Direct Biomimetic Synthesis of β-Carboline Alkaloids from Two Amino Acids

Article abstract of DOI:10.1021/acs.joc.8b01668

The increasing importance of enzyme mimics in organic synthesis inspired us to design a novel biomimetic synthesis of β-carboline alkaloids directly from tryptophan and a second amino acid. This novel one-pot protocol utilizes abundant and readily available starting materials and thus presents a green and user-friendly alternative to conventional methods that rely on stepwise synthesis. Driven by molecular iodine and TFA, decarboxylation, deamination, Pictet-Spengler reaction, and oxidation reactions proceeded sequentially, transforming biomass amino acids into value-added alkaloid motifs.

Full text of DOI:10.1021/acs.joc.8b01668

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Direct Biomimetic Synthesis of #-Carboline Alkaloids from Two Amino Acids
Zi-Xuan Wang, Jia-Chen Xiang, Yan Cheng, Jin-Tian Ma, Yan-Dong Wu, and An-Xin Wu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01668 • Publication Date (Web): 22 Aug 2018
Downloaded from http://pubs.acs.org on August 22, 2018
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Direct Biomimetic Synthesis of β-Carboline Alkaloids from
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Two Amino Acids
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Zi-Xuan Wang†, Jia-Chen Xiang†, Yan Cheng, Jin-Tian Ma, Yan-Dong Wu, and
An-Xin Wu*
Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of
Chemistry, Central China Normal University, Wuhan 430079, P. R. China
E-mail: chwuax@mail.ccnu.edu.cn.
TOC Graphic:
Abstract: The increasing importance of enzyme mimics in organic synthesis inspired
us to design a novel biomimetic synthesis of β-carboline alkaloids directly from
tryptophan and a second amino acid. This novel one-pot protocol utilizes abundant
and readily available starting materials and thus presents a green and user-friendly
alternative to conventional methods that rely on stepwise synthesis. Driven by
molecular iodine and TFA, decarboxylation, deamination, Pictet-Spengler reaction
and oxidation reaction proceeded sequentially, transforming biomass amino acids into
value-added alkaloid motifs.
β-carboline motifs belonging to the tricyclic pyrido[3,4-b]indole ring system are
broadly existing in natural products.1 Members of this alkaloid family usually have
diverse substituents at the positions ortho to the N atom.2 Exhibiting antitumor,3
neurotoxin,4 cytotoxic,5 as well as monoamine oxidase inhibitive6 activities, this
alkaloid family has received considerable attention from the synthetic point of view
(Figure 1). Classic methods rely on separate steps for condensation, cyclization, and
aromatization using tryptamine derivatives and aldehydes (Figure 1a).7 Alternatively,
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pre-installed tryptamine based amides were employed and then treated with POCl3 to
afford cyclization products.8 Further aromatizations were accomplished by
stoichiometric DDQ,9 IBX,10 PhI(OAc)211 or other oxidants including expensive metal
catalyst.12 The Banwell group reported an elegant, three-step synthesis involving
cross-coupling, reductive cyclization, and aromatization (Figure 1b).13 Thermal
electrocyclisation of the azahexatriene system was also developed as an alternative
approach to the synthesis of the β-carboline backbone (Figure 1c).14 However, the use
of toxic aldehydes, user-unfriendly reagents (e.g. POCl3, Na) or relative expensive
metal catalysts are not recommended from the angle of ideal synthesis.15 As a result, a
facile synthesis of the β-carboline backbone with green materials, easy operation and
a one-pot protocol is still desired.
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Figure 1. Conventional methods and our design for β-carboline synthesis.
The biosynthesis of β-carboline alkaloids is generally believed to proceed via the
combination of tryptophan with a second amino acid (Figure 2a)16 by a tandem
enzymatic processes.17 Considering that there is no chemical synthesis of β-carboline
using two amino acids, we proposed to set oxidative, acidity, and high temperature
conditions to mimic18-21 the functions of sequential decarboxylases,22 deaminases,23
Pictet-Spenglerase,24 and oxidases (Figure 2b). Herein, we report a synthesis of
β-carbolines from two amino acids with a one-pot, user-friendly protocol.
Figure 2. The biosynthesis and biomimic synthesis hypothesis of β-carboline
from two amino acids.
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Initially, we investigated the reaction between tryptophan (1a) and
phenylglycine (2a) in the presence of a green oxidant, I2, in DMSO, with
representative results shown in Table 1. Since the desired
β-carboline
derivatives could not be obtained in the absence of other additives (entry 1), we
introduced Brønsted acids into the reaction, achieving the best results in the
case of TFA (entries 2–6). Lewis acids could also promote the reaction (entries
7–9), but did not lead to better results. The use of additional oxidants such as
TBHP, PhI(OAc)2, oxone, and DDQ in the presence of TFA resulted in reduced
yields (entries 10–13). Finally, under optimized conditions (120 °C, 1.5 equiv.
I2), 3aa could be isolated in 52% yield.
Table 1. Reaction Optimization.
I2
additive
temp
acid
entry
yieldb (%)
(°C)
(1.0 equiv)
(equiv)
(0.2 equiv)
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2
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.5
0.5
2.0
-
-
110
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120
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120
trace
10
HCl
-
3
TFA
TsOH
TfOH
HI
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6
-
trace
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7
FeCl3
CuBr2
AlCl3
TFA
TFA
TFA
TFA
TFA
TFA
TFA
-
8
21
-
9
42
-
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TBHP
36
PhI(OAc)2
18
oxone
trace
trace
52
DDQ
-
-
-
16
38
aReaction conditions: 1a (0.24 mmol), 2a (0.2 mmol), acid and I2 were added in
solvent (3.0 mL) and stirred for 24 h. Reactions were carried out in a pressure vessel.
bIsolated yields.
With the optimized conditions in hand, we investigated the substrate scope
(Scheme 1), choosing several substituted phenylglycines to react with
tryptophan. Electron-neutral 2b smoothly reacted under the chosen conditions
to afford the corresponding
β-carboline 3ab in 48% yield. Notably, the
sensitive-group-bearing 2-amino-2-(4-hydroxyphenyl)acetic acid afforded 3ac
in 45% yield without requiring protection. Pleasingly, a broad range of
halogenated substrates (2-F, 2-Cl, 2-Br, 4-F, 4-Cl) reacted to afford products
suitable for further functionalization (3ad–3ah, yields of 46–56%). The
reaction was not hindered by the introduction of electron-withdrawing 2-CF3
and 3-CF3 groups (3ai, 44%; 3aj, 52%), whereas the use of aliphatic amino
acids resulted in poor yields. For example, glycine afforded 3ak norharman (a
potent tremor-producing neurotoxin) in 20% yield, whereas valine cannot
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furnish 3al. The reactions of 2-aminobutanoic acid and leucine also proceeded
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in low yields (17 and 16%, respectively).
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Scheme 1. Scope of amino acids.
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Reaction conditions:
mmol) were added in DMSO (3.0 mL) and stirred at 120 C for 24 h.
Reactions were carried out in a pressure vessel. Isolated yields.
1 (0.24 mmol), 2 (0.2 mmol), TFA (0.2 mmol) and I2 (0.3
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Thus, compared to the reaction of amino acids bearing a strongly
electron-withdrawing aromatic ring, those of aliphatic amino acids exhibited lower
reactivity in the Pictet-Spengler reaction step. Subsequently, we explored the scope of
tryptophan modification. A common tryptophan analogue, 5-OH-tryptophan, afforded
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3ba in 46% yield, and 5-Cl-tryptophan was also tolerated under the reaction
conditions (3ca, 39%). Electron-rich 5-OMe-tryptophan furnished 3da in 43% yield,
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and
1-methyltryptophan
afforded
3ea
in
51%
yield.
Using
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1-(tert-butoxycarbonyl)tryptophan as starting material, the desired product could not
be obtained. Instead of that, the N-Boc cleavage product 3aa was isolated (46%). The
reaction of tryptophan methyl ester hydrochloride resulted in the formation of 3fa
(50%), indicating that esterification of the carboxyl group in tryptophan blocked
decarboxylation but did not hinder other reactions in the sequence. Unfortunately, an
attempt to replace tryptophan with histidine was unsuccessful.
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Further mechanistic insights were obtained by performing a series of
control experiments (Scheme 2). Under “standard conditions”, 2a afforded the
expected benzaldehyde
conditions, 1a was not converted into the corresponding aldehyde
dimerization product , affording a complex mixture of unrecognized products
(entry 2). This behavior was ascribed to the sensitivity of the indole-containing
backbone of to oxidizing conditions in the absence of . The catabolism of
the second amino acid has priority to take place in present of I2 in this
conversion. Treatment of 1a with afforded the desired 3aa in 65% yield,
confirming that is a key intermediate (entry 3). According to literature, the
reaction of 1a with in AcOH affords cyclic product
.25 Under our standard
conditions, afforded 3aa in almost quantitative yield, thus being possibly
4
in 83% yield (entry 1). However, under the same
5
or
6
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2
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4
M
M
formed as an intermediate in our synthetic sequence (entry 4). Next, we
investigated the effect of carboxyl groups in the substrate on the reaction
outcome (entry 5). The combination of tryptamine with phenylglycine
furnished product 3aa in only 35% yield, with an even lower yield of 14%
observed for tryptophan/benzylamine. Finally, no reaction was observed for the
tryptamine/benzylamine combination, demonstrating that the presence of
carboxyl as pre-existing functional groups in both substrates have critical for
reactivity and indicating that the above conversion is promoted by
decarboxylative oxidation26 of amino acids.
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Scheme 2. Control Experiments.
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Based on our experimental results and previous reports,26 we offer a
putative mechanism (Scheme 3) featuring I2-triggered decarboxylative
oxidation leading to the formation of an imine intermediate. Under acidic
conditions, the above intermediate is hydrolyzed to the corresponding aldehyde,
with the sum of these steps operating as a formal oxidative deamination of
amino acids. Subsequently, the aldehyde is trapped by tryptophan via the
Pictet-Spengler reaction to afford a cyclic intermediate, with the following
I2-mediated NH-oxidation and decarboxylative oxidation (occurring via α-NH
elimination and
and affording
β
-CH elimination, respectively) facilitating C-ring desaturation
β-carboline alkaloids. HI, produced as a by-product of the
oxidation reaction, can be recycled back to I2 utilizing DMSO.27
Scheme 3. Mechanistic Proposal.
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Conclusion
In conclusion, we described a straightforward synthesis of
β-carboline
alkaloids from two amino acids enzyme-mimetically. Since amino acids are
easily available biomass material, this metal-free transformation is of high
significance28 due to its green and user-friendly nature. Compared to the
traditional two step synthesis, it holds advantages in pot-economy, avoiding the
use of toxic aldehydes and offering advances in concept. Moreover, the
preparation of β-carboline motifs in a biomimetic way supports the hypothetical
biogenetic origin of alkaloids belonging to the β-carboline family.
Experimental Section
General Methods.
Unless otherwise stated, all starting materials and catalysts were obtained from
commercial suppliers and used without further purification. All new compounds were
fully characterized. TLC analysis was performed using precoated glass plates.
Column chromatography was performed using silica gel (200–300 mesh). IR spectra
were recorded as KBr pellets with absorption in cm–1. 1H NMR spectra were recorded
in CDCl3 on 600 MHz spectrometers and resonances (δ) are given in ppm relative to
TMS (internal standard). 13C NMR spectra were recorded in CDCl3 or DMSO-d6 on
100/150 MHz NMR spectrometers. HRMS were obtained on a 7.0T FTMS equipped
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with ESI. The mass analyzer type used for HRMS measurement is TOF. Melting
points were determined using an electrothermal capillary melting point apparatus and
not corrected.
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General procedure for the synthesis
ꢀ
for 3 (3aa as an example)
A mixture of tryptophan 1a (0.24 mmol), phenylglycine 2a (0.2 mmol), TFA (0.2
mmol), I2 (0.3 mmol) and DMSO (3.0 mL) were added in a pressure vessel, then
o
stirred at 120 C for 24 h. Then added 50 mL water and 30 mL saturated brine
solution to the mixture and extracted with EtOAc 3 times (3 × 50 mL). The extract
was washed with 10% Na2S2O3 solution, dried over anhydrous Na2SO4 and
concentrated under reduced pressure. The crude product was purified by column
chromatography (eluent: petroleum ether /EtOAc=3/1) to afford the product 3aa as
yellow solid.
ꢀ
for 2-amino-3-(1-benzyl-1H-indol-3-yl)propanoic acid ( N-Bn tryptophan).
2-amino-3-(1-benzyl-1H-indol-3-yl)propanoic acid (N-Bn tryptophan) was
synthesized according to a previously known procedure. [29]
Analytical Data for target compound
1-phenyl-9H-pyrido[3,4-b]indole (3aa): yield 52% (25.4 mg), compound 3aa was
reported previously;[30] yellow solid, mp = 240–242 °C; IR (KBr) νmax: 2361, 1623,
1559, 1494, 1456, 1416, 1321, 1276, 1233, 736 cm−1; 1H NMR (600 MHz, DMSO-d6)
δ 11.54 (s, 1H), 8.46 (d, J = 4.8 Hz, 1H), 8.26 (d, J = 7.8 Hz, 1H), 8.11 (d, J = 4.8 Hz,
1H), 8.08–7.97 (m, 2H), 7.66 (d, J = 8.4 Hz, 1H), 7.61 (t, J = 7.8 Hz, 2H), 7.54 (dt, J
= 14.8, 7.8 Hz, 2H), 7.26 (t, J = 7.2 Hz, 1H).13C NMR (150 MHz, DMSO-d6) δ 142.2,
141.1, 138.4, 133.0, 129.2, 128.8, 128.6, 128.4, 128.2, 121.6, 120.9, 119.6, 113.9,
112.5. HRMS (ESI): m/z [M+H]+ calcd for C17H13N2: 245.1073; found: 245.1095.
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1-(p-tolyl)-9H-pyrido[3,4-b]indole (3ab): yield 48% (24.8 mg), compound 3ab was
reported previously;[31] yellow solid; mp = 195–198 °C; IR (KBr) νmax: 1624, 1562,
1496, 1320, 1278, 820, 740 cm−1; 1H NMR (600 MHz, CDCl3) δ 9.06 (s, 1H), 8.49 (d,
J = 4.8 Hz, 1H), 8.12 (d, J = 7.8 Hz, 1H), 7.88 (d, J = 4.8 Hz, 1H), 7.78 (d, J = 7.8 Hz,
2H), 7.49 (t, J = 7.8 Hz, 1H), 7.43 (d, J = 8.4 Hz, 1H), 7.28–7.25 (m, 3H), 2.35 (s,
3H). 13C NMR (150 MHz, CDCl3) δ 143.0, 140.4, 139.0, 138.6, 135.4, 133.4, 129.7,
128.3, 127.9, 121.7, 121.6, 120.0, 113.5, 111.5, 21.3. HRMS (ESI): m/z [M+H]+ calcd
for C18H15N2: 259.1230; found: 259.1229.
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4-(9H-pyrido[3,4-b]indol-1-yl)phenol (3ac): yield 45% (23.4 mg), yellow solid; mp =
291–294 °C; IR (KBr) νmax: 1627, 1611, 1565, 1516, 1497, 1454, 1321, 1262, 1261,
1097, 1023, 842, 802, 748 cm−1; 1H NMR (600 MHz, DMSO-d6) δ 11.43 (s, 1H), 9.80
(s, 1H), 8.39 (d, J = 4.8 Hz, 1H), 8.23 (d, J = 7.2 Hz, 1H), 8.03 (d, J = 4.8 Hz, 1H),
7.89 (d, J = 8.1 Hz, 2H), 7.65 (d, J = 7.8 Hz, 1H), 7.53 (t, J = 7.2 Hz, 1H), 7.24 (t, J =
7.2 Hz, 1H), 7.00 (d, J = 8.4 Hz, 2H). 13C NMR (100 MHz, DMSO-d6) δ 157.7, 142.3,
140.8, 137.9, 132.4, 129.5, 129.0, 128.7, 127.8, 121.3, 120.7, 119.3, 115.4, 112.9,
112.3. HRMS (ESI): m/z [M+H] + calcd for C17H13N2O: 261.1022; found: 261.1023.
1-(2-fluorophenyl)-9H-pyrido[3,4-b]indole (3ad): yield 52% (27.2 mg), yellow solid;
mp = 197–201 °C; IR (KBr) νmax: 1625, 1599, 1501, 1423, 1323, 1234, 832, 763, 740,
619 cm−1; 1H NMR (600 MHz, DMSO-d6) δ 11.44 (s, 1H), 8.48 (d, J = 5.4 Hz, 1H),
8.27 (d, J = 7.8 Hz, 1H), 8.18 (d, J = 5.4 Hz, 1H), 7.76 (t, J = 7.8 Hz, 1H), 7.62–7.57
(m, 3H), 7.47–7.39 (m, 2H), 7.26 (t, J = 7.2 Hz, 1H). 13C NMR (100 MHz, DMSO-d6)
δ 160.7, 158.2, 140.7, 138.0, 137.9, 133.9, 131.6, 130.6, 130.5, 128.3, 128.2, 125.9,
125.8, 124.6, 121.6, 120.4, 119.3, 116.1, 115.9, 114.3, 112.0. HRMS (ESI): m/z
[M+H]+ calcd for C17H12FN2: 263.0979; found: 263.0983.
1-(2-chlorophenyl)-9H-pyrido[3,4-b]indole (3ae): yield 56% (31.1 mg), brown solid;
mp = 198–201 °C; IR (KBr) νmax: 1626, 1564, 1498, 1454, 1434, 1321, 1235, 744,
619 cm−1; 1H NMR (600 MHz, CDCl3) δ 8.54 (d, J = 5.4 Hz, 1H), 8.49 (s, 1H), 8.16
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(d, J = 7.8 Hz, 1H), 8.00 (d, J = 5.4 Hz, 1H), 7.61–7.56 (m, 1H), 7.54–7.51 (m, J =
7.2 Hz, 2H), 7.43 (d, J = 8.4 Hz, 1H), 7.41-7.40 (m, 2H), 7.30 (t, J = 7.8 Hz, 1H). 13C
NMR (150 MHz, DMSO-d6) δ 141.3, 141.0, 137.8, 137.2, 133.9, 132.5, 131.9, 130.3,
129.8, 128.3, 127.4, 121.8, 120.7, 119.5, 114.5, 112.2. HRMS (ESI): m/z [M+H]+
calcd for C17H12ClN2: 279.0684; found: 279.0685.
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1-(2-bromophenyl)-9H-pyrido[3,4-b]indole (3af): yield 47% (30.3 mg), yellow oil; IR
(KBr) νmax: 1626, 1600, 1563, 1498, 1454, 1321, 1236, 1018, 827, 744, 619 cm−1; 1H
NMR (600 MHz, DMSO-d6) δ 11.32 (s, 1H), 8.42 (d, J = 5.4 Hz, 1H), 8.27 (d, J = 7.8
Hz, 1H), 8.17 (d, J = 5.4 Hz, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.63–7.51 (m, 4H), 7.51–
7.46 (m, 1H), 7.30–7.21 (m, 1H). 13C NMR (150 MHz, DMSO-d6) δ 142.9, 140.9,
139.1, 137.7, 133.6, 132.8, 131.8, 130.4, 128.2, 127.9, 122.6, 121.8, 120.7, 119.4,
114.5, 112.2. HRMS (ESI): m/z [M+H]+ calcd for C17H12BrN2: 323.0178; found:
323.0175.
1-(4-fluorophenyl)-9H-pyrido[3,4-b]indole (3ag): yield 46% (24.1 mg), compound
3ag was reported previously;[32] yellow solid; mp = 202–205 °C; IR (KBr) νmax: 1625,
1606, 1511, 1497, 1469, 1453, 1404, 1233, 846, 821, 737 cm−1; 1H NMR (600 MHz,
CDCl3) δ 8.82 (s, 1H), 8.53 (d, J = 5.4 Hz, 1H), 8.16 (d, J = 7.8 Hz, 1H), 7.94 (d, J =
5.4 Hz, 1H), 7.92–7.88 (m, 2H), 7.55 (t, J = 7.8 Hz, 1H), 7.49 (d, J = 8.4 Hz, 1H),
7.31 (t, J = 7.2 Hz, 1H), 7.19 (t, J = 8.4 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ
161.6, 141.7, 140.3, 139.1, 134.3, 133.2, 129.8, 129.7, 128.5, 121.7, 120.3, 116.1,
115.9, 113.8, 111.5. HRMS (ESI): m/z [M+H]+ calcd for C17H12FN2: 263.0979; found:
263.0979.
1-(4-chlorophenyl)-9H-pyrido[3,4-b]indole (3ah): yield 48% (26.7 mg), white solid;
mp = 207–209 °C; IR (KBr) νmax: 1626, 1495, 1470, 1455, 1423, 1321, 1233, 1089,
1012, 830, 743 cm−1; 1H NMR (600 MHz, CDCl3) δ 9.15 (s, 1H), 8.51 (s, 1H), 8.14 (d,
J = 7.2 Hz, 1H), 7.93 (s, 1H), 7.79 (s, 2H), 7.52 (t, J = 7.2 Hz, 1H), 7.47–7.45 (m, 1H),
7.36 (s, 2H), 7.30 (t, J = 7.2 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 141.6, 140.4,
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139.5, 136.9, 134.8, 133.4, 130.1, 129.4, 129.3, 128.7, 121.8, 120.4, 114.1, 111.6.
HRMS (ESI): m/z [M+H]+ calcd for C17H12ClN2: 279.0684; found: 279.0688.
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1-(2-(trifluoromethyl)phenyl)-9H-pyrido[3,4-b]indole (3ai): yield 44% (27.5 mg),
yellow solid; mp = 52–55 °C; IR (KBr) νmax: 2361, 1627, 1561, 1502, 1455, 1316,
1170, 1114, 751 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.50 (d, J = 5.2 Hz, 1H), 8.21 (s,
1H), 8.16 (d, J = 7.6 Hz, 1H), 7.99 (d, J = 5.2 Hz, 1H), 7.86 (d, J = 7.6 Hz, 1H), 7.59–
7.65 (m, 2H), 7.51–7.55 (m, 2H), 7.39 (d, J = 8.0 Hz, 1H), 7.30 (t, J = 7.6 Hz, 1H).
13C NMR (100 MHz, CDCl3) δ 141.4, 140.4, 138.6, 136.3, 134.2, 132.0, 131.4, 129.6,
129.4, 129.1, 128.6, 127.0, 126.9, 125.2, 122.5, 121.9, 121.6, 120.3, 114.4, 111.5.
HRMS (ESI): m/z [M+H]+ calcd for C18H12F3N2: 313.0947; found: 313.0951.
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1-(3-(trifluoromethyl)phenyl)-9H-pyrido[3,4-b]indole (3aj): yield 52% (32.4 mg),
yellow solid; mp = 137–140 °C; IR (KBr) νmax: 2360, 1626, 1338, 1164, 1126, 745
cm−1; 1H NMR (400 MHz, CDCl3) δ 9.28 (s, 1H), 8.51 (d, J = 5.2 Hz, 1H), 8.11 (d, J
= 4.0 Hz, 2H), 7.97 (d, J = 7.6 Hz, 1H), 7.93 (d, J = 5.2 Hz, 1H), 7.56 (d, J = 7.6 Hz,
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1H), 7.53–7.44 (m, 2H), 7.41 (d, J = 8.4 Hz, 1H), 7.28 (t, J = 7.6 Hz, 1H). C NMR
(100 MHz, CDCl3) δ 141.1, 140.7, 139.2, 139.0, 133.5, 131.5, 131.2, 131.1, 130.4,
129.3, 128.7, 125.3, 125.2, 125.0, 124.9, 122.5, 121.7, 121.6, 120.4, 114.4, 111.7.
HRMS (ESI): m/z [M+H]+ calcd for C18H12F3N2: 313.0947; found: 313.0969.
9H-pyrido[3,4-b]indole (3ak): yield 20% (6.7 mg), yellow solid; mp = 171–172 °C;
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IR (KBr) νmax: 1626, 1561, 1499, 1448, 1331, 1284, 1243, 1034, 733, 600 cm−1; H
NMR (600 MHz, CDCl3) δ 9.82 (s, 1H), 8.96 (s, 1H), 8.46 (d, J = 4.8 Hz, 1H), 8.13 (d,
J = 7.8 Hz, 1H), 7.97 (d, J = 4.8 Hz, 1H), 7.54 (s, 2H), 7.29 (s, 1H). 13C NMR (150
MHz, CDCl3) δ 140.8, 138.2, 136.1, 133.3, 129.1, 128.6, 121.7, 121.2, 120.0, 114.9,
111.7. HRMS (ESI): m/z [M+H]+ calcd for C11H9N2:169.0760; found: 169.0759.
1-ethyl-9H-pyrido[3,4-b]indole (3am): yield 17% (6.7 mg), compound 3am was
reported previously;[33] yellow solid; mp = 198–201 °C; IR (KBr) νmax: 1625, 1565,
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1503, 1455, 1429, 1324, 1242, 1230, 1023, 821, 802, 742 cm−1; 1H NMR (600 MHz,
CDCl3) δ 9.96 (s, 1H), 8.42 (d, J = 4.2 Hz, 1H), 8.13 (d, J = 7.8 Hz, 1H), 7.86 (d, J =
4.2 Hz, 1H), 7.50-7.48 (m, 2H), 7.27 (t, J = 6.6 Hz, 1H), 3.18 (d, J = 7.8 Hz, 2H),
1.43 (t, J = 7.2 Hz, 3H). 13C NMR (150 MHz, CDCl3) δ 146.9, 140.5, 138.1, 134.1,
128.6, 128.1, 121.8, 121.7, 119.8, 113.0, 111.6, 27.3, 12.9. HRMS (ESI): m/z [M+H]+
calcd for C13H13N2:197.1073; found: 197.1074.
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1-isobutyl-9H-pyrido[3,4-b]indole (3an): yield 16% (7.2 mg), yellow solid; mp =
162–164 °C; IR (KBr) νmax: 1625, 1565, 1505, 1454, 1426, 1322, 1245, 746 cm−1; 1H
NMR (600 MHz, CDCl3) δ 8.90 (s, 1H), 8.41 (d, J = 4.8 Hz, 1H), 8.13 (d, J = 7.8 Hz,
1H), 7.84 (d, J = 4.8 Hz, 1H), 7.54 (s, 2H), 7.29 (s, 1H), 3.02 (d, J = 7.2 Hz, 2H),
2.40–2.32 (m, 1H), 0.98 (d, J = 6.6 Hz, 6H). 13C NMR (150 MHz, CDCl3) δ 145.1,
140.2, 134.6, 128.7, 128.3, 121.9, 121.8, 120.0, 112.8, 111.6, 43.2, 28.8, 22.8. HRMS
(ESI): m/z [M+H]+ calcd for C15H17N2:225.1386; found: 225.1389.
1-(furan-2-yl)-9H-pyrido[3,4-b]indole (3ao): yield 46% (21.5 mg), compound 3ao
was reported previously;[34] yellow solid; mp = 79–81 °C; IR (KBr) νmax: 1653, 1627,
1574, 1559, 1496, 1456, 1427, 1380, 1322, 1006, 830, 742 cm−1; 1H NMR (600 MHz,
CDCl3) δ 9.48 (s, 1H), 8.47–8.41 (m, 1H), 8.11 (d, J = 7.8 Hz, 1H), 7.85 (s, 1H), 7.67
(s, 1H), 7.56 (s, 2H), 7.35–7.27 (m, 2H), 6.63 (s, 1H). 13C NMR (150 MHz, CDCl3) δ
154.3, 142.7, 140.4, 138.7, 133.3, 131.2, 130.2, 128.6, 121.6, 121.2, 120.1, 113.6,
112.3, 111.6, 108.7. HRMS (ESI): m/z [M+H]+ calcd for C15H11N2O:235.0866; found:
235.0863.
1-phenyl-9H-pyrido[3,4-b]indol-6-ol (3ba): yield 46% (23.9 mg), yellow solid; mp =
1
115–116 °C; IR (KBr) νmax: 3445, 2361, 1650, 1559 cm−1; H NMR (400 MHz,
DMSO-d6) δ 11.22 (s, 1H), 9.23 (s, 1H), 8.39 (d, J = 5.2 Hz, 1H), 8.07–8.02 (m, 2H),
8.00 (d, J = 5.2 Hz, 1H), 7.61–7.57 (m, 3H), 7.51–7.46 (m, 2H), 7.13–7.10 (m, 1H).
13C NMR (100 MHz, DMSO-d6) δ 151.1, 142.1, 138.6, 137.6, 135.3, 133.7, 128.9,
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128.7, 128.4, 128.3, 121.5, 118.4, 113.9, 113.1, 105.5. HRMS (ESI): m/z [M+H]+
calcd for C17H13N2O:261.1022; found: 261.1022.
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6-chloro-1-phenyl-9H-pyrido[3,4-b]indole (3ca): yield 39% (21.7 mg), yellow solid;
mp = 121–123 °C; IR (KBr) νmax: 2928, 2857, 2360, 1624, 1561, 1448, 1272, 1264,
1066, 761, 696, 611 cm−1; 1H NMR (600 MHz, CDCl3) δ 9.29 (s, 1H), 8.47 (d, J = 4.8
Hz, 1H), 8.05 (s, 1H), 7.84–7.80 (m, 3H), 7.41 (d, J = 6.0 Hz, 3H), 7.36 (d, J = 7.2 Hz,
1H), 7.29 (d, J = 8.4 Hz, 1H). 13C NMR (150 MHz, CDCl3) δ 143.3, 139.3, 138.7,
138.0, 134.0, 129.0, 128.8, 128.6, 128.0, 125.5, 122.8, 121.2, 113.7, 112.6. HRMS
(ESI): m/z [M+H]+ calcd for C17H12ClN2:279.0684; found: 279.0687.
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6-methoxy-1-phenyl-9H-pyrido[3,4-b]indole (3da): yield 43% (23.6 mg), compound
3da was reported previously;[32] yellow solid; mp = 193–196 °C; IR (KBr) νmax: 1631,
1561, 1495, 1470, 1435, 1285, 1214, 1036, 816, 758, 693 cm−1; 1H NMR (400 MHz,
CDCl3) δ 8.50 (d, J = 4.8 Hz, 1H), 8.45 (s, 1H), 7.92 (d, J = 7.2 Hz, 2H), 7.85 (d, J =
4.8 Hz, 1H), 7.58–7.49 (m, 3H), 7.43–7.45 (m, 1H), 7.36 (d, J = 8.8 Hz, 1H), 7.17 (d,
J = 8.8 Hz, 1H), 3.93 (s, 3H). 13C NMR (150 MHz, DMSO-d6) δ 153.8, 141.2, 136.7,
136.0, 133.3, 129.9, 129.1, 128.9, 128.6, 120.9, 119.2, 114.4, 113.5, 103.4, 55.6.
HRMS (ESI): m/z [M+H]+ calcd for C18H15N2O:275.1179; found: 275.1198.
9-methyl-1-phenyl-9H-pyrido[3,4-b]indole (3ea): yield 51% (26.3 mg), black solid;
mp = 95–97 °C; IR (KBr) νmax: 1619, 1446, 1401, 1228, 1049, 1033, 1018, 787, 701,
617 cm−1; 1H NMR (600 MHz, CDCl3) δ 8.52 (d, J = 5.4 Hz, 1H), 8.16 (d, J = 7.8 Hz,
1H), 7.95 (d, J = 5.4 Hz, 1H), 7.63 (d, J = 7.8 Hz, 2H), 7.59 (t, J = 7.8 Hz, 1H), 7.52–
7.46 (m, 3H), 7.40 (d, J = 8.4 Hz, 1H), 7.30 (t, J = 7.2 Hz, 1H), 3.44 (s, 3H). 13C
NMR (150 MHz, CDCl3) δ 144.1, 142.8, 139.8, 138.3, 134.9, 130.0, 129.5, 128.4,
128.3, 128.1, 121.4, 121.1, 119.8, 113.5, 109.7, 32.9. HRMS (ESI): m/z [M+H]+ calcd
for C18H15N2:259.1230; found: 259.1237.
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9-benzyl-1-phenyl-9H-pyrido[3,4-b]indole (3fa): yield 12% (8.0 mg), white solid; mp
= 145–147 °C; IR (KBr) νmax: 1618, 1555, 1491, 1443, 1406, 1345, 1312, 1283, 1199,
997, 785, 743, 696 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.54 (d, J = 5.2 Hz, 1H), 8.20
(d, J = 8.0 Hz, 1H), 8.01 (d, J = 5.2 Hz, 1H), 7.54–7.47 (m, 1H), 7.40–7.33 (m, 3H),
7.32–7.24 (m, 4H), 7.13–7.03 (m, 3H), 6.55 (d, J = 7.2 Hz, 2H), 5.19 (s, 2H). 13C
NMR (100 MHz, CDCl3) δ 144.3, 142.6, 139.2, 138.4, 136.8, 134.3, 130.6, 129.2,
128.6, 128.3, 127.9, 127.0, 125.6, 121.5, 121.3, 120.2, 113.6, 110.5, 48.0. HRMS
(ESI): m/z [M+H]+ calcd for C24H19N2:335.15428; found: 335.15448.
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methyl 1-phenyl-9H-pyrido[3,4-b]indole-3-carboxylate (3ga): yield 50% (30.2 mg),
compound 3ga was reported previously;[35] yellow solid; mp = 255–258 °C; IR (KBr)
ν
max: 1720, 1638, 1627, 1561, 1498, 1458, 1437, 1252, 1100, 1046, 1025 cm−1; 1H
NMR (400 MHz, DMSO-d6) δ 11.89 (s, 1H), 8.90 (s, 1H), 8.40 (d, J = 7.2 Hz, 1H),
8.00 (d, J = 6.6 Hz, 2H), 7.73–7.49 (m, 5H), 7.31 (s, 1H), 3.93 (s, 3H). 13C NMR (100
MHz, DMSO-d6) δ 166.1, 142.1, 141.5, 137.5, 136.7, 134.6, 129.2, 129.0, 128.8,
128.7, 128.6, 122.0, 121.1, 120.4, 116.7, 112.8, 52.1. HRMS (ESI): m/z [M+H]+ calcd
for C19H15N2O2:303.1128; found: 303.1138.
ASSOCIATED CONTENT
Supporting Information
1
Crystallographic data and copies of the H and 13C NMR spectra are involved. This
material is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: chwuax@mail.ccnu.edu.cn.
Author Contributions
† Zi-Xuan Wang and Jia-Chen Xiang contributed equally.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
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We are grateful to the National Natural Science Foundation of China
(Grant 21472056, 21602070 and 21772051) and the Fundamental Research
Funds for the Central Universities (CCNU15ZX002 and CCNU16A05002) for
financial support. It was also supported by the 111 Project B17019. We
acknowledge an Excellent Doctoral Dissertation Cultivation Grant from Central
China Normal University (2017YBZZ022).
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