Selective reduction of condensed N-heterocycles using water as a solvent and a hydrogen source

Article abstract of DOI:10.1039/c2ob26903a

The reduction of unprotected indoles and quinolines is described using water as a hydrogen source. The method is based on the application of a RANEY type Ni-Al alloy in an aqueous medium. During the reaction the Al content of the alloy, used as reductants, reacts with water in situ providing hydrogen and a RANEY Ni catalyst, thus the alloy serves as a hydrogen generator as well as a hydrogenation catalyst. The simplicity and efficacy of the method are illustrated by the selective reduction of a variety of substituted indoles and quinolines to indolines and tetrahydroquinolines, respectively.

Full text of DOI:10.1039/c2ob26903a

Organic &
Biomolecular Chemistry
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Selective reduction of condensed N-heterocycles using
water as a solvent and a hydrogen source
Cite this: Org. Biomol. Chem., 2013, 11,
1209
Hyejin Cho, Fanni Török and Béla Török*
The reduction of unprotected indoles and quinolines is described using water as a hydrogen source. The
method is based on the application of a RANEY® type Ni–Al alloy in an aqueous medium. During the
reaction the Al content of the alloy, used as reductants, reacts with water in situ providing hydrogen and
a RANEY® Ni catalyst, thus the alloy serves as a hydrogen generator as well as a hydrogenation catalyst.
The simplicity and efficacy of the method are illustrated by the selective reduction of a variety of substi-
tuted indoles and quinolines to indolines and tetrahydroquinolines, respectively.
Received 28th September 2012,
Accepted 13th December 2012
DOI: 10.1039/c2ob26903a
www.rsc.org/obc
hydrogenation of these heterocycles.16 Despite some progress
the reports are mostly limited to N-protected indoles.17 The
Introduction
Reduction of functional groups is a fundamental transform- reduction of unprotected indoles by heterogeneous catalytic
ation in synthetic organic chemistry.1 Due to the large variety hydrogenation using hydrogen gas requires harsh conditions
of organic compounds a broad array of reduction methods (H2 pressure of 150 bar, T of 227 °C).18
were described.2 The focus of recent developments is the use
In a recent work we described a new acid-assisted hetero-
of safe and convenient reagents and solvents to address the geneous catalytic hydrogenation for the selective reduction of
ever growing concern of safety and sustainability and to mini- unprotected indoles partially solving the problem.19
mize or, preferably, eliminate waste.3
The heterogeneous catalytic hydrogenation of quinolines
Hydrogenation of N-heterocycles is a difficult task due to also attracted attention, although the number of practical
the highly resonance stabilized aromatic nucleus.4 The fact examples are limited.20 Expanding on our interest in develop-
that the product secondary amine could act as a poison to ing new environmentally benign synthetic methologies,21 we
most industrially common heterogeneous metal catalysts rep- explored the application of the aqueous Ni–Al alloy hydrogen-
resents another major problem.5 The products can also ation system in which hydrogen is generated in situ.22 With
undergo further hydrogenation to form by products up to per- the rise of the green or sustainable chemistry concept,23 con-
hydrogenated compounds. Extended efforts have been devoted sidering water as a possible solvent or reagent attracts great
to the selective hydrogenation of these compounds, particu- attention in organic synthesis.24 In the field of reductions,
larly indoles and quinolines. Since Paul Sabatier’s pioneering water was also used as a solvent for example in the hydrogen-
work on Ni-catalyzed hydrogenations,6 heterogeneous catalytic ation of CvN double bonds catalyzed by cyclodextrin-stabil-
hydrogenation7 has become one of the longest known pro- ized Pd nanoparticles.25 The application of the Ni–Al and
cedures in organic synthesis. The selective reduction of N-hetero- various other transition metal–Al alloys (Co, Cu, Fe) in dilute
cycles, however, still presents a challenge due to a multitude alkaline aqueous solution was introduced and pioneered by
of problems.8 Several protocols were developed for the Tashiro and Fukata for the reduction of aryl ketones,
reduction of indoles9 and quinolines10 by stoichiometric phenols, naphthalenes, biphenyls, acenaphthene and benzo-
methods. While being effective, these methods have selectivity phenones or several dehalogenation reactions.26 While
problems.11 Homogeneous catalytic methods for the hydrogen- our current work builds on the beforementioned prelimin-
ation of N-protected indoles12–14 or quinolines15 were also aries our combined use of ultrasonic irradiation and alkali-
reported. Heterogeneous catalysts have been used for the free aqueous medium resulted in a tamed Ni–Al alloy,
which allowed for the more selective reductions of
heterocycles.
Herein we describe the selective reduction of unprotected
indoles and quinolines in water using a nickel–aluminium
University of Massachusetts Boston, 100 Morrissey Blvd., Boston, MA, USA. E-mail:
bela.torok@umb.edu; Fax: (+1)-617-287-6030; Tel: (+1)-617-287-6159
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reaction time and activation method, were tested. The data in
Table 1 reveal some major characteristics of the reduc-
tion. While the aluminium content of the Ni–Al alloy reacts
at ambient temperature, it shows a significant lag-phase
and provides near complete conversion only after 72 h
(entries 1–3).
The selectivity is 100% at low conversion, but after longer
reaction times and higher conversion selectivity drops to 65%
indicating the formation of, mainly overhydrogenated, by-pro-
ducts. Higher temperature resulted in more rapid reaction,
while maintaining high selectivity (entry 4). The application of
microwave irradiation at the same temperature did not result
in major improvement (entry 5). Interestingly, ultrasonic acti-
vation appeared to be an effective method with good initial
yield and excellent selectivity (entry 6), however, the increased
reaction times only yielded minor improvement in the conver-
sion (entry 7). Nevertheless, these experiments (entries 6
and 7) indicated that ultrasounds had a beneficial effect on
the reaction that could be, at least in part, explained by the
well-known surface cleaning effect of ultrasonic waves.29
Since the in situ generation of hydrogen is a crucial part of
Scheme 1 Selective reduction of indoles and quinolines in water by a Ni–Al
alloy.
alloy (Scheme 1). The products indolines and tetrahydroquino-
lines are biologically active compounds of pharmaceutical
importance.27
Results and discussion
The selective reduction of indole as a highly activated aromatic
compound is particularly difficult; the presence of even weak
electrophiles initiates polymerization.28 The other problem is
overhydrogenation, mainly to octahydroindole. Due to the for-
mation of Al(OH)3 in the present reaction, the pH of the
system will be basic and it was expected that earlier problems,
such as polymerization, can be avoided. Thus, first the effect
of the reaction conditions on the yield and selectivity was
assessed using the hydrogenation of indole as a test reaction
(Table 1).
the reaction mechanism,
a clean, oxide-free aluminium
surface is of utmost importance. The removal of the surface
Al2O3 layer shortens the induction period and results in rapid
reaction rates (entry 4 vs. 12). In addition, the presonication of
metal catalysts results in smaller particle size, thus a greater
surface area for the remaining metal (Ni), which, in our experi-
ence, improves reaction rates.30 It was also observed that
longer sonochemical pretreatment resulted in lower yields
(entries 13 and 14). This phenomenon is most likely due to the
partial dissolution of the Al content of the alloy, thus reducing
the amount of hydrogen generated for the subsequent reac-
tion. It appears that a 1 h presonication improves the perform-
ance by surface cleaning and particle size reduction, however,
the excessive consumption of the hydrogen source (Al) upon
oversonication of the alloy decreases the yield. Based on the
data above, it was concluded that 1 h presonication combined
with conventional heating at 50 °C are the best parameters for
the reaction.
Based on our experience in handling of Ni–Al initiated
reductions22 a broad variety of parameters, such as temperature,
Table 1 Effect of experimental parameters on the synthesis of indoline via the
reduction of indole by a Ni–Al/H2O systema
Entry
Methodb
T [°C]
Time [h]
Conv.c [%]
Sel.c [%]
1
2
3
4
5
6
7
8
CH
CH
CH
CH
MW
US
US
1 h preUS, CH
1 h preUS, CH
1 h preUS, CH
1 h preUS, CHd
1 h preUS, CH
2 h preUS, CH
2 h preUS, MW
25
25
25
110
110
25
25
25
25
25
50
110
110
110
24
48
72
3
2
1
0
3
0
100
65
Table 2 Effect of experimental parameters on the synthesis of tetrahydroqui-
noline via the reduction of quinoline by a Ni–Al/H2O systema
96
54
54
43
58
74
97
84
83
93
80
74
93
100
100
100
77
72
77
100
91
95
2
24
48
72
24
3
3
1
9
Entry
Methodb
T [°C]
Time [h]
Conv.c [%]
Sel.c [%]
10
11
12
13
14
1
2
3
4
1 h preUS, CH
1 h preUS, CH
1 h preUS, CH
1 h preUS, MW
25
24
3
1
32
97
93
100
65
80
90
93
110
110
110
100
1
a Reactions were carried out with 200 mg Ni–Al, 3 mL water, 0.34 mmol
indole. b CH, conventional heating; MW, microwave irradiation; US,
ultrasonic irradiation; preUS, presonication of the alloy only.
c Conversion and selectivity were determined by GC. d The
presonication was carried out in the presence of indole.
a Reactions were carried out with 1 h presonicated 200 mg Ni–Al, 3 mL
water, 0.31 mmol quinoline. b CH, conventional heating; MW,
microwave irradiation; US, ultrasonic irradiation; preUS, presonication
of the alloy only. c Conversion and selectivity were determined by GC.
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Table 3 Synthesis of indolines via the reduction of indoles by a Ni–Al/H2O
systema
Table 4 Synthesis of tetrahydroquinolines via the reduction of quinolines by a
Ni–Al/H2O systema
R1
R2
T [°C]
Time [h]
Yieldb [%]
T
Time
Yieldb,c
[%]
Entry
Entry R1
R2
R3
Method [°C] [h]
1
2
3
4
5
6
7
8
H
6-CH3
6-OCH3
7-CH3
8-CH3
6-CH3
H
H (isoquinoline)
H
H
H
H
110
110
110
110
110
110
110
150
1
1
1
1
1
1
2
2
92
93
97
99
92
95
72
81
1
2
3
4
5
6
7
8
H
H
H
H
H
H
H
H
H
3-
H
CH3
H
H
H
H
H
H
B
A
B
B
A
A
A
B
50
25
80
80
25
25
25
50
24
24
8
8
48
3
83
79
77
84
70
73c
78
68
5-CH3
7-CH3
5-CO2CH3
7-C2H5
5-OCH3
4,6-Di-
(OCH3)
H
2-CH3
3-CH3
H
24
42
a Reactions were carried out with 200 mg Ni–Al, 3 mL water, 0.34 mmol
quinoline; MW, microwave irradiation; preUS, presonication of the
alloy only. b GC yields.
CH3
a Method A: 200 mg Ni–Al, presonicated for 1 h in 3 mL water, then
0.34 mmol indole. Method B: 200 mg Ni–Al, sonicated for 1 h in 3 mL
water with 0.34 mmol indole then stirred for the required time. b GC
yields. c The reaction was carried out with continuous sonication.
conversion in the hydrogenation of indoles also increases with
temperature so does the amount of by-products, which
As our goal was to extend the method to other condensed decreases the overall yield in high temperature reactions.
N-heterocycles, the reduction of quinoline was studied
(Table 2) mainly under the previously optimized conditions.
The key step in the reaction mechanism involves the reac-
tion of the Al content of the alloy in water, which is used as a
Due to the positive effect of presonication on the reduction reductant and generates the hydrogen necessary for the
of indole this method was further optimized for quinoline. reduction. The Al2O3 layer that commonly forms on the
Table 2 indicates that these conditions work well for quinoline surface of Al makes this process extremely slow as shown by
as well. The only major change is that in this reduction the the long lag-period in Table 1 (entries 1–3).
microwave heating provided the best conversion and selecti-
vity, thus better overall yield. Therefore, these conditions the addition of a base that would also improve the dissolution
(entry 4) were selected for further investigations of quinolines.
rate of aluminium.24 The presence of a base, however, often
This long induction period can significantly be reduced by
After identifying the optimum reaction conditions for our caused selectivity problems, mainly significant and uncontrol-
test substrates, efforts were made to further explore the scope lable overhydrogenation.24 Since selectivity is an important
of this reduction method. We uniformly adopted the use of issue here, especially in the case of indoles, we decided to
the 1 h ultrasonic pretreatment that largely eliminated the lag avoid the use of a base, in order to tame the reduction system,
phase of the reaction. The data obtained with several substi- as well as to keep it as green as possible. Thus, we opted for
tuted indoles are summarized in Table 3.
the use of a physical surface cleaning method and applied
As shown (Table 3), a variety of substituted indoles were ultrasonic irradiation in the form of a bath. Bath-type sonica-
hydrogenated to the corresponding indolines in good yields. It tors are known to work better under heterogeneous con-
was observed, however, that the substituted indoles showed ditions26,27 such as the target reaction in this work. While
stronger sensitivity than that of an unsubstituted indole ultrasounds exposed the Al surface to the aqueous medium
(Table 1). Thus, further optimization was carried out with the lack of a base resulted in the evolution of hydrogen at a
these compounds and the data in Table 3 reflect the best con- moderate rate, which helped to avoid undesired side reactions,
ditions found. Several reactions were carried out at room temp- most commonly overhydrogenation. The presence of Ni, an
erature due to the low selectivity values observed at higher active, hydrogenation capable transition metal ensures the
temperatures.
appropriate and rapid use of the hydrogen formed. The flow of
Similarly to indoles, the scope of the reduction was also the reaction is illustrated in Fig. 1.
investigated using a variety of quinoline derivatives. The data
are tabulated in Table 4.
As compared to other “dissolving metal” type reductions
the current process carries several advantages, most of which
As the data in Table 4 indicate that the yields of quinoline are related to the use of the Ni–Al alloy.
reduction are generally about 10% higher than that of indoline
(i) The reaction can be carried out with unprotected
synthesis (Table 3). The improved yields are most likely due to indoles, which eliminates the protection and deprotection
the significantly lower reactivity of the quinoline moiety, steps required in earlier reports and the losses of product and
which makes it resistant toward secondary reactions and waste formation associated with these steps. (ii) The reaction
allows the application of higher temperatures. While the is carried out in neat water, a benign, readily available and
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Experimental
General information
All indoles, quinolines and the Al–Ni alloy (50% Al–50% Ni)
were purchased from Sigma-Aldrich and used without further
purification. Solvents used in synthesis were of minimum
purity of 99.5% and were purchased from Thermo Fisher
Scientific. Water used as a solvent in the reactions was deio-
nized water. The mass spectrometric identification of the pro-
ducts has been carried out by an Agilent 6850 gas
chromatograph-5973 mass spectrometer system (70 eV electron
impact ionization) using a 30 m long DB-5 type column (J&W
Scientific). The 1H and 13C spectra were obtained on a
300 MHz Varian NMR spectrometer, in CDCl3 using tetra-
methylsilane or the residual solvent signal for reference. The
temperature was 25 °C (accuracy 1 °C) and controlled by the
Varian control unit.
Fig. 1 Reduction of indoles and quinolines by a presonicated Ni–Al alloy in
water.
Representative procedures for the reduction of indoles to
indolines
inexpensive solvent without the use of any other chemicals
(acids or bases). It must be mentioned, however, that an
organic solvent, ethyl acetate, was used to extract the products
from the aqueous medium, thus adding an organic solvent to
the process. The combined use of ultrasounds and alkali-free
aqueous medium significantly moderates the Ni–Al alloy and,
in general, allows obtaining selectivities much higher than
those described in earlier studies that used NaOH and similar
solutions. The reduction in activity is indicated by slower and
more controlled H2 formation, which decreases the potential
hazards associated with reductive agents; (iii) due to the con-
trolled rate of hydrogen formation the selectivity is high; (iv)
the use of aluminium as a reductant makes the reaction
simple and safe, one does not have to face the safety and
environmental problems associated with the use of Na or Zn/
Hg; (v) the Ni content of the alloy forms a RANEY® Ni type
hydrogenation catalyst that adsorbs hydrogen readily and
ensures the economic use of the alloy as well as the effective
hydrogenation of the substrates; (vi) considering all of the
above, the reaction does not generate harmful waste. The only
by-product that forms is an alumina supported Ni catalyst (Ni/
Al2O3) that could be filtered and used in other hydrogenation
processes.
Procedure A. Al–Ni alloy (200 mg) was suspended in 3 mL of
deionized water and sonicated (Branson 1510MTH ultrasonic
bath) for 1 h. Then, indole (40 mg, 0.34 mmol) was added to
the preactivated alloy. The reaction mixture was stirred for 3 h
at 110 °C. After the completion of the reaction, the alloy was
removed by filtration. The filtrate was extracted with two por-
tions of 2 mL of ethyl acetate (EtOAc). The organic extracts
were combined and dried over Na2SO4. The solvent was
removed in a vacuum and the crude product was purified by
flash chromatography.
Procedure B. Al–Ni alloy (200 mg) and indole (40 mg,
0.34 mmol) were suspended in 3 mL of deionized water and
sonicated (Branson 1510MTH ultrasonic bath) for 1 h. Then,
the reaction mixture was stirred for 24 h at 50 °C. After the
completion of the reaction, the alloy was removed by filtration.
The filtrate was extracted with two portions of 2 mL of EtOAc.
The organic extracts were combined and dried over Na2SO4.
The solvent was removed in a vacuum and the crude product
was purified by flash chromatography.
Representative procedure for the reduction of quinoline to
tetrahydroquinoline
Al–Ni alloy (200 mg) was suspended in 3 mL of deionized
water and sonicated (Branson 1510MTH ultrasonic bath) for
1 h. Then, the mixture was transferred into a microwave reac-
Conclusions
In summary, a Ni–Al alloy induced reduction methodology was tion tube and quinoline (40 mg, 0.31 mmol) was added to the
developed for the synthesis of indolines and tetrahydroquino- preactivated alloy. The reaction mixture was stirred for 1 h at
lines from unprotected indoles and quinolines using alu- 110 °C in a CEM Discover microwave reactor. After the com-
minium as a reductant and water as a solvent as well as a pletion of the reaction, the alloy was removed by filtration. The
hydrogen source. The reactions were carried out in a simple filtrate was extracted with two portions of 2 mL of EtOAc. The
setting and under mild conditions. Products were obtained in organic extracts were combined and dried over Na2SO4. The
good to excellent yields and high selectivities. The method, solvent was removed in a vacuum and the crude product was
with its effective, inexpensive, simple and selective design pro- purified by flash chromatography.
vides a convenient solution for the reduction of indoles and
quinolines and most likely can be extended to the reduction of spectra are in good correlation with previous reports. The spec-
The compounds are known in the literature10,19 and their
a broad range of substrates.
tral characterization of the products is given below.
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Indoline (Table 3, entry 1). Colorless oil, Rf = 0.30 (20% 9.9 Hz, 6H), 3.70 (t, J = 8.7 Hz, 1H), 3.38 (m, 1H), 3.14 (dd, J =
EtOAc in hexane); 1H NMR (300.128 MHz, CDCl3), δ (ppm) 8.7, 5.1, 1H), 1.26 (d, J = 6.6 Hz, 3H); 13C NMR (75.474 MHz,
7.21 (d, J = 7.2 Hz, 1H), 7.11 (t, J = 7.8 Hz, 1H), 6.80 (t, J = 7.5 CDCl3), δ (ppm) 161.2, 157.0, 153.1, 112.8, 89.3, 88.6, 55.5,
Hz, 1H), 6.72 (d, J = 7.8 Hz, 1H), 3.59 (t, J = 8.4 Hz, 2H), 55.3, 55.0, 34.5, 19.0; MS-C11H15NO2 (193) m/z (%): 193
3.10 (t, J = 8.1 Hz, 2H); 13C NMR (75.474 MHz, CDCl3), (M+, 38), 178 (100), 163 (18), 147 (20), 132 (7).
δ (ppm) 151.4, 129.1, 126.9, 124.4, 118.4, 109.2, 47.1, 29.6;
MS-C8H9N (119) m/z (%): 119 (M+, 100), 91 (21), 77 (2), 65 (6), (10% EtOAc in hexane); 1H NMR (300.128 MHz, CDCl3),
58 (7). δ (ppm) 7.00 (m, 2H), 6.65 (t, J = 6.0 Hz, 1H), 6.50 (d, J = 6.0
Tetrahydroquinoline (Table 4, entry 1). Yellow oil, Rf = 0.34
1-Methylindoline (Table 3, entry 2). Brown oil, Rf = 0.25 Hz, 1H), 3.32 (t, J = 6.0 Hz, 2H), 2.80 (t, J = 6.0 Hz, 2H), 1.98
(10% EtOAc in hexane); 1H NMR (300.128 MHz, CDCl3), (m, 2H); 13C NMR (75.474 MHz, CDCl3), δ (ppm) 144.7, 129.4,
δ (ppm) 7.07 (m, 2H), 6.66 (t, J = 7.5 Hz, 1H), 6.48 (d, J = 126.6, 121.3, 116.8, 114.1, 41.9, 26.9, 22.1; MS-C9H11N (133)
8.1 Hz, 1H), 3.27 (t, J = 8.4 Hz, 2H), 2.92 (t, J = 8.4 Hz, 2H), 2.74 m/z (%): 132 (M+, 100), 118 (21), 104 (8), 77 (10).
(s, 3H); 13C NMR (75.474 MHz, CDCl3), δ (ppm) 153.3, 130.2,
127.2, 124.1, 117.6, 107.1, 56.0, 36.2, 28.6; MS-C9H11N (133) oil, Rf = 0.32 (10% EtOAc in hexane); H NMR (300.128 MHz,
m/z (%): 133 (M+, 100), 117 (41), 103 (4), 91 (10), 77 (6).
CDCl3), δ (ppm) 6.70 (s, 2H), 6.33 (d, J = 9.0 Hz, 1H), 3.18 (t, J =
6-Methyl-tetrahydroquinoline (Table 4, entry 2). Light yellow
1
5-Methylindoline (Table 3, entry 3). Light brown oil, Rf = 6.0 Hz, 2H), 2.65 (t, J = 6.0 Hz, 2H), 2.12 (s, 3H), 1.85 (m, 2H);
0.25 (20% EtOAc in hexane); 1H NMR (300.128 MHz, CDCl3), 13C NMR (75.474 MHz, CDCl3), δ (ppm) 142.3, 130.0, 127.2,
δ (ppm) 6.93 (s, 1H), 6.80 (d, J = 7.8 Hz, 1H), 6.52 (d, J = 7.5 126.2, 121.5, 114.4, 42.1, 26.8, 22.4, 20.4; MS-C10H13N (147)
Hz, 1H), 3.47 (t, J = 8.1 Hz, 2H), 2.95 (t, J = 8.1 Hz, 2H), 2.23 m/z (%): 146 (M+, 100), 132 (34), 117 (17), 91(12).
(s, 3H); 13C NMR (75.474 MHz, CDCl3), δ (ppm) 149.4, 129.9,
6-Methoxy-tetrahydroquinoline (Table 4, entry 3). Light
128.2, 127.7, 125.6, 109.6, 47.8, 30.2, 21.0; MS-C9H11N (133) yellow oil, Rf = 0.16 (10% EtOAc in hexane); 1H NMR
m/z (%): 133 (M+, 100), 117 (28), 103 (5), 77 (9), 65 (7).
(300.128 MHz, CDCl3), δ (ppm) 6.51 (m, 2H), 6.38 (d, J = 9.0
7-Methylindoline (Table 3, entry 4). Light brown oil, Rf = Hz, 1H), 3.65 (s, 3H), 3.17 (t, J = 6.0 Hz, 2H), 2.67 (t, J = 6.0 Hz,
0.30 (10% EtOAc in hexane); 1H NMR (300.128 MHz, CDCl3), 2H), 1.85 (m, 2H); 13C NMR (75.474 MHz, CDCl3), δ (ppm)
δ (ppm) 6.99 (d, J = 6.0 Hz, 1H), 6.87 (d, J = 9.0 Hz, 1H), 6.66 151.8, 138.7, 122.9, 115.6, 114.8, 112.8, 55.7, 42.3, 27.1 22.4;
(t, J = 6.0 Hz, 1H), 3.56 (t, J = 9.0 Hz, 2H), 3.05 (t, J = 9.0 Hz, MS-C10H13NO (163) m/z (%): 163 (M+, 51), 148 (100), 130 (5),
2H), 2.13 (s, 3H); 13C NMR (75.474 MHz, CDCl3), δ (ppm) 118 (7).
150.0, 128.6, 128.1, 122.1, 118.9, 118.8, 47.2, 30.1, 16.8; MS-
C9H11N (133) m/z (%): 132 (M+, 100), 117 (42), 103 (6), 77 (9), oil, Rf = 0.34 (10% EtOAc in hexane); H NMR (300.128 MHz,
65 (7). CDCl3), δ (ppm) 6.80 (d, J = 6.0 Hz, 1H), 6.40 (d, J = 6.0 Hz,
7-Methyl-tetrahydroquinoline (Table 4, entry 4). Light yellow
1
Methyl indoline-5-carboxylate (Table 3, entry 5). Light 1H), 6.26 (s, 1H), 3.23 (t, J = 6.0 Hz, 2H), 2.68 (t, J = 6.0 Hz,
orange solid, Rf = 0.20 (20% EtOAc in hexane); M.P.: 67–69 °C; 2H), 2.18 (s, 3H), 1.88 (m, 2H); 13C NMR (75.474 MHz, CDCl3),
1H NMR (300.128 MHz, CDCl3), δ (ppm) 7.76 (m, 2H), 6.55 δ (ppm) 144.5, 136.3, 129.3, 118.5, 117.8, 114.7, 41.9, 26.5,
(d, J = 8.4 Hz, 1H), 3.84 (s, 3H), 3.65 (t, J = 8.4 Hz, 2H), 3.07 22.3, 21.1; MS-C10H13N (147) m/z (%): 147 (M+, 100), 132 (53),
(t, J = 8.4 Hz, 2H); 13C NMR (75.474 MHz, CDCl3), δ (ppm) 117 (20), 91 (13).
125.9, 199.4, 130.7, 128.7, 126.1, 107.4, 100.0, 51.6, 47.3, 28.8;
MS-C10H11NO2 (177) m/z (%): 177 (M+, 82), 146 (100), 118 (27), oil, Rf = 0.39 (10% EtOAc in hexane); H NMR (300.128 MHz,
89 (12), 72 (6). CDCl3), δ (ppm) 6.77 (t, J = 6.0 Hz, 2H), 6.47 (t, J = 6.0 Hz, 1H),
8-Methyl-tetrahydroquinoline (Table 4, entry 5). Light yellow
1
7-Ethylindoline (Table 3, entry 6). Brown oil, Rf = 0.33 (20% 3.28 (t, J = 6.0 Hz, 2H), 2.70 (m, 2H), 1.98 (s, 3H), 1.85 (m, 2H);
EtOAc in hexane); 1H NMR (300.128 MHz, CDCl3), δ (ppm) 13C NMR (75.474 MHz, CDCl3), δ (ppm) 142.6, 127.8, 127.3,
7.90 (d, J = 7.2 Hz, 1H), 6.98 (d, J = 7.2 Hz, 1H), 6.79 (t, J = 7.5 121.1, 120.8, 116.3, 42.3, 27.2, 22.1, 17.1; MS-C10H13N (147)
Hz, 1H), 3.63 (t, J = 8.1 Hz, 2H), 3.55 (bs, 1H), 3.12 (t, J = 8.4 m/z (%): 146 (M+, 100), 132 (43), 117 (19), 91 (12).
Hz, 2H), 2.56 (q, J = 7.5 Hz, 2H), 1.31 (t, J = 7.5 Hz, 3H);
2,6-Dimethyl-tetrahydroquinoline (Table 4, entry 6). Light
13C NMR (75.474 MHz, CDCl3), δ (ppm) 149.3, 128.7, 125.9, yellow oil, Rf = 0.45 (10% EtOAc in hexane); 1H NMR
124.8, 122.0, 118.8, 47.1, 29.9, 24.0, 13.1; MS-C10H13N (147) (300.128 MHz, CDCl3), δ (ppm) 6.73 (d, J = 6.0 Hz, 2H), 6.36
m/z (%): 147 (M+, 63), 132 (100), 117 (24), 105 (7), 91 (6).
(d, J = 6.0 Hz, 1H), 3.31 (m, 1H), 2.67 (m, 2H), 2.16 (s, 3H), 1.85
5-Methoxyindoline (Table 3, entry 7). Light brown oil, Rf = (m, 1H), 1.52 (m, 1H), 1.15 (d, J = 6.0 Hz, 3H); 13C NMR
0.25 (30% EtOAc in hexane); 1H NMR (300.128 MHz, CDCl3), (75.474 MHz, CDCl3), δ (ppm) 142.4, 129.8, 127.2, 126.2, 121.2,
δ (ppm) 6.78 (s, 1H), 6.60 (m, 2H), 3.75 (s, 3H), 3.50 (t, J = 8.4 114.2, 47.3, 30.3, 26.5, 22.6, 20.4; MS-C11H15N (161) m/z (%):
Hz, 2H), 3.00 (t, J = 8.1 Hz, 2H); 13C NMR (75.474 MHz, 161 (M+, 37), 146 (100), 131 (23), 91 (53).
CDCl3), δ (ppm) 153.6, 145.5, 131.3, 112.2, 111.6, 110.2, 56.0,
47.9, 30.6; MS-C9H11NO (149) m/z (%): 149 (M+, 54), 134 (100), Rf = 0.39 (10% EtOAc in hexane); 1H NMR (300.128 MHz,
117 (3), 104 (9), 77 (7). CDCl3), δ (ppm) 6.88 (m, 2H), 6.53 (t, J = 6.0 Hz, 1H), 6.41 (d, J =
3-Methyl-tetrahydroquinoline (Table 4, entry 7). Yellow oil,
4,6-Dimethoxy-3-methylindoline (Table 3, entry 8). Light 9.0 Hz, 1H), 3.18 (m, 1H), 2.73 (t, J = 6.0 Hz, 1H), 2.66 (m, 1H),
brown oil, Rf = 0.25 (20% EtOAc in hexane); 1H NMR 2.34 (m, 1H), 1.98 (m, 1H), 0.98 (d, J = 6.0 Hz, 3H); 13C NMR
(300.128 MHz, CDCl3), δ (ppm) 5.90 (m, 2H), 3.76 (d, J = (75.474 MHz, CDCl3), δ (ppm) 144.2, 129.5, 126.6, 121.1, 116.9,
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113.8, 48.8, 35.4, 27.1, 19.0; MS-C10H13N (147) m/z (%):
K. Kaneda, T. Ito, K. Sato, T. Kurokawa and T. Ito, Org.
Lett., 2004, 6, 2213.
147 (M+, 100), 132 (4), 118 (44), 104 (14), 91 (14).
Tetrahydro-isoquinoline (Table 4, entry 8). Light brown oil, 13 R. Kuwano and M. Kashiwabara, Org. Lett., 2006, 8, 2653.
Rf = 0.11 (50% EtOAc in hexane); 1H NMR (300.128 MHz, 14 A. Baeza and A. Pfaltz, Chem.–Eur. J., 2010, 16, 2036.
CDCl3), δ (ppm) 7.03 (m, 3H), 6.93 (t, J = 6.0 Hz, 1H), 3.93 15 W.-B. Wang, S.-M. Lu, P.-Y. Yang, X.-W. Han and
(s, 2H), 3.06 (t, J = 6.0 Hz, 2H), 2.72 (t, J = 6.0 Hz, 2H), 2.02
(s, 1H); 13C NMR (75.474 MHz, CDCl3), δ (ppm) 135.8, 134.7,
129.2, 126.1, 125.9, 125.6, 48.2, 43.8, 29.1; MS-C9H11N (133)
m/z (%): 132 (M+, 100), 117 (12), 104 (80), 78 (18).
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Acknowledgements
Financial support provided by University of Massachusetts
Boston and National Institute of Health (R-15 AG025777-03A1)
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