spengler Spirocyclisation using
β
-cyclodextrin-SO H as a recyclable catalyst
3
a
Tukaram D. Urmode, Monali A. Dawange, Vaishali S. Shinde and Radhika S. Kusurkar *
a
Department of Chemistry, Savitribai Phule Pune University, Pune-411007, Maharashtra, India.
rsk@chem.unipune.ac.in
Abstract
A recyclable catalyst, β-cyclodextrin-SO H in aqueous medium was used effectively for the
3
synthesis of spiroindolones (tetrahydrospiro-β-carbolines as well as tetrahydrospiro-γ-carbolines)
in a Pictet-Spengler spirocyclisation. The products were obtained in good yield in an
environmental friendly procedure.
Keywords: Pictet-Spengler Spirocyclisation, Spiroindolone, tetrahydrospiro-β-carboline,
tetrahydrospiro-γ-carboline, Green synthesis
1
. Introduction
Literature survey reveals that β-cyclodextrin-SO
3
H catalyst have gathered attention of many
researcher owing to its use in aqueous media for ring closure and also for the multi-component
1
one-pot condensation reaction. β-Cyclodextrin-SO H represents a derivatized cyclodextrin
3
which is chemically modified by replacing one of the hydroxyl group on the ring of cyclodextrin
2
by -SO H group and displays improved solubility in water compared to the β-cyclodextrin. Use
3
of low amount of catalyst in easily available solvent like water and simple workup procedure are
some of the advantages of this catalyst.
Recently, green chemistry involving development of environmentally benign chemical processes
and sustainable technologies is in demand. Water is a preferred solvent as green media as it is
3
cheapest, safest, environment friendly and non-toxic solvent. As most of organic compounds are
insoluble in water, the use of water as a medium for organic reactions is one of the latest
challenges for modern organic chemists. Green synthesis based on water mediated reactions has
4
attracted more attention from the scientific community due to the reduction in pollution caused
by organic solvents.
2

ACCEPTED MANUSCRIPT
Spiroindolones are members of spirooxindole alkaloids and many of them are naturally occurring
and bioactive molecules. Due to its interesting framework having one spiro stereocentre and
various biological properties, it has gained a lot of attention. Pictet Spengler reaction is one of
5
, 6i
6a
the commonly used synthetic routes for these scaffolds. Various acids catalyst like silica gel,
6
b,c
6d
6e,f
6g
chiral
phosphoric
acid,
carbon-SO H,
glacial
acetic
acid,
p-TsOH,
3
6
h
6i
6j
chlorotrimethylsilane, HCl and metal catalyst like gold etc. have been implemented for the
synthesis of spiroindolones. Many of these catalysts suffer drawbacks like expensive catalysts,
low yields of products, environmentally hazardous and harsh reaction conditions. Nevertheless,
environmental friendly approach employing aqueous phase organic synthesis can be an
7
alternative which would overcome the difficulties related with the catalyst and organic solvents.
A few syntheses are reported for spirooxindoles, using Pictet Spengler reaction in aqueous
8
medium. However there is no report available for the synthesis of spiroindolones in water. Thus,
we envisioned an environmental friendly synthetic approach for spiroindolones using β-
3
cyclodextrin-SO H as a recyclable catalyst in water using Pictet-Spengler spirocyclisation
reaction.
2
. Result and discussions
Initially, it was planned to synthesize spiroindolone scaffold containing tetrahydrospiro-β-
carboline unit, starting from tryptamine (1a) and isatin (2a). The required catalyst β-
2
cyclodextrin-SO
3
H was prepared as a white solid using the reported procedure from
°
chlorosulfonic acid and β-cyclodextrin in CH Cl at 0 C. The -SO H contents were measured by
2
2
3
2
-1
titration method and this data was matching with the reported value (0.52 mequiv.g. ). The
starting isatins (except 2g) were commercially available.
Having all starting materials in hand, the model reaction for the synthesis of tetrahydrospiro-β-
carboline was carried out by treating tryptamine 1a with isatin 2a using 20 mol% β-cyclodextrin-
SO H catalyst in water as a solvent. The reaction was quite sluggish at RT. However, when
3
°
heated at 80 C, complete consumption of starting materials was observed within 12 h along with
the formation of a new compound. The compound after subsequent purification and
characterization was found to be the expected product, tetrahydrospiro-β-carboline i. e. 2',3',4',9'-
tetrahydrospiro[indoline-3,1'-pyrido[3,4-b]indol]-2-one (3a) (Scheme 1). The NMR data of 3a
6
c
was well matching with the literature report.
3

ACCEPTED MANUSCRIPT
Scheme 1. Synthesis of 2',3',4',9'-tetrahydrospiro[indoline-3,1'-pyrido[3,4-b]indol]-2-one (3a)
The catalyst in aqueous solution after work up was directly used for the next batch of the same
reaction to furnish the product in 92% yield. Even after third run, using the same catalyst in the
aqueous medium, yield of the product was found to be up to 90%. This indicated that the catalyst
could be recycled for three runs.
[
a]
Table 1. Synthesis of tetrahydrospiro-β-carboline (3b-3j)
4

ACCEPTED MANUSCRIPT
a
Reaction condition: 1a (0.31 mmol), 2 (0.31 mmol), were heated in presence of β-cyclodextrin-
°
b
3
SO H (0.06 mmol) in water (5 mL) at 80 C for 8-12 h. Isolated yield.
3
After achieving the synthesis of 3a using the catalyst β-cyclodextrin-SO H, the scope of the
reaction was studied. The optimized protocol was employed for the reaction of tryptamine with
various substituted isatins. In all the cases corresponding tetrahydrospiro-β-carbolines 3b-3j
5

ACCEPTED MANUSCRIPT
were obtained in good to excellent yields within short period of time (Table 1). The reaction was
well tolerated by isatins bearing electron withdrawing groups (-F, -Cl, -Br) as well as electron
donating groups (-Me, -OMe). All the synthesized tetrahydrospiro-β-carbolines were well
characterized by analytical and spectral data which was matching with the previous literature
6
c, d
reports.
9
Tetrahydro-γ-carbolines are the precursors of naturally occurring γ-carbolines. These are less
1
0
studied than the β-carboline analogues though they exhibit range of biological activities.
6
j
Literature survey revealed that tetrahydrospiro-γ-carbolines are not much reported. Thus, the
synthesis of tetrahydrospiro-γ-carbolines was undertaken by using the present protocol in which
isotryptamine 1b is used instead of tryptamine 1a as a starting material.
[
a]
Table 2. Synthesis of tetrahydrospiro-γ-carbolines (3k-3s)
6

ACCEPTED MANUSCRIPT
a
Reaction condition: 1b (0.31 mmol), 2 (0.31 mmol), were heated in presence of β-cyclodextrin-
°
b
SO H (0.06 mmol) in water (5 mL) at 80 C for 8-12 h. Isolated yield.
3
7

ACCEPTED MANUSCRIPT
Reaction of isotryptamine 1b with various substituted isatins was carried out using the recyclable
β-cyclodextrin-SO H catalyst in aqueous medium. Even in this case, the isotryptamine 1b
3
smoothly underwent spirocyclisation with substituted isatins using the same procedure and
furnished the corresponding tetrahydrospiro-γ-carbolines 3k-3s in little lower yields. The results
are summarized in table 2.
The products tetrahydrospiro-γ-carbolines were characterized by HRMS and spectral data.
3
Change in the substitution pattern on isatins (electron withdrawing groups like -Cl, -Br, -OCF , -
I as well as electron donating group like -Me) did not much affect the rate and the yield of the
reaction.
3
. Conclusion
Synthesis of range of tetrahydrospiro-β as well as γ-carbolines have been demonstrated using
recyclable β-cyclodextrin-SO H catalyst in water as a reaction solvent. Good to excellent yields
3
of the products were obtained within short time by using this catalyst with simple starting
materials. The catalyst was found to be efficient for the spirocyclisation reaction and can be
recycled for three batches of the same reaction. Use of mild reaction condition along with the use
3
of catalytic amount of cheap and easily available β-cyclodextrin-SO H in aqueous medium,
makes the present protocol important from the environmental perspective.
4
. Experimental
4
.1 General Remarks
Chemicals and solvents received from commercial sources were used without further
1
13
purification. H NMR spectra and C NMR spectra were recorded on Bruker (400 MHz and 500
MHz) spectrometer. Coupling constants (J) are reported in hertz (Hz) and chemical shifts are
reported in parts per million (δ). Melting points were determined using a Thomas Hoover
capillary melting point apparatus and uncorrected. Column chromatography was performed
using silica gel (100-200 mesh). Exact mass measurements were performed on Bruker impact
HD Q-TOF analyzer in the ESI mode. IR spectra were recorded by a Shimadzu FT-IR 8400
Spectrometer. The routine monitoring of reactions were performed using TLC (Merck kieselgel
6
0 0.20 mm layer, UV254).
8

ACCEPTED MANUSCRIPT
Starting tryptamine 1a and isatins 2 were commercially available. Isotryptamine 1b and isatin 2g
1
1
were prepared according to the literature report.
4
4
.2 Synthetic Procedures and Characterization Data
.2.1. General procedure for preparation of sulfonated β-cyclodextrin (β-CD-SO
2
3
H)
Chlorosulfonic acid (1.572 g, 13.5 mmol) was added dropwise under stirring to the mixture of β-
°
cyclodextrin (7.660 g, 6.75 mmol) in CH Cl (35 mL) and was kept at 0 C for 3 h. Further, the
2
2
mixture was stirred for 2 h at room temperature to remove HCl. Then, the mixture was filtered,
washed with methanol (30 mL) and dried at RT which furnished sulfonated β-cyclodextrin as
3
white powder (7.92 g, 88%). The –SO H contents were measured by titration method and were
-1
matching with the value 0.52 mequiv.g.
.2.2. General procedure for spirocyclization (A)
Sulfonated-β-cyclodextrin (β-CD-SO H) (76 mg, 0.06 mmol) was dissolved in water (5 mL) at
4
3
RT by stirring to get the clear solution in 50 mL round bottom flask. Further, isatin 2 (0.31
mmol) and tryptamine 1a/ isotryptamine 1b (0.31 mmol) were added to the solution under
°
constant stirring and mixture was heated at 80 C for 8-12 h. The progress of the reaction was
monitored by TLC. After completion of reaction, it was cooled to room temperature, water was
added to it. The aqueous phase was extracted with ethyl acetate. The organic extracts were
combined, washed with brine and dried over sodium sulfate. The solvent was evaporated in
vacuo and the crude product obtained was purified by column chromatography using
chloroform/methanol (99:1) as an eluent furnishing the product. The spectral and analytical data
6
c,d,f
of all the reported products is consistent with the previous
reports.
4
.2.3. 2',3',4',9'-Tetrahydrospiro[indoline-3,1'-pyrido[3,4-b]indol]-2-one (3a)
2
-(1H-indol-3-yl)ethan-1-amine 1a (50 mg, 0.31 mmol) and isatin 2a (46 mg, 0.31 mmol) were
reacted using the general procedure A. The product was obtained as a brown solid (85 mg, 94%);
1
mp 178-180 (Lit. 176–177 °C); R 0.25 (CHCl /MeOH = 99/1); H NMR (400 MHz, CDCl ) δ
f
3
3
9
2
2
1
.19 (br s, 1H), 8.33 (br s, 1H), 7.51 (d, J = 7.7 Hz, 1H), 7.15-6.94 (m, 4H), 6.90 (t, J = 7.2 Hz,
H), 6.59 (d, J = 7.7 Hz, 1H), 3.62-3.47 (m, 1H), 3.28-3.08 (m, 1H), 2.86 (dd, J = 11.4, 5.7 Hz,
1
3
H), 2.85 (br s, 1H); C NMR (100 MHz, CDCl ) δ 179.4, 140.9, 136.4, 132.1, 129.9, 129.8,
3
27.0, 124.9, 123.2, 122.4, 119.5, 118.5, 112.1, 111.3, 111.1, 62.1, 40.0, 22.0.
9

ACCEPTED MANUSCRIPT
4
.2.4. 5-Chloro-2',3',4',9'-tetrahydrospiro[indoline-3,1'-pyrido[3,4-b]indol]-2-one (3b)
2
-(1H-indol-3-yl)ethan-1-amine 1a (50 mg, 0.31 mmol) and 5-chloroisatin 2b (57 mg, 0.31
mmol) were reacted using the general procedure A. The product was obtained as a white solid
1
(85 mg, 85%); mp 227-229°C; R
f
0.25 (CHCl
3
/MeOH = 99/1); H NMR (400 MHz, CDCl
3
) δ
8
.80 (br s, 1H), 7.92 (br s, 1H), 7.54-7.35 (m, 1H), 7.08-7.00 (m, 3H), 7.00-6.90 (m, 2H), 6.51
(
(
d, J = 8.2 Hz, 1H), 3.57 (dd, J = 12.4, 5.6 Hz, 1H), 3.28-3.12 (m, 1H), 2.93-2.71 (m, 2H), 1.87
1
3
br s, 1H); C NMR (100 MHz, CDCl ) δ 178.9, 139.1, 136.4, 133.7, 129.8, 129.0, 128.8, 127.0,
3
1
4
2
25.5, 122.9, 119.9, 118.7, 112.7, 111.8, 111.3, 62.2, 40.1, 29.8.
.2.5. 5-Bromo-2',3',4',9'-tetrahydrospiro[indoline-3,1'-pyrido[3,4-b]indol]-2-one (3c)
-(1H-indol-3-yl)ethan-1-amine 1a (50 mg, 0.31 mmol) and 5-bromoisatin 2c (70 mg, 0.31
mmol) were reacted using the general procedure A. The product was obtained as a brown solid
1
(
105 mg, 91%); semisolid; R 0.25 (CHCl /MeOH = 99/1); H NMR (400 MHz, CDCl ) δ 9.02
f
3
3
(br s, 1H), 8.09 (br s, 1H), 7.62-7.39 (m, 1H), 7.26-7.22 (m, 1H), 7.20-7.14 (m, 1H), 7.12-7.06
(m, 2H), 7.04-6.99 (m, 1H), 6.54 (d, J = 8.0 Hz, 1H), 3.88-3.51 (m, 1H), 3.35-3.20 (m, 1H),
1
3
3
1
4
2
.01-2.83 (m, 2H), 1.96 (br s, 1H); C NMR (100 MHz, CDCl ) δ 178.9, 139.7, 136.4, 134.0,
3
32.7, 129.0, 128.2, 126.9, 122.9, 119.8, 118.7, 116.0, 112.6, 112.3, 111.3, 62.2, 40.1, 22.0.
.2.6. 5-Fluoro-2',3',4',9'-tetrahydrospiro[indoline-3,1'-pyrido[3,4-b]indol]-2-one (3d)
-(1H-indol-3-yl)ethan-1-amine 1a (50 mg, 0.31 mmol) and 5-fluoroisatin 2d (52 mg, 0.31
mmol) were reacted using the general procedure A. The product was obtained as a brown solid
7
d
1
(
80 mg, 83%); mp 230-232 (lit. 229-230°C); R 0.25 (CHCl /MeOH = 99/1); H NMR (400
f 3
6
MHz, DMSO-d ) δ 10.49 (br s, 1H), 10.42 (br s, 1H), 7.52-7.42 (m, 1H), 7.24-7.14 (m, 1H),
7
2
.14-7.00 (m, 2H), 7.00-6.84 (m, 3H), 3.63-3.53 (m, 1H), 3.16-3.06 (m, 1H), 2.88-2.76 (m, 1H),
13
.77-2.67 (m, 1H) (One -NH proton was not seen); C NMR (100 MHz, DMSO-d ) 178.7, 158.4
6
(d, J = 238 Hz, C-F), 138.7, 136.5, 131.5, 126.8, 121.7, 118.9, 115.8 115.78 (d, J = 24 Hz), 112.7
1
4
2
12.58 (d, J = 24 Hz), 111.5, 111.23 (d, J = 7.7 Hz) 110.9, 61.93, 44.87, 21.79.
.2.7. 4,7-Dichloro-2',3',4',9'-tetrahydrospiro[indoline-3,1'-pyrido[3,4-b]indol]-2-one (3e)
-(1H-indol-3-yl)ethan-1-amine 1a (50 mg, 0.31 mmol) and 4,7-dichloroisatin 2e (67 mg, 0.31
mmol) were reacted using the general procedure A. The product was obtained as a white solid
1
(93 mg, 83%); mp 264-265 °C; R
f
0.25 (CHCl
3
/MeOH = 99/1); H NMR (400 MHz, DMSO-d
6
)
δ 11.01 (br s, 1H), 10.58 (br s, 1H), 7.47 (d, J = 7.6 Hz, 1H), 7.37 (d, J = 8.7 Hz, 1H), 7.18 (d, J
1
0

ACCEPTED MANUSCRIPT
=
7.9 Hz, 1H), 7.04 (t, J = 7.3 Hz, 1H), 6.97 (dd, J = 13.9, 8.0 Hz, 2H), 3.66- 3.57 (m, 1H), 3.19-
1
3
3
.06 (m, 1H), 2.82-2.69 (m, 2H) (one -NH proton was not seen); C NMR (100 MHz, DMSO-
d6) δ 177.7, 142.6, 136.2, 130.9, 129.9, 129.3, 128.9, 126.6, 123.8, 121.4, 118.6, 118.1, 113.2,
-1
+
1
11.4, 111.3, 62.5, 38.9, 21.6. FTIR ν 3033, 2922, 1627, 1032, 788, cm ; HRMS (ESI) [M + H]
found m/z 358.0511, calcd for C H Cl N O 358.0508.
1
8
14
2
3
4
.2.8. 7-Fluoro-2',3',4',9'-tetrahydrospiro[indoline-3,1'-pyrido[3,4-b]indol]-2-one (3f)
-(1H-indol-3-yl)ethan-1-amine 1a (50 mg, 0.31 mmol) and 7-fluoroisatin 2f (52 mg, 0.31
2
mmol) were reacted using the general procedure A. The product was obtained as a yellow solid
1
(78 mg, 81%); mp 157-159 °C; R
f
0.25 (CHCl
3
/MeOH = 99/1); H NMR (400 MHz, DMSO-d
6
)
δ 10.96 (br s, 1H), 10.50 (br s, 1H), 7.46 (d, J = 7.6 Hz, 1H), 7.23-7.12 (m, 2H), 7.09-6.86 (m,
H), 3.62 (ddd, J = 12.6, 8.0, 4.8 Hz, 1H), 3.13 (dt, J = 12.4, 4.5 Hz, 1H), 2.90-2.67 (m, 2H) (one
4
13
-
NH proton was not seen); C NMR (100 MHz, DMSO-d ) δ 178.7, 148.2, 136.5, 136.2 (d, J =
6
3
.5 Hz), 131.7, 126.9, 122.9 (d, J = 5.7 Hz), 121.7, 121.1 (d, J = 2.8 Hz), 119.4, 118.4,(d, J = 17
Hz), 111.5, 110.7, 61.8, 39.4, 22.0.
4
.2.9. 1-Methyl-2',3',4',9'-tetrahydrospiro[indoline-3,1'-pyrido[3,4-b]indol]-2-one (3g)
2
-(1H-indol-3-yl)ethan-1-amine 1a (50 mg, 0.31 mmol) and N-methylisatin 2g (51 mg, 0.31
mmol) were reacted using the general procedure A. The product was obtained as a yellow solid
1
(
70 mg, 74%); mp 219-221 °C; R 0.25 (CHCl /MeOH = 99/1); H NMR (400 MHz, DMSO-d )
f
3
6
δ 10.35 (br s, 1H), 7.45 (d, J = 7.6 Hz, 1H), 7.35 (t, J = 7.6 Hz, 1H), 7.12 (m, 3H), 7.05-6.92 (m,
H), 3.16 (s, 3H), 3.16-3.13 (m, 4H), 2.72-2.78 (m, 2H), (one -NH and aliphatic protons was not
3
1
3
seen); C NMR (100 MHz, DMSO-d
6
) δ 176.8, 144.0, 136.2, 132.3, 131.7, 129.4, 126.7, 124.4,
1
4
2
22.7, 121.5, 118.7, 118.1, 111.3, 110.6, 109.1, 79.3, 61.1, 26.4, 21.8.
.2.10. 5-Methyl-2',3',4',9'-tetrahydrospiro[indoline-3,1'-pyrido[3,4-b]indol]-2-one (3h)
-(1H-indol-3-yl)ethan-1-amine 1a (50 mg, 0.31 mmol) and 5-methylisatin 2h (51 mg, 0.31
mmol) were reacted using the general procedure A. The product was obtained as a yellow solid
1
(79 mg, 83%); mp 266-268 °C; R
f
0.25 (CHCl
3
/MeOH = 99/1); H NMR (400 MHz, DMSO-d
6
)
δ 10.39 (br s, 1H), 10.35 (br s, 1H), 7.45 (d, J = 7.6 Hz, 1H), 7.17 (d, J = 7.8 Hz, 1H), 7.09-6.93
(m, 3H), 6.91 (s, 1H), 6.82 (d, J = 7.8 Hz, 1H), 3.58 (ddd, J = 12.6, 7.7, 4.9 Hz, 1H), 3.14 (dt, J =
1
3
1
2.6, 4.8 Hz, 1H), 2.89-2.64 (m, 2H), 2.19 (s, 3H) (one -NH proton was not seen); C NMR
1
1

ACCEPTED MANUSCRIPT
(100 MHz, DMSO-d
6
) δ 178.3, 139.8, 136.0, 133.0, 131.8, 130.4, 129.1, 126.5, 125.1, 121.0,
1
4
2
18.2, 117.6, 111.1, 110.1, 109.5, 61.2, 39.1, 21.7, 20.5.
.2.11. 5,7-Dimethyl-2',3',4',9'-tetrahydrospiro[indoline-3,1'-pyrido[3,4-b]indol]-2-one (3i)
-(1H-indol-3-yl)ethan-1-amine 1a (50 mg, 0.31 mmol) and 5,7-dimethylisatin 2i (55 mg, 0.31
mmol) were reacted using the general procedure A. The product was obtained as a white solid
1
(50 mg, 51%); mp 266-268 °C; R
f
0.25 (CHCl
3
/MeOH = 99/1); H NMR (400 MHz, DMSO-d
6
)
δ 10.38 (br s, 1H), 10.36 (br s, 1H), 7.44 (d, J = 7.6 Hz, 1H), 7.20-7.13 (m, 1H), 7.07-6.92 (m,
2
H), 6.90-6.87 (m, 1H), 6.76-6.68 (m, 1H), 3.59 (ddd, J = 12.7, 7.9, 4.8 Hz, 1H), 3.13 (dt, J =
2.6, 4.8 Hz, 1H), 2.87-2.66 (m, 2H), 2.25 (s, 3H), 2.15 (s, 3H) (one -NH proton was not seen);
1
1
3
C NMR (100 MHz, DMSO-d ) δ 178.7, 138.3, 136.0, 132.6, 132.0, 130.5, 130.4, 126.5, 122.4,
6
1
4
2
20.9, 118.7, 118.2, 117.6, 111.0, 110.0, 61.4, 39.1, 21.7, 20.4, 16.4.
.2.12. 5-Methoxy-2',3',4',9'-tetrahydrospiro[indoline-3,1'-pyrido[3,4-b]indol]-2-one (3j)
-(1H-indol-3-yl)ethan-1-amine 1a (50 mg, 0.31 mmol) and 5-methoxyisatin 2j (56 mg, 0.31
mmol) were reacted using the general procedure A. The product was obtained as a Orange solid
1
(
45 mg, 45%); mp 253-255 °C; R 0.25 (CHCl /MeOH = 99/1); H NMR (400 MHz, DMSO-d )
f
3
6
δ 10.40 (br s, 1H), 10.27 (br s, 1H), 7.45 (d, J = 7.6 Hz, 1H), 7.17 (d, J = 7.8 Hz, 1H), 7.06-6.93
m, 2H), 6.85-6.81 (m, 2H), 6.69 (d, J = 1.6 Hz, 1H), 3.65-3.57 (m, 4H), 3.12 (dt, J= 12.5, 4.6
Hz, 1H), 2.88 (ddd, J = 13.5, 8.2, 5.2 Hz, 1H), 2.72 (dt, J = 15.1, 4.4 Hz, 1H) (one -NH proton
(
1
3
was not seen); C NMR (100 MHz, DMSO-d
6
) δ 178.3, 154.9, 136.1, 135.5, 133.9, 131.7,
1
4
2
26.6, 121.1, 118.3, 117.7, 114.0, 111.1, 110.2, 61.5, 55.4, 40.1, 21.6.
.2.13. 2',3',4',5'-Tetrahydrospiro[indoline-3,1'-pyrido[4,3-b]indol]-2-one (3k)
-(1H-indol-2-yl)ethan-1-amine 1b (50 mg, 0.31 mmol) and isatin 2a (46 mg, 0.31 mmol) were
reacted using the general procedure A. The product was obtained as a brown solid (61 mg, 68%);
1
mp 184-186 °C; R
f
0.25 (CHCl
3
/MeOH = 99/1); H NMR (500 MHz, DMSO-d
6
) δ 10.97 (br s,
1
6
1
H), 10.39 (br s, 1H), 7.25-7.20 (m, 2H), 7.00 (d, J = 7.2 Hz, 1H), 6.94 (d, J = 7.7 Hz, 1H), 6.91-
.83 (m, 2H), 6.66 (t, J = 7.4 Hz, 1H), 6.36 (d, J = 7.8 Hz, 1H), 3.72-3.67 (m, 1H), 3.16-3.11 (m,
1
3
H), 2.92-2.89 (m, 1H), 2.77-2.72 (m, 1H) (one -NH proton was not seen); C NMR (125 MHz,
DMSO-d ) δ 179.6, 141.9, 135.7, 135.3, 131.5, 128.6, 124.6, 124.3, 121.6, 120.2, 118.4, 116.8,
6
-1
+
1
10.8, 109.3, 60.7, 38.5, 23.3; FTIR ν 3033, 2922, 1627, 1032, 788, cm ; HRMS (ESI) [M + H]
found m/z 290.1289, calcd for C H N O 290.1288.
1
8
16
3
1
2

ACCEPTED MANUSCRIPT
4
.2.14 5-Chloro-2',3',4',5'-tetrahydrospiro[indoline-3,1'-pyrido[4,3-b]indol]-2-one (3l)
2
-(1H-indol-2-yl)ethan-1-amine 1b (50 mg, 0.31 mmol) and 5-chloro isatin 2b (57 mg, 0.31
mmol) were reacted using the general procedure A. The product was obtained as a brown solid
1
(65mg, 65%); mp 172-174 °C; R
f
0.28 (CHCl
3
/MeOH = 99/1); H NMR (400 MHz, DMSO-d
6
)
δ 11.02 (br s, 1H), 10.54 (br s, 1H), 7.29-7.26 (m, 2H), 7.02 (d, J = 2.1 Hz, 1H), 6.98-6.95 (m,
2
2
H), 6.71 (t, J = 7.5 Hz, 1H), 6.39 (d, J = 7.9 Hz, 1H), 3.70-3.64 (m, 1H), 3.16-3.11 (m, 1H),
1
3
.95-2.91 (m, 1H), 2.78-2.75 (m, 1H) (one -NH proton was not seen); C NMR (100 MHz,
DMSO-d ) δ 179.5, 140.8, 136.1, 136.0, 135.3, 128.4, 125.6, 124.5, 124.2, 120.2, 118.6, 116.5,
6
-1
1
10.9, 110.8, 106.3, 61.0, 38.5, 23.3; FTIR ν 3272, 2922, 1616, 1454, 1088, 742 cm ; HRMS
+
(
ESI) [M + H] found m/z 324.0900, calcd for C H ClN O 324.0898.
1
8
15
3
4
2
.2.15 5-Bromo-2',3',4',5'-tetrahydrospiro[indoline-3,1'-pyrido[4,3-b]indol]-2-one (3m)
-(1H-indol-2-yl)ethan-1-amine 1b (50 mg, 0.31 mmol) and 5-bromo isatin 2c (71 mg, 0.31
mmol) were reacted using the general procedure A. The product was obtained as a brown solid
1
(68 mg, 60%); mp 195-197 °C; R
f
0.48 (CHCl
3
/MeOH = 99/1); H NMR (400 MHz, DMSO-d
6
)
δ 11.04 (br s, 1H), 10.55 (br s, 1H), 7.41 (dd, J = 8.2, 2.0 Hz, 1H), 7.27 (d, J = 8.1 Hz, 1H), 7.13
d, J = 1.8 Hz, 1H), 6.98-6.91 (m, 2H), 6.72 (t, J = 7.5 Hz, 1H), 6.39 (d, J = 7.9 Hz, 1H), 3.68-
.64 (m, 1H), 3.15-3.12 (m, 1H), 2.95-2.89 (m, 1H), 2.88 -2.72 (m, 1H) (one -NH proton was not
(
3
1
3
seen); C NMR (100 MHz, DMSO-d ) δ 179.4, 141.2, 136.4, 136.1, 135.3, 131.2, 127.2, 124.1,
6
1
7
4
2
20.2, 118.6, 116.5, 113.3, 111.3, 111, 106.3, 60.9, 38.5, 23.3; FTIR ν 2921, 1656, 1386, 1089,
-1
+
71 cm ; HRMS (ESI) [M + H] found m/z 368.0395, calcd for C H BrN O 368.0393.
1
8
15
3
.2.16. 5-Fluoro-2',3',4',5'-tetrahydrospiro[indoline-3,1'-pyrido[4,3-b]indol]-2-one (3n)
-(1H-indol-2-yl)ethan-1-amine 1b (50 mg, 0.31 mmol) and 5-fluoro isatin 2d (52 mg, 0.31
mmol) were reacted using the general procedure A. The product was obtained as a brown solid
1
(57 mg, 60%); mp 153-155 °C; R
f
0.47 (CHCl
3
/MeOH = 99/1); H NMR (400 MHz, DMSO-d
6
)
δ 11.02 (br s, 1H), 10.44 (br s, 1H), 7.27 (d, J = 8.1 Hz, 1H), 7.10-7.03 (m, 1H), 6.98-6.90 (m,
H), 6.87 (dd, J = 8.2, 2.6 Hz, 1H), 6.71 (t, J = 7.5 Hz, 1H), 6.39 (d, J = 7.9 Hz, 1H), 3.71-3.66
m, 1H), 3.24-3.05 (m, 1H), 3.00-2.84 (m, 1H), 2.78-2.63 (m, 1H) (one -NH proton was not
2
(
1
3
seen); C NMR (100 MHz, DMSO-d ) δ 179.9, 138.0, 136.1, 135.4, 126.8, 124.3, 120.3, 118.6,
6
1
16.6, 114.9, 112.3, 111.0, 110.1, 106.5, 61.2, 38.5, 23.3; FTIR ν 3200, 2921, 1642, 1490, 782
-1
+
cm ; HRMS (ESI) [M + H] found m/z 308.1196, calcd for C H FN O 308.1194.
1
8
15
3
1
3

ACCEPTED MANUSCRIPT
4
.2.17. 4,7-Dichloro-2',3',4',5'-tetrahydrospiro[indoline-3,1'-pyrido[4,3-b]indol]-2-one (3o)
-(1H-indol-2-yl)ethan-1-amine 1b (50 mg, 0.31 mmol) and 4, 7-dichloro isatin 2e (68 mg, 0.31
2
mmol) were reacted using the general procedure A. The product was obtained as a brown solid
1
(55 mg, 50%); mp 262-264 °C; R
f
0.33 (CHCl
3
/MeOH = 99/1); H NMR (400 MHz, DMSO-d
6
)
δ 11.04 (br s, 1H), 10.99 (br s, 1H), 7.35 (d, J = 8.7 Hz, 1H), 7.28 (d, J = 8.1 Hz, 1H), 6.97-6.90
m, 1H), 6.88 (d, J = 8.7 Hz, 1H), 6.78-6.67 (m, 1H), 6.33 (d, J = 7.9 Hz, 1H), 3.80-3.70 (m,
(
1
H), 3.20-3.09 (m, 1H), 2.98-2.85 (m, 1H), 2.76-2.67 (m, 1H) (one -NH proton was not seen);
1
3
C NMR (100 MHz, DMSO-d ) δ 179.1, 141.6, 136.7, 135.3, 130.7, 130.1, 129.1, 124.1, 123.6,
6
1
20.1, 118.6, 115.9, 112.5, 111, 103.6, 62.2, 38.3, 23.3; FTIR ν 3404, 2922, 1643, 1490, 742
-1
+
cm ; HRMS (ESI) [M + H] found m/z 358.0511, calcd for C H Cl N O 358.0508.
1
8
14
2
3
4
.2.18. 7-Fluoro-2',3',4',5'-tetrahydrospiro[indoline-3,1'-pyrido[4,3-b]indol]-2-one (3p)
2
-(1H-indol-2-yl)ethan-1-amine 1b (50 mg, 0.31 mmol) and 7-fluoro isatin 2f (52 mg, 0.31
mmol) were reacted using the general procedure A. The product was obtained as a brown solid
1
(52 mg, 55%); mp > 180 °C; R
f
0.42 (CHCl
3
/MeOH = 99/1); H NMR (400 MHz, DMSO-d
6
) δ
1
6
1
1
6
1.02 (br s, 1H), 10.90 (br s, 1H), 7.26 (d, J = 8.1 Hz, 1H), 7.15 (m, 1H), 6.96-6.83 (m, 3H),
.74-6.67 (m, 1H), 6.38 (d, J = 7.9 Hz, 1H), 3.75-3.60 (m, 1H), 3.16-3.08 (m, 1H), 2.97-2.86 (m,
1
3
H), 2.81-2.70 (m, 1H) (one -NH proton was not seen); C NMR (100 MHz, DMSO-d ) δ 179.6,
6
36.9, 136, 135.3, 124.2, 122.4, 122.4, 120.5, 120.2, 118.5, 116.5, 115.5, 115.4, 110.9, 106.5,
-1
+
0.9, 38.3, 23.3; FTIR ν 3043, 2922, 1642, 1458, 1163, 755 cm . HRMS (ESI) [M + H] found
m/z 308.1196, calcd for C H FN O 308.1194.
1
8
15
3
4
.2.19. 5-Methyl-2',3',4',5'-tetrahydrospiro[indoline-3,1'-pyrido[4,3-b]indol]-2-one (3q)
2
-(1H-indol-2-yl)ethan-1-amine 1b (50 mg, 0.31 mmol) and 5-methyl isatin 2h (50 mg, 0.31
mmol) were reacted using the general procedure A. The product was obtained as a brown solid
1
(66 mg, 70%); mp 173-175 °C; R
f
0.30 (CHCl
3
/MeOH = 99/1); H NMR (400 MHz, DMSO-d
6
)
δ 10.97 (br s, 1H), 10.30 (br s, 1H), 7.25 (d, J = 8.0 Hz, 1H), 7.01 (d, J = 7.7 Hz, 1H), 6.92 (t, J =
7
1
.5 Hz, 1H), 6.85-6.83 (m, 2H), 6.70 (t, J = 7.5 Hz, 1H), 6.42 (d, J = 7.8 Hz, 1H), 3.71-3.65 (m,
H), 3.17-3.13 (m, 1H), 2.95-2.87 (m, 1H), 2.77-2.73 (m, 1H), 2.14 (s, 3H) (one -NH proton was
1
3
not seen); C NMR (100 MHz, DMSO-d ) δ 179.8, 139.3, 135.7, 135.3, 134.1, 130.2, 128.6,
6
1
25.0, 124.4, 120.0, 118.3, 116.8, 110.7, 108.9, 107.2, 60.8, 38.6, 23.4, 20.5.; FTIR ν 3150,
1
4

ACCEPTED MANUSCRIPT
-1
+
2
922, 1684, 1456, 1087, 727 cm ; HRMS (ESI) [M + H] found m/z 304.1444, calcd for
C H N O 304.1444.
19
18
3
4
.2.20. 5-(Trifluoromethoxy)-2',3',4',5'-tetrahydrospiro[indoline-3,1'-pyrido[4,3-b]indol]-2-one
3r)
-(1H-indol-2-yl)ethan-1-amine 1b (50 mg, 0.31 mmol) and 5-(trifluoromethoxy) isatin 2k (72
(
2
mg, 0.31 mmol) were reacted using the general procedure A. The product was obtained as a
1
brown solid (83 mg, 72%); mp 177-179 °C; R 0.37 (CHCl /MeOH = 99/1); H NMR (400
f
3
MHz, DMSO-d ) δ 11.03 (br s, 1H), 10.58 (br s, 1H), 7.27-7.23 (m, 2H), 7.04 (d, J = 8.4 Hz,
6
1
3
H), 6.97 (d, J = 1.5 Hz, 1H), 6.95-6.88 (m, 1H), 6.73-6.65 (m, 1H), 6.35 (d, J = 7.9 Hz, 1H),
.79-3.64 (m, 1H), 3.18-3.05 (m, 1H), 2.93 (m, 1H), 2.74 (m, 1H) (one -NH proton was not
1
3
seen); C NMR (100 MHz, DMSO-d
6
) δ 179.9, 143.3, 141.1, 136.2, 135.7, 135.4, 124.2, 121.7,
1
1
21.4, 120.3, 118.6, 118.0, 116.4, 111.0, 110.2, 106.2, 61.1, 38.4, 23.3; FTIR ν 3022, 2922,
-1
+
640, 1458, 1163, 760, 655 cm ; HRMS (ESI) [M + H] found m/z 374.1112, calcd for
374.1111.
19 15 3 3 2
C H F N O
4
.2.21. 5-Iodo-2',3',4',5'-tetrahydrospiro[indoline-3,1'-pyrido[4,3-b]indol]-2-one (3s)
2
-(1H-indol-2-yl)ethan-1-amine 1b (50 mg, 0.31 mmol) and 5-iodoisatin 2l (85 mg, 0.31 mmol)
were reacted using the general procedure A. The product was obtained as a brown solid (93 mg,
1
7
2%); mp 169-171°C; R 0.23 (CHCl /MeOH = 99/1); H NMR (400 MHz, DMSO-d ) δ 11.03
f
3
6
(br s, 1H), 10.52 (br s, 1H), 7.56 (dd, J = 8.1, 1.6 Hz, 1H), 7.27-7.26 (m, 2H), 6.93 (t, J = 7.6 Hz,
1
H), 6.80 (d, J = 8.1 Hz, 1H), 6.71 (t, J = 7.5 Hz, 1H), 6.40 (d, J = 7.8 Hz, 1H), 3.67-3.63 (m,
H), 3.20-3.07 (m, 1H), 2.95-2.89 (m, 1H), 2.75-2.67 (m, 1H) (one -NH proton was not seen);
1
1
3
C NMR (100 MHz, DMSO-d ) δ 179.3, 141.7, 137.0, 136.7, 136.1, 135.3, 132.7, 124.2, 120.2,
6
1
18.6, 116.5, 111.8, 110.9, 106.4, 60.7, 38.5, 23.3; FTIR ν 3272, 2921, 1609, 1458, 1088, 737
-1
+
3
cm ; HRMS (ESI) [M + H] found m/z 416.0258, calcd for C18H15IN O 416.0254.
Acknowledgements
TU, MD are thankful to Council of Scientific and Industrial Research, New Delhi, India for
financial assistance through fellowship and contingency.
5
1
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