Pd/Cu Cocatalyzed Oxidative Tandem C-H Aminocarbonylation and Dehydrogenation of Tryptamines: Synthesis of Carbolinones

Article abstract of DOI:10.1021/acs.joc.8b03266

The Pd/Cu cocatalyzed oxidative tandem C-H aminocarbonylation and dehydrogenation was developed, affording carbolinones with molecular oxygen as the terminal oxidant. Natural product strychnocarpine and its derivatives were prepared conveniently using this strategy.

Full text of DOI:10.1021/acs.joc.8b03266

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Article
Pd/Cu Co-Catalyzed Oxidative Tandem C–H Aminocarbonylation
and Dehydrogenation of Tryptamines: Synthesis of Carbolinones
Hui Han, Shang-Dong Yang, and Ji-Bao Xia
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b03266 • Publication Date (Web): 22 Feb 2019
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Pd/Cu Co-Catalyzed Oxidative Tandem C–H
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Aminocarbonylation and Dehydrogenation of Tryptamines:
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Synthesis of Carbolinones
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Hui Han,a,b Shang-Dong Yangb and Ji-Bao Xia*a,c
a State Key Laboratory for Oxo Synthesis and Selective Oxidation, Suzhou Research Institute of LICP,
Lanzhou Institute of Chemical Physics (LICP), University of Chinese Academy of Sciences, Chinese
Academy of Sciences, Lanzhou 730000, China
b State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, China
c Key Laboratory of Organic Synthesis of Jiangsu Province, Suzhou 215123, China
Abstract: The Pd/Cu co-catalyzed oxidative tandem C–H aminocarbonylation and
dehydrogenation is developed affording carbolinones with molecular oxygen as the
terminal oxidant. Natural product strychnocarpine and its derivatives are prepared
conveniently using this strategy.
INTRODUCTION
Over 80% of all known active pharmaceutical ingredients (APIs) contain
heterocyclic aromatic rings with a majority of
N-containing aromatic
heterocycles. The carbolinone ring system appears as a substructure in a large
number of biologically active indole alkaloids and APIs (Figure 1).1 For example,
strychnocarpine, a natural tetrahydro-β-carbolinone isolated from Strychnos
elaeocarpa, exhibits stimulation of 5-hydroxytryptamine (5-HT) receptors.2
Alosetron, a tetrahydro-γ-carbolinone, is a FDA-approved drug molecule treating
women with severe diarrhea-predominant irritable bowel syndrome. In addition,
carbolinones are versatile intermediates for the synthesis of indole-containing
natural products.3 Therefore, chemists have devoted great efforts to the
development of efficient methods toward these structures. There are two general
strategies for the synthesis of carbolinones. One is acid promoted Fischer indole
synthesis from the corresponding hydrazone intermediates.4 The other is
condensation of tryptamine derivatives with hazardous triphosgene or
chloroformates followed by acid promoted Friedel-Crafts acylation.5 Recently,
transition-metal-catalyzed cyclizations have also been reported for the synthesis
of these scaffolds to avoid harsh reaction conditions and multi-step syntheses.6
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Figure 1. Selected Carbolinone-containing Natural Products and Pharmaceutical Drugs
Due to high atom economy, step economy, and dramatic reduction of waste,
tandem reaction has attracted much interest in synthetic chemistry and lots of
effcient tandem reactions have been developed.7 In the past decade, chemists
have achieved
great success in
transition-metal-catalyzed
direct
functionalizations of C–H bond, and C–H carbonylation of organic molecules
with CO has been realized for the synthesis of various carbonyl compounds, such
as acids,8 ketones,9 esters,10 amides,11 imides,12 and so on.13 The strategy of using a
directing group to control the site selectivity in C–H carbonylation is widely
applied in these reactions. Using amine as a native directing group,
metal-catalyzed arene C–H aminocarbonylation of amines has been emerged to
be a more straightforward and atom-economic method for the synthesis of
benzolactams.14,15 However, stoichiometric and expensive copper or silver salts are
14
usually used as oxidants. Therefore, it is highly desirable using molecular
oxygen (O2) as an oxidant in these reactions. One pioneering example is the
Orito’s Pd-catalzyed C–H aminocarbonylation for the synthesis of benzolactams,
using sub-stoichiometric Cu(OAc)2 and air as the oxidants.16 In 2009,
Saura-Llamas and co-workers reported inspiring cyclopalladation of
L-tryptophan methyl ester hydrochloride to generate six-membered
cyclopalladated complex, which could react with CO affording the corresponding
tetrahydro-β-carbolinone in good yield (Scheme 1a).17 To the best of our
knowledge, there are only one example of catalytic C–H carbonylation for the
synthesis of carbolinone derivative. Gaunt and co-workers reported an elegant
Pd-catalyzed C–H carbonylation of
N-aryl tryptophan with stoichiometric
perester and O2 as the co-oxidants under acidic conditions, but the substituent on
the amine limited to aryl group.18 Herein, we disclose a Pd/Cu co-catalyzed
oxidative C–H aminocarbonylation with 1 atm CO for the divergent synthesis of
carbolinones under mild neutral reaction conditions (Scheme 1b). Tetrahydro-β
and γ-carbolinones were obtained via Pd/Cu co-catalyzed oxidative C–H
aminocarbonylation with O2 as the terminal oxidant. By simply controlling the
reaction conditions, Pd/Cu co-catalyzed tandem C–H aminocarbonylation and
dehydrogenation was disclosed leading to β-carbolinones for the first time.
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Scheme 1. Synthesis of Carbolinones via C–H Carbonylation
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RESULTS AND DISCUSSION
Targeted to strychnocarpine 2a, N-methyltryptamine 1a was chosen as the model
substrate to optimize the reaction conditions. With Rh(PPh3)3Cl as a catalyst, up
to 25% yield of 2a was obtained when using 2 equivalents of Cu(OAc)2 as oxidant
in diglyme at 110 ºC under a balloon pressure of CO (Table 1, Entry 1 and Table S1
in Supporting Information). When switching Rh catalyst to Pd catalyst, 2a was
obtained in 81% yield with Pd(OAc)2 as catalyst in toluene (Table 1, entry 2). To
our delight, tandem C–H aminocarbonylation and dehydrogenation was achieved
affording β-carbolinone 3a in 66% yield under identical conditions when prolong
the reaction time (Table 1, entry 3). Replacing Cu(OAc)2 with other oxidants, such
as Ag2CO3, K2S2O8 and oxone, gave 2a in less than 10% yield (Table S2 in
Supporting Information). Lowering temperature to 80 ºC led to a slightly higher
yield (Table 1, entry 4). The yield remained unchanged when the catalyst loading
was decreased to 2.5 mol% but with longer reaction time (Table 1, entry 5). Next,
we investigated the reaction with catalytic amount of Cu(OAc)2 using molecular
oxygen (O2) as the oxidant (Table S2). The best result was obtained when using
2.5 mol% Pd(OAc)2, 10 mol% Cu(OAc)2, and 75 mol% O2 at 80 ºC (Table 1, entry
6).19 Moderate yield was obtained with 1.0 mol% Pd(OAc)2 as catalyst (Table 1,
entry 7). However, formamide
4 was also formed as a byproduct without C–H
carbonylation, which maybe obtained by protonation of acyl palladium
intermediate. Solvent screening revealed that toluene was the best choice. Other
solvents gave 2a in diminished yield, such as THF, DMF, CH3CN, and diglyme
(Table S2). We then optimized the reaction conditons for the tandem C–H
aminocarbonylation and dehydrogenation leading to β-carbolinone 3a. Good
yield of 3a was obtained with 10 mol% Pd(OAc)2, 50 mol% Cu(OAc)2, 2
equivalents of O2 at 110 ºC (Table 1, entry 9). Control experiments showed that no
desired product was obtained in the absence of Pd(OAc)2, which reveals the
importance of the palladium catalyst (Table 1, entries 10 and 11). Acylation of
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amine with Cu(OAc)2 affording
(Table 1, entries 11).
Table 1. Development of Pd/Cu Co-catalyzed Tandem C–H Aminocarbonylation and Dehydrogenation for
the Synthesis of β-Carbolinonesa
5 is the side reaction without Pd(OAc)2 catalyst
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Entry
Catalyst
Cu(OAc)2
2 equiv
1 equiv
1 equiv
1 equiv
1 equiv
10 mol%
10 mol%
25 mol%
50 mol%
-
O2
T (°C)
110
110
110
80
Time (h)
Yield of 2a (%)b
Yield of 3a (%)
1c
2
Rh(PPh3)Cl (10 mol%)
Pd(OAc)2 (10 mol%)
Pd(OAc)2 (10 mol%)
Pd(OAc)2 (10 mol%)
Pd(OAc)2 (2.5 mol%)
Pd(OAc)2 (2.5 mol%)
Pd(OAc)2 (1.0 mol%)
Pd(OAc)2 (10 mol%)
Pd(OAc)2 (10 mol%)
-
-
24
3
25
81
trace
trace
66d
0
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3
-
18
5
<5
85
83
91, 86d
40
0
4
-
5
-
80
13
6
0
6
0.75 equiv
0.75 equiv
2 equiv
2 equiv
-
80
0
7e
8f
9
80
6
0
110
110
110
110
12
24
3
58d
66d
0
0
10
11g
0
-
1 equiv
-
3
0
0
aReactions were conducted with 1a (0.2 mmol) and CO (1 atm, balloon) in toluene (2 mL). The yield was
b
1
c
determined by H NMR using 1,1,2,2-tetrachloroethane as internal standard. With diglyme as solvent.
dIsolated yield. With 0.6 mmol 1a as substrate, formamide 4 was isolated as a byproduct in 35% yield.
e
fWith 20 mol% PCy3 as an additive. gAcylation product 5 was detected as product.
With the optimal reaction conditions in hand, we evaluated the scope of the
Pd/Cu co-catalyzed oxidative C–H aminocarbonylation (Table 2). First, the effect
of substituents on the amine was investigated. The substrates with a variety of
alkyl group on the amine moiety gave the desired products in high yields (entries
1-5), such as n-propyl (2b), sterically hindered isopentyl (2c) and isopropyl (2d),
and removable benzyl group (2e). Low yield of 2f was obtained with allyl amine
probably due to the coordination effect of olefin (entry 6). Trace amount of 2g
was obtained with
occurred with primary amine or electron-withdrawing protecting groups on the
amine (entries 8 and 9) Ester and amide group on the alkyl chain of amine were
also tolerated and the corresponding products 2j and 2k were obtained in 86%
and 76% yield, respectively (entries 10 and 11). These two products could be
further transformed into natural product trigonostemonine A.1a Next, different
substituents on the indole core were investigated. This transformation tolerated
both electron-donating (Me, MeO) and electron-withdrawing (CO2Et) groups on
the indole (entries 12, 13 and 14). Halogen substituents (F, Cl) were also well
compatible at C5, C6, or C7 position of indole and the corresponding
tetrahydro-β-carbolinones were obtained in good yields (entries 15-18). But low
N-phenyl-substituted tryptamine (entry 7) and no reaction
.
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yield was obtained when methyl tryptophanate derivative 2s was used as
substrate, probably due to the steric hindrance of COOMe (entry 19). In addition,
the reaction run smoothly with
N-methyl-indole and the corresponding 2t was
obtained in 60% yield (entry 20). Notably, a seven-membered lactam 2u was
obtained in good yield (entry 21). When substrate 1v with longer alkyl chain was
used as substrate, no product was obtained. This C–H aminocarbonylation was
occurred exclusively at C2 position of indole core, no C4 C–H
aminocarbonylation product was observed in these reactions. This reaction was
successfully applied in the synthesis of other indole- and pyrrole-containing
heterocycles for medicinal chemistry purposes. By installation of the amine
linkage onto the nitrogen of indole, tricyclic indole-containing heterocycles 2w
and 2x were obtained in good yield (entries 23 and 24). Employing the same
catalytic method, bicyclic pyrrole-containing heterocycle 2y was also synthesized
in good yield (entry 25).
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Table 2. Scope of Pd/Cu Co-catalyzed Oxidative C–H Aminocarbonylationa
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aReactions were carried out on 0.2 mmol scale, isolated yield was provided. bWith 25 mol% Cu(OAc)2.
cWith 5 mol% Pd(OAc)2 and 50 mol% Cu(OAc)2.
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The scope of the Pd/Cu co-catalyzed tandem oxidative C–H
aminocarbonylation and dehydrogenation was shown in Scheme 2. Various
β-carbolinones were obtained in moderate to good yield with a variety of alkyl
group on the amine moiety, such as
3d), and functionalized alkyl chain (3j). Electron-donating (MeO) and
electron-withdrawing (CO2Et) substituents on the indole core of tryptamines
n-propyl (3b), sterically hinderded isopropyl
(
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were also well tolerated and β-carbolinones 3m, 3n, and 3o were obtained in
good yields.
Scheme 2. Scope of Pd/Cu Co-catalyzed Oxidative Tandem C–H Aminocarbonylation and
Dehydrogenationa
aReactions were carried out on 0.2 mmol scale, isolated yield was provided.
Furthermore, using 2-(indol-2-yl)ethanamine derivative
Pd/Cu co-catalyzed oxidative selective C–H and N–H aminocarbonylation could
be achieved (Scheme 3). Under the standard reaction conditions, product was
6 as the substrate,
7
formed exclusively in moderate yield by indole N–H aminocarbonylation. By
addition of acetic acid as an additive, Pd/Cu co-catalyzed selective C–H
aminocarbonylation was obtained probably due to protonation of NH of indole,
affording tetrahydro-γ-carbolinone
8 in good yield, which is the core structure of
Alosetron.
Scheme 3. Pd/Cu Co-catalyzed Selective C–H vs N–H Aminocarbonylation
By simple reduction with LiAlH4, tetrahydro-β-carbolinone 2a was
transformed into natural product tetrahydro-β-carboline 9
easily (Scheme 4a).20
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Scheme 4. Transformation of 2a and Mechanistic Experiments
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Several experiments were conducted to provide some insights into the reaction
mechanism. Although formamide
reaction,21 no desired product 2a was obtained when using
the standard condition with or without CO, indicating that
4
was detected in the C–H aminocarbonylation
as substrate under
was not the
4
4
intermediate (Scheme 4b). In addition, control experiment showed that the
dehydrogenation reaction could be performed smoothly using 2a as the substrate
without Pd catalyst (Scheme 4c). A plausible reaction pathway was proposed in
Scheme 5. Coordination of the amine group of 1a to palladium(II) could facilitate
the metalation of the indol nucleus at 2 position (C–H activation) to form the
six-membered metallacycle intermediate
Pd center of intermediate , followed by the insertion of CO in the C–Pd bond
and loss of HOAc forge the seven-membered cyclopalladated intermediate II. By
insertion of CO into the N–Pd bond of , another seven-membered
I. Then a molecule of CO coordinates to
I
I
cyclopalladated intermediate III could also be formed possibly. Reductive
elimination of II or III leaded to the product 2a and generated Pd(0), which was
oxidized by Cu(II) to regenarate Pd(II) catalyst. Cu(II) was reduced to Cu(I),
which was reoxidized to Cu(II) by O2 to close the second catalytic cycle. Under
higher reaction temperature, 2a could be oxidized to 3a via dehydrogenation
through a similar Cu(II)/Cu(I) catalysis with O2 as the final oxidant.
Scheme 5. Plausible Reaction Pathways for Pd/Cu Co-catalyszd Tandem C-H Aminocarbonylation and
Dehydrogenation
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CONCLUSION
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In summary, we have developed an efficient Pd/Cu co-catalyzed tandem oxidative
C–H aminocarbonylation and dehydrogenation reaction for the divergent
synthesis of carbolinones under mild reaction conditions. By simply controlling
the reaction conditions, β-carbolinones, tetrahydro-β-carbolinones, and
tetrahydro-γ-carbolinone can be selectively obtained. Natural product
strychnocarpine and its analogs have been synthesized using this method.
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Further application of this strategy in the synthesis of
are ongoing in our laboratory.
N-containing heterocycles
EXPERIMENTAL SECTION
General information. All C–H aminocarbonylation reactions were carried out under 1
atm CO in oven-dried Schlenk tube. Thin layer chromatography (TLC) employed glass
0.25 mm silica gel plates. Flash chromatography columns were packed with 200-300
o
mesh silica gel in petroleum (bp. 60-90 C). The high resolution MS analyses were
performed on Thermo Fisher Scientific LTQ FT Ultra with DART Positive Mode or
Agilent 6530 Accurate–Mass Q-TOF LC/MS with ESI mode. NMR spectra were recorded
1
13
on a 400 MHz for H NMR and 100 MHz for C NMR, using tetramethylsilane as an
internal reference and CDCl3, CD3OD, DMSO-d6 as solvent. Chemical shift values for
protons are reported in parts per million (ppm, δ scale) downfield from
tetramethylsilane and are referenced to residual proton of CDCl3 (δ 7.26), residual
proton (δ 2.50) in DMSO-d6 and residual proton (δ 3.31) in CD3OD. Multiplicity is
indicated by one or more of the following: s (singlet); d (doublet); t (triplet); q (quartet);
p (pentet); m (multiplet); br (broad). Chemical shifts for carbons are reported in parts
per million (ppm, δ scale) downfield from tetramethylsilane and are referenced to the
carbon resonance of CDCl3 (δ 77.0), DMSO-d6 (δ 39.5) and CD3OD (49.0). All melting
points were determined on IA9000 series digital melting point apparatus and are
uncorrected. Infrared spectra were recorded on a FT/IR Analyzer Thermo Fisher Nicolet
6700 Fourier-transform infrared spectrometer ATR.
General procedure A for the Pd/Cu co-catalyzed C–H aminocarbonylation. An
oven-dried Schlenk tube (10 mL) was charged with the substrate 1 (0.20 mmol, 1.0
equiv.), Pd(OAc)2 (1.1 mg, 0.005 mmol, 2.5 mol%) and Cu(OAc)2 (3.6 mg, 0.02 mmol, 10
mol%). The tube was purged and backfilled with CO (3 cycles) from a balloon.
Anhydrous toluene (2.0 mL) and O2 (3.75 mL, 0.15 mmol, d ≈ 1.29 at room temperature,
75 mol%) were injected via a syringe into the tube. After stirring for 6 hours at 80 oC, the
reaction mixture was cooled and concentrated under reduced pressure. The residue was
purified by column chromatography (petroleum ether/EtOAc 5:1~1:1) to give the pure
desired product 2.
General procedure B for the synthesis of β-carbolinones. An oven-dried 10 mL
tube was charged with the substrate 1 (0.20 mmol, 1.0 equiv.), Pd(OAc)2 (4.5 mg, 0.02
mmol, 10 mol%) and Cu(OAc)2 (18.2 mg, 0.1 mmol, 50 mol%). The tube was purged and
backfilled with CO (3 cycles) from a balloon. Anhydrous toluene (2.0 mL) and O2 (10.0
mL, 0.40 mmol, d ≈ 1.29 at room temperature, 200 mol%) were injected into the tube
sequentially. After stirring for 18 h ~ 24 h at 110 oC, the reaction mixture was cooled and
concentrated under reduced pressure. The residue was purified by column
chromatography (CH2Cl2/MeOH 40:1~20:1) to give the pure product 3.
General procedure C for the synthesis of 1 (1a, 1g, 1q, 1r, 1t). To a mixture of the
substrate (5.0 mmol, 1.0 equiv.) in anhydrous THF (10 mL) was added dropwise oxalyl
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chloride (1.27 mL, 10.0 mmol, 2.0 equiv.) at 0 °C . the reaction mixture was warmed up
to room temperature and stirred until the substrate disappeared. The mixture was
then concentrated to give the residue, the residue was dissolved in dry THF (20.0 mL)
and the relevant amine (15.0 mmol, 3.0 equiv.) was added at 0 °C. The resulting
mixture was stirred for 2 hours at room temperature. The mixture was concentrated
under vacuum to give the residue. To a solution of LiAlH4 (760.0 mg, 20.0 mmol, 4.0
equiv.) in anhydrous THF (40.0 mL) was added the above obtained residue, the
reaction was refluxed for 4 hours until the substrate consumed and then quenched by
H2O (0.8 mL), 0.2 M NaOH (1.6 mL), H2O (2.5 mL). After a small scoop of MgSO4
(~200 mg) was added, the mixture stirred for another 10 minutes. The solid particles
were filtered and washed with EtOAc (50.0 mL), then the combined filtrate was
concentrated under reduced pressure. The crude product was purified by flash
chromatography to yield pure product.
General procedure D for the synthesis of 1 (1b-1f, 1n). Under nitrogen atmosphere,
to a 500 mL flask, a stirred solution of tryptamine (800 mg, 5.0 mmol, 1.0 equiv.) in
anhydrous methanol (120 mL) was added glacial acetic acid (1.1mL, 20.0 mmol, 4.0
equiv.) and sodium cyanoborohydride (628.4 mg, 10.0 mmol, 2.0 equiv.) in one
portion, followed by adding the solution of the relevant aldehyde or ketone (5.0 mmol,
1.0 equiv.) in anhydrous methanol (130 mL) dropwise over 40 min. The resulting
solution was stirred at room temperature for 2–10 h. Aqueous Na2CO3 (2 M) was added
to adjust pH to 8–9 and the methanol was removed under reduce pressure. The
residue was partitioned between CHCl3 and water, and the organic layer was washed
with water and brine, dried over Na2SO4, and concentrated in vacuum. The crude
product was purified by column chromatography on silica gel.
General procedure E for the synthesis of 1 (1l, 1m, 1o, 1p, 6). Suspend tryptamine
(5.0 mmol) in a vigorously stirred mixture of aqueous sodium hydroxide solution (4 M
in water, 25 mL, 100.0 mmol) and CH2Cl2 (25 mL). The reaction mixture was cooled to
0 °C. Methyl chloroformate (0.46 mL, 6 mmol, 1.2 equiv.) was dropwise added to the
reaction mixture. The mixture was allowed to warm to room temperature after
completion of the addition. The phases were separated and the aqueous phase was
extracted with CH2Cl2 after the 2 hours. The combined organic phase was washed with
water and brine, dried over Na2SO4, and concentrated in vacuum. The crude product
was added to a solution of LiAlH4 (760.0 mg, 20.0 mmol, 4.0 equiv.) in anhydrous THF
(40.0 mL), and the reaction was refluxed for 4 hours until the substrate consumed and
then quenched by H2O (0.8 mL), 0.2 M NaOH (1.6 mL), H2O (2.5 mL). After a small
scoop of MgSO4 (~200 mg) was added, the mixture stirred for another 10 minutes. The
solid particles were filtered, washed with EtOAc (50.0 mL), and the combined filtrate
was concentrated under reduced pressure. The crude product was purified by flash
chromatography to yield pure product.
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Procedure for the Pd/Cu co-catalyzed C–H aminocarbonylation on millimolar
scale. An oven-dried Schlenk tube (250 mL) was charged with the substrate 1a (348.0
mg, 2.0 mmol, 1.0 equiv.), Pd(OAc)2 (11.2 mg, 0.05 mmol, 2.5 mol%) and Cu(OAc)2 (36.3
mg, 0.2 mmol, 10 mol%). The tube was purged and backfilled with CO (3 cycles) from a
balloon. Anhydrous toluene (20 mL) and O2 (37.5 mL, 0.15 mmol, d ≈ 1.29 at room
temperature, 75 mol%) were injected via a syringe into the tube. After stirring for 6
o
hours at 80 C, the reaction mixture was cooled and concentrated under reduced
pressure. The residue was purified by column chromatography (petroleum ether/EtOAc
3:1) to give the pure desired product 2a in 45 % yield (181.0 mg).
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N-Methyl-1H-Indole-3-ethanamine 1a was synthesized according to General
procedure C from indole and methylamine. The title compound was isolated as a white
1
solid (435 mg, 50% yield).22 Rf (CH2Cl2/MeOH 10:1): 0.3; H NMR (400 MHz, CDCl3) δ
8.12 (brs, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.20 (dd, J = 7.2, 6.8 Hz,
1H), 7.12 (dd, J = 8.0, 6.8 Hz, 1H), 7.04 (s, 1H), 2.99 (t, J = 6.0 Hz, 2H), 2.93 (t, J = 6.0 Hz,
2H), 2.44 (s, 3H).
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N-(2-(1H-Indol-3-yl)ethyl)propan-1-amine 1b was synthesized according to General
procedure D from tryptamine and n-propanal. The title compound was isolated as a
o
light yellow solid (136 mg, 13% yield). mp: 58−60 C; Rf (CH2Cl2/MeOH 20:1): 0.3; 1H
NMR (400 MHz, CDCl3) δ 8.32 (brs, 1H), 7.64 (d, J = 7.6 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H),
7.20 (dd, J = 8.0, 7.2 Hz, 1H), 7.12 (dd, J = 8.0, 6.8 Hz, 1H), 7.04 (s, 1H), 3.05-2.97 (m, 4H),
2.62 (t, J = 7.2 Hz, 2H), 2.41 (brs, 1H), 1.52 (q, J = 7.2 Hz, 2H), 0.88 (t, J = 7.2 Hz, 3H);
13C{1H} NMR (100 MHz, CDCl3) δ 136.3, 127.3, 122.0, 121.9, 119.2, 118.8, 113.6, 111.1, 51.6, 49.7,
25.4, 22.8, 11.7; IRv (cm-1): 3292, 2717, 1455, 1354, 1238, 1115, 782, 739; HRMS(ESI) calcd for
C13H19N2 (M+H)+ 203.1543, found 203.1546.
N-(3-Methylbutyl)-1H-indole-3-ethanamine 1c was synthesized according to
General procedure D from tryptamine and iso-valeraldehyde. The title compound was
1
isolated as a light yellow solid (366 mg, 32% yield).22 Rf (CH2Cl2/MeOH 10:1): 0.4; H
NMR (400 MHz, CDCl3) δ 8.14 (brs, 1H), 7.64 (d, J = 7.6 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H),
7.20 (dd, J = 7.6, 7.6 Hz, 1H), 7.12 (dd, J = 7.6, 7.2 Hz, 1H), 7.04 (s, 1H), 3.00-2.97 (m, 4H),
2.64 (t, J = 7.6 Hz, 2H), 1.61-1.54 (m, 1H), 1.40-1.34 (m, 2H), 0.87 (d, J = 6.8 Hz, 6H).
N-(2-(1H-Indol-3-yl)ethyl)propan-2-amine 1d was synthesized according to General
procedure D from tryptamine and acetone. The title compound was isolated as a light
o
1
yellow solid (750 mg, 80% yield). mp: 95−97 C; Rf (CH2Cl2/MeOH 10:1): 0.4; H NMR
(400 MHz, CDCl3) δ 8.18 (brs, 1H), 7.64 (d, J = 7.6 Hz, 1H), 7.37 (d, J = 7.6 Hz, 1H), 7.20
(dd, J = 8.0, 7.2 Hz, 1H), 7.12 (dd, J = 7.6, 7.2 Hz,1H), 7.05 (s, 1H), 3.03-2.94 (m, 4H), 2.82
13
(hept, J = 6.4 Hz, 1H), 1.06 (d, J = 6.4 Hz, 6H); C{1H} NMR (100 MHz, CDCl3) δ 136.3,
127.3, 122.0, 119.2, 118.9, 113.9, 111.1, 48.6, 47.3, 25.8, 22.8; HRMS(ESI) calcd for C13H19N2
(M+H)+ 203.1543, found 203.1543.
N-(Phenylmethyl)-1H-indole-3-ethanamine 1e was synthesized according to
General procedure D from tryptamine and benzaldehyde. The title compound was
1
isolated as a light yellow solid (998 mg, 86% yield).23 Rf (CH2Cl2/MeOH 20:1): 0.4; H
NMR (400 MHz, CDCl3) δ 7.96 (brs, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.33 (d, J = 7.2 Hz, 1H),
7.29-7.14 (m, 5 H), 7.08 (dd, J = 8.0, 6.8 Hz, 1H), 7.00 (s, 1H), 3.78 (s, 2H), 2.97-2.96 (m,
4H).
N-2-Propen-1-yl-1H-indole-3-ethanamine 1f was synthesized according to General
procedure D from tryptamine and 2-propenal. The title compound was isolated as a
light yellow solid (300 mg, 30% yield).24 Rf (CH2Cl2/MeOH 10:1): 0.4; 1H NMR (400 MHz,
CDCl3) δ 8.20 (brs, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.20 (dd, J = 8.0,
7.2 Hz, 1H), 7.12 (dd, J = 7.6, 7.2 Hz, 1H), 7.04 (s, 1H), 6.00-5.87 (m,1H), 5.16 (d, J = 17.2
Hz, 1H), 5.08 (d, J = 10.4 Hz, 1H), 3.29 (d, J = 6.0 Hz, 2H), 3.03-2.96 (m, 4H), 2.01 (brs,
1H).
N-Phenyl-1H-indole-3-ethanamine 1g was synthesized according to General
procedure C from indole and phenylamine. The title compound was isolated as a white
1
solid (590 mg, 50% yield).25 Rf (CH2Cl2/MeOH 30:1): 0.3; H NMR (400 MHz, CDCl3) δ
8.00 (s, 1H), 7.62 (d, J = 7.6 Hz, 1H), 7.38 (d, J = 8.4 Hz, 1H), 7.23-7.11 (m, 4H), 7.06 (s,
1H), 6.70 (dd, J = 7.6, 7.2 Hz, 1H), 6.62 (d, J = 7.6 Hz, 2H), 3.48 (t, J = 6.8 Hz, 1H), 3.10 (t,
J = 6.8 Hz, 1H).
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N-[2-(1H-Indol-3-yl)ethyl]-acetamide 1h was synthesized according to reported
procedure from tryptamine and acetyl chloride.26 The title compound was isolated as a
light yellow solid (1.13 g, 90% yield). 1H NMR (400 MHz, CDCl3) δ 8.48 (brs, 1H), 7.58 (d,
J = 8.0 Hz, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.19 (dd, J = 7.2, 7.2 Hz, 1H), 7.11 (dd, J = 7.6, 7.2
Hz, 1H), 6.99 (s, 1H), 5.68 (brs, 1H), 3.57 (q, J = 6.8 Hz, 2H), 2.95 (t, J = 6.8 Hz, 2H), 1.90
(s, 3H).
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N-[2-(1H-Indol-3-yl)ethyl]-4-methyl-benzenesulfonamide 1i was synthesized
according to reported procedure[27] from tryptamine and p-toluenesulfonyl chloride.
1
The title compound was isolated as a light yellow solid (1.75 g, 90% yield). H NMR
(400 MHz, CDCl3) δ 8.07 (brs, 1H), 7.63 (d, J = 8.4 Hz, 2H), 7.40 (d, J = 7.6 Hz, 1H), 7.34
(d, J = 8.4 Hz, 1H), 7.26-7.15 (m, 3H), 7.05 (dd, J = 7.2, 7.2 Hz, 1H), 6.95 (s, 1H), 4.48 (brs,
1H), 3.26 (q, J = 6.4 Hz, 2H), 2.91 (t, J = 6.4 Hz, 2H), 2.39 (s, 3H).
Procedure for the synthesis of 1j. A stirred solution of tryptamine (3.2 g, 20 mmol,
2.0 equiv.) in EtOH (13 mL) was dropwised to a solution of ethyl acrylate (1.09 mL, 10.0
mmol, 1.0 equiv.) in EtOH (7 mL) at 0 °C. Then the reaction was stirred overnight at
room temperature. After concentration, the residue was purified by column
chromatography on silica gelto give 1j as a light yellow solid (2.1 g, 80% yield).[28] Rf
(CH2Cl2/MeOH 10:1): 0.3; 1H NMR (400 MHz, CDCl3) δ 8.15 (brs, 1H), 7.61 (d, J = 8.0 Hz,
1H), 7.36 (d, J = 8.0 Hz, 1H), 7.19 (dd, J = 7.6, 7.2 Hz, 1H), 7.11 (dd, J = 7.6, 7.2 Hz, 1H),
7.04 (s, 1H), 4.08 (q, J = 7.2 Hz, 2H), 2.99 (s, 4H), 2.93 (t, J = 6.8 Hz, 2H), 2.52 (t, J = 6.8
Hz, 2H), 2.04 (brs, 1H), 1.20 (t, J = 7.2 Hz, 3H).
Procedure for the synthesis of 1k. A stirred solution of tryptamine (1.7 g, 10.5 mmol,
1.5 equiv.) in EtOH (25 mL) was dropwised to a solution of N,N-dimethylacrylamide
(0.721 mL, 7.0 mmol, 1.0 equiv.) in EtOH (5 mL) at 0 °C. Then the reaction was stirred
overnight at room temperature. After concentration, the residue was purified by
column chromatography on silica gelto give 1k as a light yellow solid (1.1 g, 40% yield).
o
1
mp: 95−97 C; Rf (CH2Cl2/MeOH 10:1): 0.3; H NMR (400 MHz, CDCl3) δ 8.17 (brs, 1H),
7.61 (d, J = 8.0 Hz, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.18 (dd, J = 8.0, 7.2 Hz, 1H), 7.11 (dd, J =
7.6, 7.2 Hz, 1H), 7.05 (s, 1H), 2.98-2.91 (m, 12H), 2.52 (t, J = 6.4 Hz, 2H), 1.88 (brs, 1H);
13C{1H} NMR (100 MHz, DMSO-d6) δ 171.7, 136.3, 127.2, 122.2, 121.6, 118.8, 118.5, 112.9, 111.2,
49.7, 44.9, 36.9, 35.1, 32.7, 25.3; HRMS(ESI) calcd for C15H22N3O (M+H)+ 260.1757, found
260.1769.
N,5-Dimethyl-1H-indole-3-ethanamine 1l was synthesized according to General
procedure E from 2-(5-methyl-1H-indol-3-yl)ethan-1-amine. The title compound was
isolated as a light yellow viscous solid (700 mg, 73% yield). Rf (CH2Cl2/MeOH 10:1): 0.3;
1H NMR (400 MHz, CD3OD) δ 7.37 (s, 1H), 7.25 (d, J = 8.4 Hz, 1H), 7.14 (s, 1H), 6.97 (d, J
13
= 8.0 Hz, 1H), 3.31-3.27 (m, 2H), 3.12 (t, J = 7.2, 2H), 2.68 (s, 3H), 2.43 (s, 3H); C{1H}
NMR (100 MHz, CD3OD) δ 136.7, 129.2, 128.4, 124.4, 118.6, 112.3, 109.5, 50.9, 33.8, 23.4,
21.7; HRMS(ESI) calcd for C12H17N2 (M+H)+ 189.1386, found 189.1386.
5-Methoxy-N-methyl-1H-indole-3-ethanamine 1m was synthesized according to
General procedure E from 2-(5-methoxy-1H-indol-3-yl)ethan-1-amine. The title
compound was isolated as a light yellow viscous solid (543 mg, 53% yield).[29] Rf
1
(CH2Cl2/MeOH 10:1): 0.3; H NMR (400 MHz, DMSO-d6) δ 10.64 (brs, 1H), 7.21 (d, J =
8.8 Hz, 1H), 7.08 (s, 1H), 6.98 (s, 1H), 6.70 (d, J = 8.8 Hz, 1H), 3.75 (s, 3H), 2.78 (s, 4H),
2.34 (s, 3H).
Ethyl-3-(2-(benzylamino)ethyl)-1H-indole-5-carboxylate 1n was synthesized
according
to
General
procedure
D
from
ethyl
3-(2-aminoethyl)-1H-indole-5-carboxylate and benzaldehyde. The title compound was
isolated as a light yellow solid (1.1 g, 71% yield). mp: 106−109 oC; Rf (CH2Cl2/MeOH 10:1):
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0.3; H NMR (400 MHz, CDCl3) δ 8.39 (s, 1H), 8.19 (brs, 1H), 7.91 (d, J = 8.4 Hz, 1H),
7.38-7.23 (m, 6H), 7.09 (s, 1H), 4.41 (q, J = 7.2 Hz, 2H), 3.82 (s, 3H), 3.03-3.01 (m, 4H),
2.45 (s, 3H), 1.43 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 167.9, 139.9, 139.0,
128.5, 128.4, 128.1, 127.0, 126.9, 123.3, 121.8, 121.5, 115.1, 110.8, 60.6, 53.7, 49.3, 25.5, 14.4;
HRMS(ESI) calcd for C20H23N2O2 (M+H)+ 323.1754, found 323.1762.
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2-(5-Chloro-1H-indol-3-yl)-N-methylethan-1-amine 1o was synthesized according to
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General procedure
E
from 2-(5-chloro-1H-indol-3-yl)ethan-1-amine. The title
o
compound was isolated as a white solid (208.7 mg, 20% yield). mp: 226−228 C; Rf
(CH2Cl2/MeOH 10:1): 0.3; 1H NMR (400 MHz, CDCl3) δ 8.39 (brs, 1H), 7.59 (s, 1 H), 7.28
(d, J = 2.8 Hz, 1H), 7.15 (d, J = 8.4 Hz, 1H), 7.06 (s, 1H), 2.97-2.91 (m, 4H), 2.47 (s, 3H),
1.87 (brs, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 134.8, 128.4, 124.8, 123.6, 122.1, 118.2, 113.2,
112.2, 51.7, 36.0, 25.2; HRMS(ESI) calcd for C11H14ClN2 (M+H)+ 209.0840, found
209.0842.
2-(6-Fluoro-1H-indol-3-yl)-N-methylethan-1-amine 1p was synthesized according to
General procedure
compound was isolated as a light yellow solid (210 mg, 20% yield). mp: 209−213 C; Rf
(CH2Cl2/MeOH 10:1): 0.3; H NMR (400 MHz, CD3OD) δ 7.48 (dd, J = 5.6, 3.2 Hz, 1H),
7.06-7.02 (m, 2H), 6.81-6.76 (m, 1H), 2.93 (t, J = 8.0, 2H), 2.87 (t, J = 6.8, 2H), 2.40 (s,
3H); 13C{1H} NMR (100 MHz, CD3OD) δ 161.2 (d, J = 234.0 Hz), 138.1 (d, J = 12.0 Hz), 125.4,
123.9, 120.1 (d, J = 10.2 Hz), 113.4, 108.0 (d, J = 24.7 Hz), 98.2 (d, J = 25.7 Hz), 52.8, 35.8,
25.7; HRMS(ESI) calcd for C11H14FN2 (M+H)+ 193.1136, found 193.1146.
2-(6-Chloro-1H-indol-3-yl)-N-methylethan-1-amine 1q was synthesized according
to General procedure C from 2-(6-chloro-1H-indol-3-yl)ethan-1-amine. The title
E
from 2-(6-fluoro-1H-indol-3-yl)ethan-1-amine. The title
o
1
1
compound was isolated as a white solid (260.9 mg, 25% yield). H NMR (400 MHz,
CDCl3) δ 9.02 (brs, 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.30 (s, 1H), 7.05 (d, J = 8.4 Hz, 1H),
6.96 (s, 1H), 2.98-2.90 (m, 4H), 2.44 (s, 3H); C{1H} NMR (100 MHz, CDCl3) δ 136.8,
13
127.7, 125.9, 122.9, 119.8, 119.5, 113.3, 111.1, 51.6, 35.8, 25.0; HRMS(ESI) calcd for C11H14ClN2
(M+H)+ 209.0840, found 209.0851.
2-(7-Fluoro-1H-indol-3-yl)-N-methylethan-1-amine 1r was synthesized according to
General procedure C. The title compound was isolated as a light yellow viscous solid
(403 mg, 42% yield). Rf (CH2Cl2/MeOH 10:1): 0.2; 1H NMR (400 MHz, CD3OD) δ 7.36 (d,
J = 8.4 Hz, 1H), 7.22 (s, 1H), 6.99-6.93 (m, 1H), 6.85-6.80 (m, 1H), 3.27-3.22 (m, 2H), 3.12
(t, J = 7.6 Hz, 2H), 2.65 (s, 3H); 13C{1H} NMR (100 MHz, CD3OD) δ 151.2 (d, J = 242.0 Hz),
132.5 (d, J = 6.0 Hz), 126.1 (d, J = 13.3 Hz), 124.8, 120.0 (d, J = 6.0Hz), 115.2 (d, J = 3.0 Hz),
113.3, 107.0 (d, J = 17.0 Hz), 52.1, 35.2, 25.0; HRMS(ESI) calcd for C11H14FN2 (M+H)+
193.1136, found 193.1151.
Methyl ester-N-methyl-tryptophan 1s was synthesized according to reported
procedure.30 Rf (CH2Cl2/MeOH 20:1): 0.3; H NMR (400 MHz, CDCl3) δ 8.73 (brs, 1H),
1
7.59 (d, J = 7.6 Hz, 1H), 7.28 (d, J = 8.0 Hz, 1H), 7.16 (dd, J = 7.6, 7.2 Hz, 1H), 7.10 (dd, J =
7.6, 6.8 Hz, 1H), 6.93 (s, 1H), 3.66 (s, 3H), 3.57 (t, J = 6.4 Hz, 1H), 3.20 (dd, J = 14.2, 5.8
Hz, 1H), 3.11 (dd, J = 14.4, 7.2 Hz, 1H), 2.36 (s, 1H), 1.80 (brs, 1H).
N,1-Dimethyl-1H-indole-3-ethanamine 1t was synthesized according to the
procedure C from N-methyl-indole. The title compound was isolated as a light yellow
sticky liquid (188 mg, 20% yield).31 1H NMR (400 MHz, CDCl3) δ 7.58 (d, J = 8.0 Hz, 1H),
7.24-7.17 (m, 2H), 7.07 (dd, J = 7.6, 7.6 Hz, 1H), 6.85 (s, 1H), 3.69 (s, 3H), 32.94-2.87 (m,
4H), 2.40 (s, 3H), 2.17 (brs, 1H).
Procedure for the synthesis of 1u. Indole-3-propionic acid (10.0 mmol, 1.0 equiv.)
was dissolved in 120 mL dry THF with stirring. The inner temperature was decreased
below 3 °C using an ice bath followed by the addition of triethylamine (5.5 mL, 40
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mmol, 4 equiv). The reaction was maintained at this temperature and stirred for 10
min. Methyl chloroformate (0.85 mL, 11.0 mmol, 1.1 equiv.) was slowly dropwise added.
2-Methylamine hydrochlorate (10.1 mg, 150.0 mmol, 15 equiv.) was added in batch, the
temperature was kept and the mixture was stirred for another 30 min. The ice salt bath
was removed. The reaction mixture was further stirred for 3.5 h at room temperature.
The resulting mixture was applied to suction filtration, and the filter cake was washed
with Et2O (50 mL). The ether layers were combined, washed with water (30 mL) and
brine (30 mL × 2) respectively, dried over anhydrous MgSO4, and concentrated in
vacuo to give the crude product. The crude product was added to a solution of LiAlH4
(1.5 g, 40.0 mmol, 4.0 equiv.) in anhydrous THF (120.0 mL), the reaction was refluxed
for 4 hours until the substrate disappeared and then quenched by H2O (1.5 mL), 0.2 M
NaOH (3.0 mL), H2O (4.5 mL). After a small scoop of MgSO4 (~400 mg) was added, the
mixture was stirred for another 10 minutes. The solid particles were filtered and
washed with EtOAc (50.0 mL), then the combined filtrate was concentrated under
reduced pressure. The crude product was purified by flash chromatography to yield
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1
pure product 1u as as a white powder (1.25 g, 66%). Rf (CH2Cl2/MeOH 10:1): 0.3; H
NMR (400 MHz, CDCl3) δ 8.23 (brs, 1H), 7.61 (d, J = 7.6 Hz, 1H), 7.35 (d, J = 8.4 Hz, 1H),
7.19 (dd, J = 7.2, 6.4 Hz, 1H), 7.12 (dd, J = 8.0, 8.0 Hz, 1H), 6.97 (s, 1H), 2.81 (t, J = 7.6 Hz,
13
2H), 2.69 (t, J = 7.2 Hz, 2H), 2.45 (s, 3H), 1.97-1.90 (m, 2H), 1.72 (brs, 1H); C{1H} NMR
(100 MHz, CDCl3) δ 136.3, 127.5, 121.8, 121.2, 119.0, 118.8, 116.2, 111.1, 51.8, 36.3, 30.1, 22.8;
HRMS(ESI)
calcd
for
C12H17N2
(M+H)+
189.1386,
found
189.1386.
N-Methyl-1H-indole-3-butanamine 1v was synthesized according to the procedure
for the synthesis of 1u from 3-indolebutyric acid. The title compound was isolated as a
1
white powder (515 mg, 25% yield). Rf (CH2Cl2/MeOH 10:1): 0.2; H NMR (400 MHz,
CDCl3) δ 8.63 (s, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 7.15 (dd, J = 7.6,
7.2 Hz, 1H), 7.08 (dd, J = 7.2, 7.2 Hz, 1H), 6.89 (s, 1H), 2.75 (t, J = 7.6 Hz, 2H), 2.60 (t, J =
13
6.8 Hz, 2H), 2.41 (s, 3H), 1.75-1.69 (m, 2H), 1.63-1.57 (m, 2H); C{1H} NMR (100 MHz,
CDCl3) δ 136.4, 127.4, 121.6, 121.3, 118.82, 118.75, 116.2, 111.1, 51.7, 36.0, 29.4, 27.7, 24.9;
HRMS(ESI) calcd for C13H19N2 (M+H)+ 203.1543 , found 203.1541.
Procedure for the synthesis of 1w. To a 50 mL flask, a stirred solution of
2-(methylamino)ethan-1-ol (0.8 mL, 10.0 mmol, 1.0 equiv.) in anhydrous CHCl3 (10 mL)
was added thionyl chloride (1.45 mL, 20.0 mmol, 2.0 equiv.) at 0 °C and the reaction
was refluxed for 5 hours. The reaction mixture was then cooled to room temperature
and was added Et2O (15 mL). Then the reaction was stirred overnight at room
o
temperature and quenched with EtOH (2.2 mL) at 0 C. The reaction mixture was
filtered. The filter cake was washed with Et2O (4 × 10 mL). Then the filter cake was
charged into a flask and DMSO (4 mL) were added slowly, then indole (936 mg, 8.0
mmol, 0.8 equiv.) and potassium hydroxide (2.0 g, 45.0 mmol, 4.5 equiv.) were added.
The reaction mixture was stirred at room temperature until indole was consumed. The
reaction was quenched with water (10 mL), Et2O (30 mL) was added. The organic phase
was separated and the aqueous phase was extracted with Et2O (30 mL × 2). The
combined organic phase was washed with water and brine, dried over MgSO4, and
concentrated in vacuo. The residue was purified by column chromatography on silica
gel to give 1w as a light yellow liquid (553 mg, 32% yield). Rf (CH2Cl2/MeOH10:1): 0.2;
1H NMR (400 MHz, CDCl3) δ 7.63 (d, J = 7.6 Hz, 1H), 7.38 (d, J = 8.4 Hz, 1H), 7.21 (dd, J
= 8.8, 7.2 Hz, 1H), 7.12-7.09 (m, 2H), 6.50 (d, J = 3.2 Hz, 1H), 4.26 (t, J = 6.0 Hz, 2H),
3.00 (t, J = 6.0 Hz, 2H), 2.39 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 135.8, 128.5, 127.9,
121.4, 120.9, 119.3, 109.2, 101.3, 51.1, 46.0, 35.9; IRv (cm-1): 3151, 1399, 1315, 1162, 765, 742;
HRMS(ESI) calcd for C11H15N2 (M+H)+ 175.1230, found 175.1239.
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N-Benzyl-2-(1H-indol-1-yl)ethan-1-amine 1x was synthesized according to the
procedure for the synthesis of 1w from 2-(benzylamino)ethan-1-ol and indole. The title
compound was isolated as a light yellow liquid (2.26 g, 90% yield, two steps). Rf
(CH2Cl2/MeOH 10:1): 0.3; 1H NMR (400 MHz, CDCl3) δ 7.63 (d, J = 8.0 Hz, 1H), 7.38-7.34
(m, 2H), 7.31-7.18 (m, 5H), 7.14-7.09 (m, 2H), 6.05 (d, J = 2.8 Hz, 1H), 4.28 (t, J = 6.4 Hz,
13
2H), 3.75 (s, 3H), 3.39 (s, 1H), 3.05 (t, J = 6.0 Hz, 2H); C{1H} NMR (100 MHz, CDCl3) δ
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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29
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34
35
36
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139.8, 135.9, 128.6, 128.3, 128.0, 127.9, 127.0, 121.4, 120.9, 119.3, 109.3, 101.3, 53.5, 48.6, 46.5;
IRv (cm-1): 3419, 3026, 2821. 1494, 1463, 1396; HRMS(ESI) calcd for C17H19N2 (M+H)+
251.1543, found 251.1550.
N-(Phenylmethyl)-1H-Pyrrole-1-ethanamine 1y was synthesized according to the
procedure for the synthesis of 1w from 2-(benzylamino)ethan-1-ol and pyrrole. The
title compound was isolated as a light yellow liquid (1.64 g, 82% yield, two steps).32 Rf
(CH2Cl2/MeOH 20:1): 0.3; 1H NMR (400 MHz, CDCl3) δ 7.35-7.22 (m, 5H), 6.69-6.68 (m,
2H), 6.16-6.15 (m, 2H), 4.03 (t, J = 6.0 Hz, 2H), 3.77 (s, 1H), 2.96 (t, J =6.0 Hz, 2H).
N-[2-(1H-Indol-3-yl)ethyl]-N-methyl-formamide 5 was synthesized according to the
reported procedure.33 The title compound was isolated as a light yellow liquid (287.0
mg, 71% yield). Rf (petroleum ether/EtOAc 1:1): 0.1. Ratio rotamers in CDCl3: 1.9:1;
Major rotamer: 1H NMR (400 MHz, CDCl3) δ 8.40 (brs, 1H), 7.74 (s, 1H), 7.55 (d, J = 7.8
Hz, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.22-7.17 (m, 1H), 7.15-7.10 (m, 1H), 6.92 (s, 1H), 3.53 (t, J
= 6.8 Hz, 2H), 3.04-2.98 (m, 2H), 2.93 (s, 3H). Minor rotamer: 8.34 (brs, 1H), 8.05 (s,
1H), 7.64 (d, J = 7.8 Hz, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.22-7.17 (m, 1H), 7.15-7.10 (m, 1H),
7.02 (s, 1H), 3.67 (t, J = 7.6 Hz, 2H), 3.04-2.98 (m, 2H), 2.88 (s, 3H).
2-(1H-indol-2-yl)-N-methylethan-1-amine 6 was synthesized according to General
procedure E from 2-(1H-indol-2-yl)ethan-1-amine. The title compound was isolated as
o
1
a light yellow solid (592 mg, 68% yield). mp: 90−94 C; Rf (CH2Cl2/MeOH 10:1): 0.3; H
NMR (400 MHz, CDCl3) δ 9.41 (brs, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.33 (d, J = 7.6 Hz, 1H),
7.14-7.05 (m, 2H), 6.25 (s, 1H), 2.94 (s, 4H), 2.49 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3)
δ 138.8, 135.8, 128.5, 120.9, 119.7, 119.4, 110.6, 99.3, 51.2, 36.2, 27.7; HRMS(ESI) calcd for
C11H15N2 (M+H)+ 175.1235, found 175.1240.
2,9-Tetrahydro-2-methyl-1H-Pyrido[3,4-b]indol-1-one
2a
was
synthesized
according to General procedure A from 1a (0.2 mmol, 34.8 mg). The title compound
was isolated as a light yellow solid (34.4 mg, 86% yield).34 Rf (petroleum ether/EtOAc
2:1): 0.3; 1H NMR (400 MHz, CDCl3) δ 10.67 (brs, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.51 (d, J =
8.4 Hz, 1H), 7.30-7.23(m, 1H), 7.11 (dd, J = 8.0, 7.2 Hz, 1H), 3.69 (t, J = 7.2 Hz, 2H), 3.20 (s,
3H), 3.06 (t, J = 6.8 Hz, 2H); HRMS(ESI) calcd for C12H13N2O (M+H)+ 201.1022, found
201.1023.
2,9-Tetrahydro-2-propyl-1H-Pyrido[3,4-b]indol-1-one 2b was synthesized according
to General procedure A from 1b (0.2 mmol, 40.4 mg). The title compound was isolated
1
as a white solid (41.0 mg, 90% yield).35 Rf (petroleum ether/EtOAc 3:1): 0.3; H NMR
(400 MHz, CDCl3) δ 10.66 (brs, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.50 (d, J = 8.4Hz, 1H), 7.28
(ddJ = 8.0, 7.6 Hz, 1H), 7.12 (dd, J = 7.6, 7.6 Hz, 1H), 3.70 (t, J = 7.2 Hz, 2H), 3.60 (t, J =
7.2 Hz, 2H), 3.05 (t, J = 7.2 Hz, 2H), 1.72 (q, J = 7.6 Hz, 2H), 1.01 (t, J = 7.6 Hz, 3H).
2-Isopentyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-one 2c was synthesized
according to General procedure A from 1c (0.2 mmol, 46.0 mg). The title compound
was isolated as a light yellow solid (42.5 mg, 83% yield). mp: 243−249 oC; Rf (petroleum
1
ether/EtOAc 5:1): 0.3; H NMR (400 MHz, CDCl3) δ 11.06 (brs, 1H), 7.55 (dd, J = 6.8, 6.8
Hz, 2H), 7.27-7.25 (m, 1H), 7.11 (dd, J = 6.8, 6.4 Hz, 1H), 3.70-3.66 (m 4H), 3.0 (m, 2H),
1.69 (hept, J = 6.8 Hz, 1H), 1.56 (dt, J = 8.0, 6.4 Hz, 2H), 0.99 (d, J = 6.4 Hz, 6H); 13C{1H}
NMR (100 MHz, CDCl3) δ 161.5, 137.7, 127.4, 125.1, 124.3, 119.9, 119.8, 117.6, 112.7, 47.9,
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44.9, 36.8, 26.1, 22.6, 20.8; IRv (cm-1): 3449, 3184, 2955, 1619, 1556, 1429, 1299, 778, 741;
HRMS(ESI) calcd for C16H21N2O (M+H)+ 257.1648, found 257.1648.
2-Isopropyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-one 2d was synthesized
according to General procedure A from 1d (0.2 mmol, 37.6 mg). The title compound
o
was isolated as a white solid (36.4 mg, 80% yield). mp: 214−217 C; Rf (petroleum
1
ether/EtOAc 3:1): 0.3; H NMR (400 MHz, CDCl3) δ 9.37 (brs, 1H), 7.59 (d, J = 8.0 Hz,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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1H), 7.44 (d, J = 8.4, 1H), 7.30 (dd, J = 8.4, 6.8 Hz, 1H), 7.14 (dd, J = 8.0, 7.2 Hz, 1H), 5.05
(hept, J = 6.8 Hz, 1H), 3.61 (t, J = 6.8 Hz, 2H), 3.02 (t, J = 6.8 Hz, 2H), 1.02 (d, J = 6.8 Hz,
13
6H); C{1H} NMR (100 MHz, CDCl3) δ 161.1, 137.6, 127.7, 125.0, 124.4, 119.9, 119.8, 117.4,
112.6, 43.2, 40.8, 21.0, 20.0; IRv (cm-1): 3448, 2915, 1636, 1458, 1383, 1129, 1086, 845, 744;
HRMS(ESI) calcd for C14H17N2O (M+H)+ 229.1335, found 229.1335.
2-Benzyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-one 2e was synthesized
according to General procedure A from 1e (0.2 mmol, 50.0 mg). The title compound
o
was isolated as a white solid (40.8 mg, 74% yield). mp: 220−225 C; Rf (petroleum
1
ether/EtOAc 4:1): 0.3; H NMR (400 MHz, CDCl3) δ 10.46 (brs, 1H), 7.56 (d, J = 7.6 Hz,
1H), 7.45 (d, J = 8.0 Hz, 1H), 7.39-7.30 (m, 4H), 7.28-7.25 (m, 1H), 7.12 (dd, J = 7.6, 6.8
13
Hz, 1H), 4.87 (s, 2H), 3.66 (t, J = 6.8 Hz, 2H), 3.03 (t, J = 6.8 Hz, 2H); C{1H} NMR (100
MHz, CDCl3) δ 161.8, 137.7, 137.6, 128.7, 127.9, 127.5, 126.8, 125.1, 124.7, 120.0, 118.1, 112.7,
49.6, 47.5, 20.7; IRv (cm-1): 3449, 3217, 3027, 1633, 1428, 1327, 1251, 746, 695; HRMS(ESI)
calcd for C18H17N2O (M+H)+ 277.1335, found 277.1337.
2-Allyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-one 2f was synthesized according
to General procedure A from 1f (0.2 mmol, 40.0 mg). The title compound was isolated
1
as a viscous solid (13.8 mg, 25% yield). Rf (petroleum ether/EtOAc 2:1): 0.3; H NMR
(400 MHz, CDCl3) δ 10.37 (brs, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.48 (d, J = 8.4 Hz, 1H),
7.30-7.25 (m, 1H), 7.12 (dd, J = 8.4, 6.8 Hz, 1H), 5.95-5.89 (m, 1H), 5.31 (d, J = 17.2 Hz,
1H), 5.25 (d, J = 10.0 Hz, 1H), 4.26 (d, J = 6.0 Hz, 2H), 3.68 (t, J = 7.0 Hz, 2H), 3.07 (t, J =
7.0 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 161.5, 137.7, 133.4, 127.0, 125.1, 124.6, 119.99,
119.97, 118.1, 117.4, 112.7, 48.6, 47.4, 20.7; HRMS(ESI) calcd for C14H15N2O (M+H)+
227.1179, found 227.1179.
2-Benzyl-3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one 2j was synthesized according
to General procedure A from 1j (0.2 mmol, 52.0 mg). The title compound was isolated
as a light yellow solid (49.2 mg, 86% yield). mp: 135−139oC; Rf (petroleum ether/EtOAc
3:1): 0.3; 1H NMR (400 MHz, CDCl3) δ 10.05 (brs, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.48 (d, J =
8.8 Hz, 1H), 7.30 (dd, J = 8.4, 8.4 Hz, 1H), 7.14 (dd, J = 8.0, 7.2 Hz, 1H), 4.16 (q, J = 7.2
Hz, 2H), 3.89 (t, J = 7.2 Hz, 2H), 3.80 (t, J = 7.2 Hz, 2H), 3.06 (t, J = 7.2 Hz, 2H), 2.76 (t, J
= 6.4 Hz, 2H), 1.26 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 172.0, 161.8, 137.7,
126.9, 125.1, 124.7, 120.0, 119.9, 118.3, 112.7, 60.7, 49.2, 43.3, 33.4, 20.9, 14.2; HRMS(ESI)
calcd for C16H19N2O3 (M+H)+ 287.1390, found 287.1393.
2-Benzyl-3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one 2k was synthesized according
to General procedure A from 1k (0.2 mmol, 51.8 mg). The title compound was isolated
as a viscous solid (43.3 mg, 76% yield). Rf (CH2Cl2/MeOH 20:1): 0.4; 1H NMR (400 MHz,
CDCl3) δ 10.86 (brs, 1H), 7.58 (d, J = 8.0 Hz, 1 H), 7.50 (d, J = 8.0 Hz, 1 H), 7.28 (dd, J =
7.6, 7.2 Hz, 1H), 7.13 (dd, J = 7.6, 7.2 Hz, 1H), 3.94 (t, J = 6.8 Hz, 2H), 3.86 (t, J = 7.2 Hz,
13
2H), 3.05 (t, J = 6.8 Hz, 2H), 2.99 (s, 3H), 2.97 (s, 3H), 2.81 (t, J = 6.4 Hz, 2H); C{1H}
NMR (100 MHz, CDCl3) δ 171.1, 162.0, 137.7, 127.0, 125.1, 124.5, 120.0, 119.9, 118.4, 112.6,
49.6, 44.1, 37.3, 35.3, 32.1, 20.8; IRv (cm-1): 3412, 2926, 1628, 1458, 1341, 1156, 1119, 1104, 768,
744; HRMS(ESI) calcd for C16H20N3O2 (M+H)+ 286.1550, found 286.1550.
2,3,4,9-Tetrahydro-6-methyl-2-methyl-1H-Pyrido[3,4-b]indol-1-one
2l
was
synthesized according to General procedure A from 1l (0.2 mmol, 37.8 mg). The title
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compound was isolated as a light yellow solid (24.4 mg, 57% yield).34 Rf (petroleum
ether/EtOAc 2:1): 0.3; 1H NMR (400 MHz, DMSO-d6) δ 11.44 (brs, 1H), 7.34 (s, 1H), 7.26
(d, J = 8.4 Hz, 1H), 7.03 (d, J = 8.4 Hz, 1H), 3.64 (t, J = 8.0 Hz, 2H), 2.99 (s, 3H), 2.96 (t, J
= 6.8 Hz, 2H), 2.37 (s, 3H); HRMS(ESI) calcd for C13H15N2O (M+H)+ 215.1179, found
215.1177.
2,3,4,9-Tetrahydro-6-methoxy-2-methyl-1H-Pyrido[3,4-b]indol-1-one 2m was
synthesized according to General procedure A from 1m (0.2 mmol, 40.9 mg). The title
compound was isolated as a light yellow solid (24.4 mg, 58% yield).34 Rf (petroleum
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
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28
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49
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53
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59
60
1
ether/EtOAc 2:1): 0.3; H NMR (400 MHz, CDCl3) δ 9.82 (brs, 1H), 7.37 (d, J = 7.6 Hz,
1H), 6.98-6.95 (m, 2H), 3.86 (s, 3H), 3.71 (t, J = 7.2 Hz, 2H), 3.17 (s, 3H), 3.05 (t, J = 7.2
Hz, 2H); HRMS(ESI) calcd for C13H15N2O2 (M+H)+ 231.1128, found 231.1134.
Ethyl-2-benzyl-1-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-6-carboxylate 2n
was synthesized according to General procedure A from 1n (0.2 mmol, 64.4 mg). The
title compound was isolated as a light yellow solid (54.0 mg, 78% yield). mp: 202−206
1
oC; Rf (petroleum ether/EtOAc 3:1): 0.4; H NMR (400 MHz, DMSO-d6) δ 12.13 (brs,
1H),8.29 (s, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.48 (d, J = 8.8 Hz, 1H), 7.35-7.27 (m, 5H), 4.71
(s, 2H), 4.31 (q, J = 7.2 Hz, 2H), 3.61 (t, J = 6.8 Hz, 2H), 3.03 (t, J = 6.8 Hz, 2H), 1.33 (t, J =
7.2 Hz, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 166.4, 160.2, 139.8, 137.8, 128.62,
128.56, 127.6, 127.2, 124.6, 124.4, 122.9, 121.3, 119.0, 112.5, 60.3, 48.8, 47.2, 19.9, 14.3; IRv
(cm-1): 3462, 3288, 2922, 1743, 1428, 1356, 1291, 1117, 747, 700; HRMS(ESI) calcd for
C21H21N2O3 (M+H)+ 349.1547, found 349.1547.
6-Chloro-2-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-one
2o
was
synthesized according to General procedure A from 1o (0.2 mmol, 41.7 mg). The title
o
compound was isolated as a white solid (42.0 mg, 90% yield). mp: 256−257 C; Rf
1
(petroleum ether/EtOAc 3:1): 0.2; H NMR (400 MHz, DMSO-d6) δ 11.81(brs, 1H), 7.67
(s, 1H), 7.38 (d, J = 8.8 Hz, 1H), 7.19 (d, J = 8.8 Hz, 1H), 3.66 (t, J = 7.2 Hz, 2H), 3.00-2.97
(m, 5H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 160.5, 135.6, 128.5, 125.8, 124.0, 123.9, 119.3,
116.7, 114.1, 49.3, 33.6, 19.8; IRv (cm-1): 3449, 3210, 2950, 1638, 1514, 1326, 1251, 772, 736;
HRMS(ESI) calcd for C12H12ClN2O (M+H)+ 235.0633, found 235.0638.
7-Fluoro-2-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-one
2p
was
synthesized according to General procedure A from 1p (0.2 mmol, 38.4 mg). The title
o
compound was isolated as a white solid (29.2 mg, 67% yield). mp: 251−254 C; Rf
1
(petroleum ether/EtOAc 3:1): 0.4; H NMR (400 MHz, DMSO-d6) δ 11.71 (brs, 1H),
7.62-7.58 (m, 1H), 7.11-7.07 (m, 1H), 6.95-6.90 (m, 1H), 3.64 (t, J = 7.2 Hz, 2H), 3.03-2.99
(m, 5H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 160.7, 160.2 (d, J = 236.4 Hz), 137.3 (d, J =
12.8 Hz), 127.8 (d, J = 3.6 Hz), 121.7 (d, J = 16.8 Hz), 121.5, 117.5, 108.5 (d, J = 24.8 Hz), 98.0
(d, J = 25.4 Hz), 49.4, 33.5, 19.9; IRv (cm-1): 3449, 3210, 2942, 1640, 1559, 1510, 1326, 1251,
1127, 771, 721, 513; HRMS(ESI) calcd for C12H12FN2O (M+H)+ 219.0928, found 219.0929.
7-Chloro-2-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-one
2q
was
synthesized according to General procedure A from 1q (0.2 mmol, 41.7 mg). The title
o
compound was isolated as a white solid (42.0 mg, 90% yield). mp: 273−279 C; Rf
1
(petroleum ether/EtOAc 3:1): 0.2; H NMR (400 MHz, DMSO-d6) δ 11.81 (brs, 1H), 7.66
(s, 1H), 7.38 (d, J = 8.8 Hz, 1H), 7.19 (dd, J = 8.4, 2.0 Hz, 1H), 3.65 (t, J = 7.2, 2H),
13
3.00-2.96 (m, 5H); C{1H} NMR (100 MHz, DMSO-d6) δ 160.6, 135.6, 128.5, 125.8, 124.0,
123.9, 119.3, 116.7, 114.1, 49.3, 33.6, 19.8; IRv (cm-1): 3448, 2922, 1639, 1517, 1319, 1049, 804,
774, 617; HRMS(ESI) calcd for C12H12ClN2O (M+H)+ 235.0633, found 235.0638.
8-Fluoro-2-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-one
2r
was
synthesized according to General procedure A from 1r (0.2 mmol, 38.4 mg). The title
o
compound was isolated as a white solid (24.0 mg, 55% yield). mp: 203−205 C; Rf
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(petroleum ether/EtOAc 3:1): 0.2; 1H NMR (400 MHz, CDCl3) δ 10.74 (brs, 1H), 7.32 (d, J
= 8.0 Hz, 1H), 7.05-6.95 (m, 2H), 3.72 (t, J = 7.2 Hz, 2H), 3.21 (s, 3H), 3.07 (t, J = 7.2 Hz,
2H); 13C{1H} NMR (100 MHz, CDCl3) δ 161.5, 150.1 (d, J = 245.0 Hz), 128.8 (d, J = 5.0 Hz),
128.0, 126.1 (d, J = 13.0 Hz), 120.0 (d, J = 6.0 Hz), 118.1 (d, J = 3.0 Hz), 115.7 (d, J = 4.0 Hz),
109.0 (d, J = 16.0 Hz), 50.0, 34.1, 20.6; IRv (cm-1): 3453, 3195, 2931, 1644, 1577, 1504, 1326,
1227, 771, 700; HRMS(ESI) calcd for C12H12FN2O (M+H)+ 219.0928, found 219.0928.
Methyl-2-methyl-1-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylate
2s was synthesized according to General procedure A from 1s (0.2 mmol, 46.4 mg). The
title compound was isolated as a white solid (10.5 mg, 20% yield). Rf (CH2Cl2/MeOH
10:1): 0.5; 1H NMR (400 MHz, CDCl3) δ 9.84 (brs, 1H), 7.57 (d, J = 7.6 Hz, 1H), 7.48 (d, J =
7.6 Hz, 1H), 7.30 (dd, J = 8.0, 7.2 Hz, 1H), 7.14 (dd, J = 6.8, 6.8 Hz, 1H), 4.36 (d, J = 4.8
Hz, 1H), 3.65 (s, 3H), 3.56 (d, J = 16.4 Hz, 1H), 3.45 (dd, J = 15.6, 6.0 Hz, 1H), 3.22 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3) δ 171.9, 161.7, 137.5, 126.6, 125.2, 124.9, 120.22, 120.15, 115.2,
112.6, 62.7, 52.9, 34.5, 24.2; HRMS(ESI) calcd for C14H15N2O3 (M+H)+ 259.1077, found
259.1096.
2,9-Dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-one 2t was synthesized
according to General procedure A from 1t (0.2 mmol, 37.8 mg). The title compound
was isolated as a viscous solid (25.4 mg, 60% yield). Rf (petroleum ether/EtOAc 3:1):
0.3; 1H NMR (400 MHz, CDCl3) δ 7.58 (d, J = 8.4 Hz, 1H), 7.38-7.32 (m, 2H), 7.15 (dd, J =
8.0, 6.4 Hz, 1H), 4.12 (s, 3H), 3.67 (t, J = 6.8 Hz, 2H), 3.14 (s, 3H), 3.06 (t, J = 6.8 Hz,
2H);13C{1H} NMR (100 MHz, CDCl3) δ 162.2, 139.0, 126.4, 124.4, 123.9, 120.0, 199.9, 118.2,
110.2, 49.9, 34.2, 31.2, 20.6; HRMS(ESI) calcd for C13H15N2O (M+H)+ 215.1179, found
215.1179.
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3,4,5,10-Tetrahydro-2-methyl-azepino[3,4-b]indol-1(2H)-one 2u was synthesized
according to General procedure A from 1u (0.2 mmol, 37.6 mg). The title compound
was isolated as a light yellow solid (23.0mg, 53% yield).[36] mp:193−196 oC; Rf (petroleum
1
ether/EtOAc 1:1): 0.4; H NMR (400 MHz, CDCl3) δ 9.31 (brs, 1H), 7.58 (d, J = 8.0 Hz,
1H), 7.40 (d, J = 8.4 Hz, 1H), 7.31-7.26 (m, 1H), 7.11 (dd, J = 8.0, 7.2 Hz, 1H), 3.59-3.57 (m,
2H), 3.24 (s, 3H), 3.08 (t, J = 6.8 Hz, 2H), 2.23-2.18 (m, 2H).
2-Methyl-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one 2w was synthesized according
to General procedure A from 1w (0.2 mmol, 40.0 mg). The title compound was isolated
o
as a white solid (23.6mg, 59% yield). mp: 132−136 C; Rf (petroleum ether/EtOAc 1:1):
1
0.2; H NMR (400 MHz, CDCl3) δ 7.71 (d, J = 8.0 Hz, 1H), 7.35-7.29 (m, 2H), 7.28-7.25
(m, 1H), 7.18-7.13 (m, 2H), 4.29 (t, J = 5.6 Hz, 2H), 3.80 (t, J = 5.6 Hz, 2H), 3.19 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3) δ 160.3, 136.5, 129.4, 127.6, 124.4, 122.7, 120.7, 109.5, 106.0,
48.1, 40.0, 34.3; HRMS(ESI) calcd for C12H13N2O (M+H)+ 201.1022, found 201.1024.
2-Benzyl-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one 2x was synthesized according
to General procedure A from 1x (0.2 mmol, 40.0 mg). The title compound was isolated
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as a viscous solid (32.6 mg, 59% yield). Rf (petroleum ether/EtOAc 2:1): 0.3; H NMR
(400 MHz, DMSO-d6) δ 7.71 (d, J = 8.0 Hz, 1H), 7.51 (d, J = 6.0 Hz, 1H), 7.36-7.35 (m,
4H), 7.31-7.27 (m, 2H), 7.13-7.09 (m, 2H), 4.75 (s, 3H), 4.32 (t, J = 6.0 Hz, 2H), 3.73 (t, J =
13
6.0 Hz, 2H); C{1H} NMR (100 MHz, DMSO-d6) δ 159.1, 137.4, 136.2, 129.4, 128.7, 127.8,
127.4, 126.8, 124.1, 122.1, 120.5, 110.7, 104.8, 48.9, 45.5, 39.9; IRv (cm-1): 3449, 2920, 1638,
1545, 1452, 1360, 1243, 747, 722, 695; HRMS(ESI) calcd for C18H17N2O (M+H)+ 277.1335,
found 277.1336.
2-Benzyl-3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one 2y was synthesized according
to General procedure A from 1y (0.2 mmol, 40.0 mg). The title compound was isolated
1
as a viscous solid (23.3 mg, 51% yield). Rf (petroleum ether/EtOAc 2:1): 0.3; H NMR
(400 MHz, CDCl3) δ 7.32-7.26 (m, 5H), 6.98 (dd, J = 4.0, 1.6 Hz, 1H), 6.71-6.70 (m, 1H),
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6.24 (dd, J = 4.0, 2.4 Hz, 1H), 4.75 (s, 2H), 4.07 (t, J =6.0 Hz, 2H), 3.56 (t, J =6.0 Hz, 2H);
13C{1H} NMR (100 MHz, CDCl3) δ 159.6, 137.1, 128.7, 128.1, 127.5, 124.6, 122.8, 113.6, 109.9,
49.1, 45.1, 43.7; IRv (cm-1): 3449, 2925, 1638, 1545, 1452, 1360, 747, 721, 695; HRMS(ESI)
calcd for C14H15N2O (M+H)+ 227.1179, found 227.1180.
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2,9-Dihydro-2-methyl-1H-Pyrido[3,4-b]indol-1-one 3a was synthesized according to
General procedure B from 1a (0.2 mmol, 34.8 mg). The title compound was isolated as
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a viscous solid (26.1 mg, 66% yield).37 Rf (CH2Cl2/MeOH 20:1): 0.3; H NMR (400 MHz,
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CDCl3) δ 10.78 (brs, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.47 (dd, J =
8.4, 6.8 Hz, 1H), 7.26-7.22 (m, 1H), 7.11 (d, J = 6.8 Hz, 1H), 6.96 (d, J = 6.8 Hz, 1H), 3.82
(s, 3H).
2-Propyl-2,9-dihydro-1H-Pyrido[3,4-b]indol-1-one 3b was synthesized according to
General procedure B from 1b (0.2 mmol, 40.4 mg). The title compound was isolated as
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a viscous solid (33.6 mg, 75% yield). Rf (CH2Cl2/MeOH 20:1): 0.3; H NMR (400 MHz,
CDCl3) δ 11.50 (brs, 1H), 7.95 (d, J = 8.0 Hz, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.47 (dd, J = 6.8,
8.0 Hz, 1H), 7.27-7.22 (m, 1H), 7.11 (d, J = 6.4 Hz, 1H), 6.98 (d, J = 6.8 Hz, 1H), 4.21 (t, J =
6.8 Hz, 2H), 1.98-1.93 (m, 2H), 1.06 (t, J = 6.4 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ
155.9, 139.9, 128.4, 127.7, 126.6, 124.4, 122.3, 121.1, 119.9, 112.7, 101.3, 50.9, 23.1, 11.3;
HRMS(ESI)
calcd
for
C14H15N2O
(M+H)+
227.1179,
found
227.1179.
2-Isopropyl-2,9-dihydro-1H-Pyrido[3,4-b]indol-1-one 3d was synthesized according
to General procedure B from 1d (0.2 mmol, 40.4 mg). The title compound was isolated
as a viscous solid (27.8 mg, 57% yield). Rf (CH2Cl2/MeOH 20:1): 0.3; 1H NMR (400 MHz,
CDCl3) δ 10.98 (brs, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.47 (dd, J =
8.0, 7.2 Hz, 1H), 7.26-7.19 (m, 2H), 7.03 (d, J = 6.8 Hz, 1H), 5.66 (q, J = 6.8 Hz, 1H), 1.51
13
(d, J = 6.8 Hz, 6H); C{1H} NMR (100 MHz, CDCl3) δ 155.5, 139.9, 128.2, 126.5, 123.8,
122.4, 122.1, 121.1, 119.8, 112.7, 101.8, 45.9, 22.4; HRMS(ESI) calcd for C14H15N2O (M+H)+
227.1179, found 227.1178.
Ethyl 3-(1-oxo-1,9-dihydro-2H-pyrido[3,4-b]indol-2-yl)propa- noate 3j was
synthesized according to General procedure B from 1j (0.2 mmol, 52.1 mg). The title
compound was isolated as a viscous solid (28.9 mg, 51% yield). Rf (CH2Cl2/MeOH 20:1):
0.4; 1H NMR (400 MHz, CDCl3) δ 11.42 (brs, 1H), 7.94 (d, J = 7.6 Hz, 1H), 7.67 (d, J = 8.4
Hz, 1H), 7.47 (dd, J = 7.2, 7.2 Hz, 1H), 7.27-7.22 (m, 2H), 6.97 (d, J = 6.8 Hz, 1H), 4.51 (t, J
= 6.4 Hz, 2H), 4.16 (q, J = 7.2 Hz, 2H), 3.01 (t, J = 6.4 Hz, 2H), 1.23 (t, J = 7.2 Hz, 3H);
13C{1H} NMR (100 MHz, CDCl3) δ 171.5, 155.8, 139.9, 128.4, 128.1, 126.8, 124.9, 122.3, 121.1,
120.0, 112.7, 101.5, 60.9, 45.8, 34.0, 14.1; HRMS(ESI) calcd for C16H17N2O3 (M+H)+ 285.1234,
found 285.1236.
6-Methoxy-2-methyl-2,9-dihydro-1H-pyrido[3,4-b]indol-1-one 3m was synthesized
according to General procedure B from 1m (0.2 mmol, 40.5 mg). The title compound
1
was isolated as a viscous solid (32.9 mg, 72% yield). Rf (CH2Cl2/MeOH 20:1): 0.2; H
NMR (400 MHz, DMSO-d6) δ 11.82 (brs, 1H), 7.54 (s, 1H), 7.40 (d, J = 9.2 Hz, 1H), 7.34 (d,
J = 6.8 Hz, 1H), 7.05 (d, J = 9.2 Hz, 1H), 7.00 (d, J = 7.2 Hz, 1H), 3.82 (s, 1H), 3.59 (s, 1H);
13C{1H} NMR (100 MHz, DMSO-d6) δ 155.8, 154.1, 134.8, 129.5, 128.6, 123.7, 122.6, 117.5,
113.8, 102.8, 100.5, 56.0, 36.5; HRMS(ESI) calcd for C13H13N2O2 (M+H)+ 229.0972, found
229.0985.
Ethyl 2-benzyl-1-oxo-2,9-dihydro-1H-pyrido[3,4-b]indole- 6-carboxylate 3n was
synthesized according to General procedure B from 1n (0.2 mmol, 64.4 mg). The title
compound was isolated as a viscous solid (48.4 mg, 70% yield). Rf (CH2Cl2/MeOH 20:1):
0.2; 1H NMR (400 MHz, DMSO-d6) δ 12.46 (brs, 1H), 8.74 (s, 1H), 8.02 (d, J = 8.8 Hz, 1H),
7.63-7.51 (m, 2H), 7.36-7.30 (m, 2H), 7.29-7.21 (m, 2H), 5.31 (s, 2H), 4.34 (q, J = 7.2 Hz,
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2H), 1.35 (t, J = 6.8 Hz, 3H); HRMS(ESI) calcd for C21H19N2O3 (M+H)+ 347.1390, found
347.1382.
6-Chloro-2,9-dihydro-1H-Pyrido[3,4-b]indol-1-one 3o was synthesized according to
General procedure B from 1o (0.2 mmol, 41.7 mg). The title compound was isolated as a
1
viscous solid (31.2 mg, 67% yield). Rf (CH2Cl2/MeOH 20:1): 0.4; H NMR (400 MHz,
DMSO-d6) δ 12.20 (s, 1H), 8.17 (s, 1H), 7.50 (d, J = 8.8 Hz, 1H), 7.44-7.37 (m, 2H), 7.06 (d,
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J = 6.8 Hz, 1H), 3.60 (s, 3H); C{1H} NMR (100 MHz, DMSO-d6) δ 155.7, 138.1, 130.5, 129.2,
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126.8, 124.5, 123.5, 123.4, 121.4, 114.6, 100.3, 36.7; HRMS(ESI) calcd for C12H10ClN2O
(M+H)+ 233.0476, found 233.0485.
2-methyl-3,4-dihydropyrimido[1,6-a]indol-1(2H)-one 7. An oven-dried tube (10 mL)
was charged with the substrate 6 (0.20 mmol, 1.0 equiv.), Pd(OAc)2 (1.1 mg, 0.005
mmol, 2.5 mol%) and Cu(OAc)2 (18.2 mg, 0.1 mmol, 50 mol%). The tube was purged
and backfilled with CO (3 cycles) from a balloon. Anhydrous toluene (2.0 mL) and O2
(3.75 mL, 0.15 mmol, d ≈ 1.29 at room temperature, 75 mol%) were injected into the
tube. After stirring for 15 h at 80 oC, the reaction mixture was cooled and concentrated
under reduced pressure. The residue was purified by column chromatography
(petroleum ether/EtOAc 4:1) to give the pure 7 which was a viscous solid (19.2 mg, 48%
yield). 1H NMR (400 MHz, DMSO-d6) δ 8.36 (d, J = 8.4 Hz, 1H), 7.48 (d, J = 7.6 Hz, 1H),
7.28-7.24 (m, 1H), 7.21-7.17 (m, 2H), 6.28 (s, 1H), 3.54 (t, J = 6.4 Hz, 2H), 3.17 (s, 3H), 3.14
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(t, J = 6.4 Hz, 2H); C{1H} NMR (100 MHz, DMSO-d6) δ 151.7, 135.5, 134.5, 129.2, 123.5,
122.4, 119.8, 115.2, 102.4, 47.1, 35.4, 23.0; IRv (cm-1): 3455, 2925, 1643, 1547, 1310, 1075, 803,
737; HRMS(ESI) calcd for C12H13N2O (M+H)+ 201.1022, found 201.1024.
2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-1-one 8. An oven-dried tube (10
mL) was charged with the substrate 6 (0.20 mmol, 1.0 equiv.), Pd(OAc)2 (1.1 mg, 0.005
mmol, 2.5 mol%) and Cu(OAc)2 (18.2 mg, 0.1 mmol, 50 mol%). The tube was purged
and backfilled with CO (3 cycles) from a balloon. Anhydrous toluene (2.0 mL),
anhydrous acetic acid (35.6 μL, 0.2 mmol, 1.0 equiv.) and O2 (3.75 mL, 0.15 mmol, d ≈
1.29 at room temperature, 75 mol%) were injected into the tube. After stirring for 15 h
o
at 80 C, the reaction mixture was cooled and concentrated under reduced pressure.
The residue was purified by column chromatography (petroleum ether/EtOAc 4:1) to
give the pure 8 which was a viscous solid (22.0 mg, 55% yield). Rf (petroleum
ether/EtOAc 4:1): 0.3; 1H NMR (400 MHz, CDCl3) δ 8.39 (brs, 1H), 7.59 (s, 1H), 7.28 (d, J
= 2.8 Hz, 1H), 7.15 (d, J = 8.4 Hz, 1H), 7.06 (s, 1H), 2.97-2.91 (m, 4H), 2.47 (s, 3H); 13C{1H}
NMR (100 MHz, DMSO-d6) δ 164.8, 143.5, 136.0, 125.4, 121.5, 120.6, 119.6, 111.5, 105.3, 48.1,
33.2, 22.3; HRMS(ESI) calcd for C12H13N2O (M+H)+ 201.1022, found 201.1028.
2-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole 9. An oven-dried Schenk tube
(10 mL) was charged with the substrate 2a (0.10 mmol, 1.0 equiv.). The tube was purged
and backfilled with N2 (3 cycles). Anhydrous THF (1.0 mL) were injected into the tube.
The THF solution (0.5 mL) of LiAlH4 (5.0 mg, 0.13 mmol, 1.3 equiv.) was added into the
o
above obtained residue at 0 C. After stirring for 3 hours at room temperature, the
reaction was quenched by NaOH (1 N, 1.6 mL). The solid particles were filtered and
washed with EtOAc (10.0 mL), then the combined filtrate was concentrated under
reduced pressure. The residue was purified by column chromatography
(CH2Cl2/MeOH 10:1) to give the pure 9 as a light yellow solid (12.4 mg, 67% yield).[38] Rf
(CH2Cl2/MeOH 10:1): 0.3; 1H NMR (400 MHz, CD3OD) δ 7.38 (d, J = 7.6 Hz, 1H), 7.26 (d,
J = 8.0 Hz, 1H), 7.04 (dd, J = 8.0, 7.2 Hz, 1H), 6.97 (dd, J = 8.0, 7.2 Hz, 1H), 3.67 (s, 2H),
13
2.85 (s, 4H), 2.52 (s, 3H); C{1H} NMR (100 MHz, CD3OD) δ 138.0, 132.3, 128.2, 122.0,
119.7, 118.5, 111.8, 107.6, 54.1, 53.2, 45.6, 22.2.
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Supporting Information
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Development of Rh (or Pd)-catalysed aminocarbonylation, mechanistic
experiments and NMR spectra.
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AUTHOR INFORMATION
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Corresponding Author
Ji-Bao Xia: jibaoxia@licp.cas.cn
ORCID
Ji-Bao Xia: 0000-0002-2262-5488
Notes
The authors declare no competing financial interest.ACKNOWLEDGMENTS
We acknowledge financial support from NNSFC (21772208, 21702212), NSFC of
Jiangsu Province (BK20161260), and the Hundred-Talented Program of the
Chinese Academy of Sciences.
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