One-pot synthesis of highly substituted indolines

Article abstract of DOI:10.1016/j.tet.2009.11.080

A general and convenient one-pot synthesis of highly substituted indolines from arylhydrazines and aldehydes is reported. This synthesis allows introduction of substitution at essentially all positions of the indoline nucleus to achieve significant diversity in this biologically important template.

Full text of DOI:10.1016/j.tet.2009.11.080

Tetrahedron 66 (2010) 573–577
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
One-pot synthesis of highly substituted indolines
*
Kevin G. Liu , Jennifer R. Lo, Albert J. Robichaud
Neuroscience Chemistry, Pfizer Global Research and Development, CN 8000, Princeton, NJ 08543, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A general and convenient one-pot synthesis of highly substituted indolines from arylhydrazines and
aldehydes is reported. This synthesis allows introduction of substitution at essentially all positions of the
indoline nucleus to achieve significant diversity in this biologically important template.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 14 August 2009
Received in revised form
17 November 2009
Accepted 18 November 2009
Available online 20 November 2009
1. Introduction
As part of our efforts in developing therapeutic agents for CNS
diseases, we desired a convenient and versatile synthesis of 3,3-
Indolines are common structural elements in many biologically
active compounds and natural products.1–5 A great number of
methods have been developed for synthesis of this important class
of compounds. These (Scheme 1) include reduction of indoles,6–18
anionic,19–23 radical,24–26 and metal-mediated27–30 intramolecular
cyclizations, as well as several other approaches.31–33
disubstituted indolines with potential substitution at alternate
positions of the scaffold. We recently reported the synthesis of
indoles 134 and oxindoles 235 from indolenines 3, which could be
readily synthesized from arylhydrazines 4 (Scheme 2). To further
extend the utility of the indolenine template, we report herein
a general and convenient one-pot synthesis of 3,3-disubstituted
indolines 5, which allows introduction of substitution at essentially
any position of the molecule. Although sporadic synthesis of
indolines from their corresponding indolenines have been pre-
viously reported,36–41 the examples were generally limited to 3,3-
dimethylindolines and the synthesis required isolation of relatively
instable indolenines.
Reduction of indoles
R2
R2
H- or H2 / catalyst
R3
R3
N
N
R1
R1
Anionic cyclization
X
Li
R1
NH2
N
E
E+
RLi
H
4
N
R
N
R
N
R
R2
N
R2
R2
R3
R4
R3
Radical cyclization
O
R3
R1
R1
R1
R'
.
N
H
N
H
1 (R4 = H)
2 (R4 = H)
3
N
R
R'
N
R
R'
.
N
R
R2
N
R3
R4
Metal-catalyzed cyclization
R1
I
I
1. "Zr"
2. I2
X
"Pd"
5
R
N
R
Scheme 2. Synthetic utility of indolenines.
N
R
N
R
R'
Scheme 1. Selected existing syntheses of indolines.
2. Results and discussion
One critical requirement for a one-pot synthesis for a multi-
step chemical transformation is that the solvent system is
* Corresponding author. Tel.: þ1 732 274 4415; fax: þ1 732 274 4505.
E-mail address: liuk1@wyeth.com (K.G. Liu).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.11.080

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K.G. Liu et al. / Tetrahedron 66 (2010) 573–577
Table 1
One-pot synthesis of 3,3-disubstituted indolines from arylhydrazinesa
R3
N
1. HOAc
R4
R2
O
2. NaBH(OAc)3
R5CHO (7)
R1
R1
R3
NH2
R2
N
H
+
(one-pot)
R4
R
5 (R = H or R5CH2)
4
6
Entry
1
4b
6
7
5
Yield (%)c
59
O
O
d
NH2
NH2
NH2
NH2
NH2
NH2
H
H
N
N
H
H
5a
2
3
4
5
6
d
d
d
d
d
58
63
73
0
N
H
N
H
5b
O
H
H
N
H
N
H
5c
O
N
H
N
H
5d
O
H
N
H
N
H
5e
O
73
H
O
N
H
N
H
5f
Cbz
N
H
7
8
NH2
d
50
49
N
H
N
Cbz
N
H
5g
O
O
d
NH2
H
N
H
O
N
H
5h
F
O
O
O
F
9
d
d
d
47
56
77
NH2
H
H
H
N
H
N
H
5i
10
11
NH2
N
H
N
H
5j
Cl
Cl
NH2
Cl
N
N
Cl
H
H
5k
O
12
d
66
NH2
N
H
N
H
5l

K.G. Liu et al. / Tetrahedron 66 (2010) 573–577
575
Table 1 (continued)
Entry
4b
6
7
5
Yield (%)c
O
O
O
13
14
N
55
44
NH2
H
H
N
H
5m
H
O
NH2
H
N
H
N
5n
Cl
Cl
O
O
15
N
63
H
Cl
5o
NH2
H
Cl
N
H
Cl
Cl
O
O
16
60
H
H
N
NH2
Cl
Cl
N
H
5p
a
Reaction conditions: 1. 4 (3.57 mmol), 6 (3.57 mmol) in AcOH (11.9 mL), 60–80 ꢀC, 1-3 h; 2. NaBH(OAc)3 (4.64 mmol, 1.3 equiv) or NaBH(OAc)3 (8.20 mmol, 2.3 equiv) and
aldehyde 7 (3.57 mmol).
b
All hydrazines used were HCl salts except phenylhydrazine.
Isolated yield after chromatography.
c
O
compatible with all the reactions in the synthetic sequence. In our
efforts to develop a one-pot synthesis of indolines 5 from aryl-
H
NH2
N
H
hydrazines 4, composed of a Fischer indole reaction, indolenine 3
C]N bond reduction, and final reductive amination with a suit-
able aldehyde, we chose acetic acid as the solvent system because
we have previously demonstrated the utility of this solvent for
indolenine formation.34,35 Furthermore, acetic acid has been
commonly used as a catalyst for imine reduction and reductive
amination with mild reducing agents such as NaBH3CN and NaB-
H(OAc)3.42 For our purposes we chose the less toxic reducing agent
NaBH(OAc)3 for indolenine reduction and reductive amination.
Although initially it was our concern that NaBH(OAc)3 may de-
compose in acetic acid solvent, we envisioned that C]N bond
reduction and reductive amination could be significantly acceler-
ated in acetic acid and therefore may successfully compete with
the decomposition.
H+
N
H+
8
+
N
H
H
N
H
B:
9
Scheme 3. Rearrangement of spiroindolenines.
To further demonstrate that introduction of substitution at the
1-position could also be carried out in this one-pot procedure,
hexanal or benzaldehyde was added after the initial indolenine
formation followed by addition of NaBH(OAc)3 and the desired
products were isolated in good yields (entries 13–16).
To explore the feasibility, scope and limitations of this one-pot
approach, a number of arylhydrazines 4, a-branched aldehydes 6
(for indolenine formation), and aldehydes 7 (for reductive ami-
nation) were utilized and the results are summarized in Table 1. In
almost all cases, the indolenine formation went smoothly in neat
acetic acid. In general, the reaction was complete in several hours
at 80 ꢀC with free arylhydrazines and at 60 ꢀC with arylhydrazine
HCl salts, where progress of the reactions was best monitored by
LC–MS. The one exception that we encountered to this general
process was in the case of cyclopentane carboxaldehyde (entry 5).
The reaction intermediate, the indolenine 8 quickly rearranged to
the indole product 9 (Scheme 3), presumably due to the ring
constrain of cyclopentane. In all other examples investigated, the
indolenine reduction went smoothly at temperatures below 20 ꢀC
as soon as the addition of NaBH(OAc)3 was complete. In practice,
the reaction mixture was diluted (2–3 times) with 1,2-di-
chloroethane before the reduction due to the high freezing point
of acetic acid (16.2 ꢀC).
3. Conclusion
We have developed a convenient and general one-pot synthesis
of 3,3-disubstituted indolines from arylhydrazines via Fischer in-
dole synthesis followed by indolenine reduction and reductive
amination. This synthesis allows introduction of substitution at
essentially all positions of the indole nucleus to achieve significant
diversity in this biologically important template.
4. Experimental
4.1. General
All solvents and reagents were obtained commercially and used
as received. 1H and 13C NMR spectra were recorded on a Varian

576
K.G. Liu et al. / Tetrahedron 66 (2010) 573–577
instrument in the cited deuterated solvents. Chemical shifts are
given in ppm, and coupling constants are in Hertz. All final
compounds were purified by flash chromatography using
220–400 mesh silica gel. Thin-layer chromatography was done on
silica gel 60 F-254 (0.25-nm thickness) plates. Visualization was
accomplished with UV light and/or 10% phosphomolybdic acid in
ethanol. Mass spectra were recorded on either a Finnigan or
a Hewlett–Packard spectrometer. LC–MS was run on an Agilent
system with a Hewlett–Packard mass spectrometer.
2H) 5.35 (s, 1H) 6.40 (d, J¼7.7 Hz, 1H) 6.47 (dt, J¼7.4 and 1.0 Hz, 1H)
6.83 (dt, J¼7.6 and 1.3 Hz, 1H) 6.91 (d, J¼7.3 Hz, 1H). 13C NMR
(100 MHz, DMSO-d6) d ppm 23.3, 26.0, 36.8, 46.0, 56.7, 109.2, 117.3,
122.6, 127.7, 138.4, 151.9. HRMS Calcd for (MþH)þ: C13H17Nþ:
188.1434, Found: 188.1437.
4.3.6. Benzyl spiro[indoline-3,40-piperidine]-10-carboxylate (5g). Yield
50%. 1H NMR (400 MHz, DMSO-d6)
d ppm 1.52–1.66 (m, 4H) 2.85–
3.10 (m, 4H) 3.27 (s,1H) 3.92 (d, J¼13.7 Hz, 2H) 5.05 (s, 2H) 6.44–6.51
(m, 2H) 6.87 (dt, J¼7.7 and 1.1 Hz, 1H) 6.94 (d, J¼7.3 Hz,1H) 7.26–7.36
4.2. General procedure for one-pot synthesis of indolines
(m, 5H). 13C NMR (100 MHz, DMSO-d6)
d ppm 35.8, 41.5, 44.4, 55.7,
66.9, 109.5, 117.7, 122.9, 128.1, 128.2, 128.5, 129.0, 136.7, 137.7, 151.9,
155.2. HRMS Calcd for (MþH)þ: C20H23N2O2þ: 323.1754, Found:
323.1758.
4.2.1. Synthesis of N1-unsubstituted indolines. A mixture of arylhy-
drazine 4 or its HCl salt (3.57 mmol) and a,a-branched aldehyde 6
(3.57 mmol) in AcOH (11.9 mL) was stirred at 60–80 ꢀC for 1–3 h (in
general, 80 ꢀC for free hydrazines and 60 ꢀC for hydrazine HCl salts).
The reaction was ideally monitored by LC–MS. Upon completion,
the reaction mixture was cooled with cold water and diluted with
1,2-dichloroethane (11.9 mL) followed by treatment with NaB-
H(OAc)3 (4.64 mmol, 1.3 equiv) in portions with cooling in cold
water and was then stirred for 10 min followed by 20 min at room
temperature. The reaction mixture was concentrated to dryness
and extracted with EtOAc and washed with Na2CO3. The organic
layer was dried over Na2SO4 and purified by chromatography with
EtOAc/hexanes or CH2Cl2/hexanes to provide the indoline products.
4.4. 20,30,50,60-Tetrahydrospiro[indoline-3,40-pyran] (5h)
Yield 49%. 1H NMR (400 MHz, DMSO-d6)
d
ppm 1.45 (dd, J¼13.2
and 1.7 Hz, 2H) 1.75 (dt, J¼13.0 and 4.6 Hz, 2H) 3.40–3.51 (m, 2H)
3.74–3.78 (m, 2H) 5.44 (s, 1H) 6.44 (d, J¼7.8 Hz, 1H) 6.50 (dt, J¼7.4
and 1.0 Hz, 1H) 6.86 (dt, J¼7.7 and 1.3 Hz, 1H) 6.96 (d, J¼7.3 Hz, 1H).
13C NMR (100 MHz, DMSO-d6)
d ppm 36.9, 43.7, 56.2, 64.8, 109.3,
117.5, 122.9, 128.0, 137.0, 152.0. HRMS Calcd for (MþH)þ:
C12H16NOþ: 190.1226, Found: 190.1227.
4.4.1. 50-Fluorospiro[cyclohexane-1,30-indoline] (5i). Yield 47%. 1H
4.2.2. Synthesis of N1-unsubstituted indolines. The same procedure
was followed except aldehyde 7 (3.57 mmol) was added before
NaBH(OAc)3 (8.20 mmol, 2.3 equiv) reduction.
NMR (400 MHz, DMSO-d6) d ppm 1.17–1.69 (m, 10H) 3.26
(d, J¼10.7 Hz, 2H) 5.26 (s, 1H) 6.36 (dd, J¼8.3 and 4.4 Hz, 1H) 6.64
(dt, J¼9.6 and 2.4 Hz, 1H) 6.78 (dd, J¼8.8 and 2.4 Hz, 1H). 13C NMR
(100 MHz, DMSO-d6) d ppm 23.2, 25.8, 36.3, 46.4, 57.1, 109.2, 109.3,
4.3. Characterization of compounds 5a–5p
110.1, 110.3,113.4, 113.6, 140.4, 140.4, 148.2, 155.0, 157.3. HRMS Calcd
for (MþH)þ: C13H17FNþ: 206.1340, Found: 206.1342.
4.3.1. 3-Ethyl-3-methylindoline (5a). Yield 59%. 1H NMR (400 MHz,
DMSO-d6)
d
ppm 0.74 (t, J¼7.5 Hz, 3H) 1.13 (s, 3H) 1.44–1.55 (m, 2H)
4.4.2. 50-Methylspiro[cyclohexane-1,30-indoline] (5j). Yield 56%. 1H
3.04 (dd, J¼8.9 and 2.2 Hz, 2H) 3.04 (dd, J¼8.9 and 1.6 Hz, 2H) 5.3 (s,
NMR (400 MHz, DMSO-d6)
3.20 (s, 2H) 5.12 (s, 1H) 6.33 (d, J¼7.5 Hz, 1H) 6.65 (d, J¼7.2 Hz, 1H)
6.73 (s, 1H). 13C NMR (100 MHz, DMSO-d6)
ppm 21.3, 23.4, 26.0,
d ppm 1.21–1.58 (m, 10H) 2.12 (s, 3H),
1H) 6.42 (d, J¼7.6 Hz, 1H) 6.48 (dt, J¼7.3 and 1.0 Hz, 1H) 6.83–6.88
(m, 2H). 13C NMR (100 MHz, DMSO-d6)
d
ppm 9.6, 26.0, 33.2, 45.3,
d
58.9, 109.1, 117.3, 122.8, 127.6, 137.1, 152.2. HRMS Calcd for (MþH)þ:
36.8, 46.0, 56.9, 109.2, 123.4, 125.9, 128.0, 138.7, 149.6. HRMS Calcd
C11H16Nþ: 162.1277, Found: 162.1278.
for (MþH)þ: C14H20Nþ: 202.1590, Found: 202.1593.
4.3.2. 3,3-Diethylindoline (5b). Yield 58%. 1H NMR (400 MHz,
4.4.3. 40,60-Dichlorospiro[cyclohexane-1,30-indoline] (5k). Yield 77%.
DMSO-d6)
d
ppm 0.70 (t, J¼7.5 Hz, 6H) 1.43–1.60 (m, 4H) 3.16
1H NMR (400 MHz, DMSO-d6)
d ppm 1.08–1.33 (m, 3H) 1.47–1.58
(d, J¼1.7 Hz, 2H) 5.28 (s, 1H) 6.41 (d, J¼7.7 Hz, 1H) 6.46 (dt, J¼7.3
(m, 5H) 2.05 (dt, J¼13.1 and 3.5 Hz, 2H) 3.36 (d, J¼1.1 Hz, 2H) 6.15 (s,
and 0.9 Hz, 1H) 6.82–6.87 (m, 2H). 13C NMR (100 MHz, DMSO-d6)
1H) 6.34 (d, J¼1.7 Hz, 1H) 6.40 (d, J¼1.7 Hz, 1H). 13C NMR (100 MHz,
d
ppm 9.3, 31.0, 49.1, 56.5, 109.0, 117.0, 123.5, 127.6, 135.0, 152.9.
DMSO-d6) d ppm 22.7, 25.6, 33.4, 47.9, 56.4, 107.1, 116.8, 130.4, 131.3,
HRMS Calcd for (MþH)þ: C12H18Nþ: 176.1434, Found: 176.1435.
133.3, 155.2. HRMS Calcd for (MþH)þ: C13H16Cl2Nþ: 256.0660,
Found: 256.0659.
4.3.3. 3-Methyl-3-propylindoline (5c). Yield 63%. 1H NMR (400 MHz,
DMSO-d6)
d
ppm 0.79 (t, J¼7.3 Hz, 3H) 1.00–1.12 (m, 1H) 1.14 (s, 3H)
4.4.4. 3,3-Dimethyl-2-phenylindoline (5l). Yield 66%. 1H NMR
(400 MHz, DMSO-d6) d ppm 0.65 (S, 3H) 1.45 (S, 3H) 4.53 (d,
1.22–1.30 (m, 1H) 1.36–1.52 (m, 2H) 3.04 (dd, J¼8.9 and 2.3 Hz, 1H)
3.21 (dd, J¼8.9 and 1.9 Hz, 1H) 5.31 (s, 1H) 6.41 (d, J¼7.7 Hz, 1H) (dt,
J¼7.4 and 1.1 Hz, 1H) 6.82–6.88 (m, 2H). 13C NMR (100 MHz, DMSO-
J¼2.1 Hz, 1H) 6.49 (d, J¼1.7 Hz, 1H) 6.56 (d, J¼1.7 Hz, 1H) 6.69 (d,
J¼1.4 Hz, 1H) 7.27–7.36 (m, 5H). 13C NMR (100 MHz, DMSO-d6)
d6)
d
ppm 15.3, 18.2, 26.5, 43.4, 45.1, 59.3, 109.1, 117.3, 122.7, 127.5,
d ppm 22.4, 26.1, 46.8, 73.9, 107.6, 117.6, 128.1, 128.3, 128.7, 130.6,
137.4, 152.1. HRMS Calcd for (MþH)þ: C12H18Nþ: 176.1434, Found:
131.6, 133.4, 139.5, 154.1. HRMS Calcd for (MþH)þ: C16H16Cl2Nþ:
176.1437.
292.0654, Found: 292.0658.
4.3.4. 3-Methyl-3-phenylindoline (5d). Yield 73%. 1H NMR (400 MHz,
4.4.5. 10-Hexylspiro[cyclohexane-1,30-indoline] (5m). Yield 55%. 1H
DMSO-d6)
d
ppm 1.58 (s, 3H) 3.42 (d, J¼8.9 Hz, 1H) 3.56 (d, J¼9.0 Hz,
NMR (400 MHz, DMSO-d6)
d
ppm 0.82 (t, J¼7.0 Hz, 3H) 1.10–1.70
1H) 5.51 (s,1H) 6.53–6.57 (m, 2H) 6.86 (dd, J¼7.9 and 1.0 Hz,1H) 6.93
(m, 18H) 2.98 (t, J¼7.2 Hz, 2H) 3.13 (s, 2H), 6.35 (d, J¼7.5 Hz, 1H)
(dt, J¼7.5 and 1.3 Hz, 1H) 7.10–7.15 (m, 1H) 7.20–7.28 (m, 4H). 13C
6.48 (dt, J¼7.4 and 0.8 Hz, 1H) 6.80–6.92 (m, 2H). 13C NMR
NMR (100 MHz, DMSO-d6)
d
ppm 27.1, 49.6, 63.4, 109.8, 117.9, 124.1,
(100 MHz, DMSO-d6) d ppm 14.5, 22.8, 23.3, 25.9, 26.9, 27.0, 31.7,
126.5, 126.8, 128.0, 128.7, 137.1, 148.8, 152.2. HRMS Calcd for (MþH)þ:
36.8, 44.6, 48.4, 62.5, 107.1, 117.3, 122.5, 128.0, 139.0, 151.8. HRMS
C15H16Nþ: 210.1277, Found: 210.1281.
Calcd for (MþH)þ: C19H30Nþ: 272.2373, Found: 272.2376.
4.3.5. Spiro[cyclohexane-1,30-indoline] (5f). Yield 73%. 1H NMR
4.4.6. 10-Benzylspiro[cyclohexane-1,30-indoline] (5n). Yield 44%. 1H
(400 MHz, DMSO-d6)
d
ppm 1.25–1.65 (m, 10H) 3.22 (d, J¼2.1 Hz,
NMR (400 MHz, DMSO-d6) d ppm 1.21–1.29 (m, 3H) 1.46–1.57 (m,

K.G. Liu et al. / Tetrahedron 66 (2010) 573–577
577
6. Kumar, Y.; Florvall, L. Synth. Commun. 1983, 13, 489–493.
7H) 3.13 (s, 2H) 4.25 (s, 2H) 6.46 (d, J¼7.9 Hz, 2H) 6.53 (t, J¼7.3 Hz,
7. Gribble, G. W.; Nutaitis, C. F.; Leese, R. M. Heterocycles 1984, 22, 379–386.
8. Ketcha, D. M.; Lieurance, B. A. Tetrahedron Lett. 1989, 30, 6833–6836.
9. Kotsuki, H.; Ushio, Y.; Ochi, M. Heterocycles 1987, 26, 1771–1774.
10. Lanzilotti, A. E.; Littell, R.; Fanshawe, W. J.; McKenzie, T. C.; Lovell, F. M. J. Org.
Chem. 1979, 44, 4809–4813.
2H) 6.89–7.0 (m, 2H) 7.19–7.31 (m, 6H). 13C NMR (100 MHz, DMSO-
d6)
d ppm 23.3, 25.9, 36.7, 44.7, 52.4, 62.9, 107.4, 117.7, 122.7, 127.6,
128.0, 128.3, 129.0, 139.0, 139.1, 151.5. HRMS Calcd for (MþH)þ:
C20H24Nþ: 278.1903, Found: 278.1907.
11. Kikugawa, Y. J. Chem. Res., Synop. 1977, 212–213.
12. Berger, J. G. Synthesis 1974, 508–510.
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2213–2215.
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(5o). Yield 63%. 1H NMR (400 MHz, DMSO-d6)
d ppm 0.81
(t, J¼7.0 Hz, 3H) 1.10–1.70 (m, 14H) 2.08 (dt, J¼13.2 and 4.0 Hz, 2H)
2.45–2.46 (m, 2H) 3.06 (d, J¼7.2 Hz, 2H) 3.27 (s, 2H), 6.36 (d,
J¼1.7 Hz, 1H) 6.41 (d, J¼1.7 Hz, 1H). 13C NMR (100 MHz, DMSO-d6)
d
ppm 14.5, 22.6, 22.7, 25.6, 26.5, 26.7, 31.7, 33.4, 46.4, 46.9, 61.7,
105.1, 116.5, 130.2, 131.8, 133.9, 154.4. HRMS Calcd for (MþH)þ:
C19H28Cl2Nþ: 340.1593, Found: 340.1599.
4.4.8. 10-Benzyl-40,60-dichlorospiro[cyclohexane-1,30-indoline]
(5p). Yield 60%. 1H NMR (400 MHz, DMSO-d6)
d ppm 1.11–1.25 (m,
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6.48 (dd, J¼8.8 and 1.7 Hz, 2H) 7.20–7.32 (m, 5H). 13C NMR
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(100 MHz, DMSO-d6)
d ppm 22.6, 25.5, 33.4, 46.6, 50.8, 62.2, 105.5,
117.0,127.8,128.1,129.2,130.3,131.8,133.9,138.0,154.2. HRMS Calcd
for (MþH)þ: C20H22Cl2Nþ: 346.1124, Found: 346.1129.
Acknowledgements
We thank James Mattes, Yanxuan Cai, Donald Herold, Sergio
Anis, and Alvin Bach for their discovery analytical chemistry
support.
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