Organic base-promoted efficient dehydrogenative/decarboxylative aromatization of tetrahydro-β-carbolines into β-carbolines under air

Article abstract of DOI:10.1016/j.tetlet.2019.02.020

Organic base DBN has been identified as an efficient reagent for promoting the dehydrogenative/decarboxylative aromatization of tetrahydro-β-carbolines under air atmosphere, to access the corresponding β-carbolines in moderate to good yields. The utility of this protocol for the gram-scale synthesis of β-carboline alkaloids eudistomin U (7) and harmane (10) has also been demonstrated.

Full text of DOI:10.1016/j.tetlet.2019.02.020

Accepted Manuscript
Organic base-promoted efficient dehydrogenative/decarboxylative aromatiza-
tion of tetrahydro-β-carbolines into β-carbolines under air
Ziquan Zhao, Yan Sun, Lilin Wang, Xuan Chen, Yanpei Sun, Long Lin, Yulin
Tang, Fei Li, Dongyin Chen
PII:
S0040-4039(19)30141-8
https://doi.org/10.1016/j.tetlet.2019.02.020
TETL 50614
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
31 December 2018
1 February 2019
8 February 2019
Please cite this article as: Zhao, Z., Sun, Y., Wang, L., Chen, X., Sun, Y., Lin, L., Tang, Y., Li, F., Chen, D., Organic
base-promoted efficient dehydrogenative/decarboxylative aromatization of tetrahydro-β-carbolines into β-
carbolines under air, Tetrahedron Letters (2019), doi: https://doi.org/10.1016/j.tetlet.2019.02.020
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Ziquan Zhao, Yan Sun, Lilin Wang, Xuan Chen, Yanpei Sun, Long Lin, Yulin Tang, * Fei Li, * Dongyin Chen*

1
Tetrahedron Letters
Organic base-promoted efficient dehydrogenative/decarboxylative aromatization of
tetrahydro-β-carbolines into β-carbolines under air
Ziquan Zhao a, Yan Sun a, Lilin Wang b, Xuan Chen a, Yanpei Sun a, Long Lin a, Yulin Tang b,c,*, Fei Li a,*
and Dongyin Chen a,
a Department of Medicinal Chemistry, School of Pharmacy, Nanjing Medical University, Nanjing 211166, People’s Republic of China
b Department of Pharmacy, Sir Run Run Hospital, Nanjing Medical University, Nanjing 211166, People’s Republic of China
c Department of Pharmacy, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, People’s Republic of China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Organic base DBN has been identified as an efficient reagent for promoting the
dehydrogenative/decarboxylative aromatization of tetrahydro-β-carbolines under air atmosphere, to
access the corresponding β-carbolines in moderate to good yields. The utility of this protocol for
the gram-scale synthesis of β-carboline alkaloids eudistomin U (7) and harmane (10) has also been
demonstrated.
Available online
2018 Elsevier Ltd. All rights reserved.
Keywords:
β-Carboline
Dehydrogenation
Decarboxylation
Aromatization
19
20
sulfur, 2-iodoxybenzoic acid (IBX), (diacetoxyiodo)benzene
(PhI(OAc)2), chloranil 18 or dichlorodicianoquinone (DDQ).
Other reagents like trichloroisocyanuric acid (TCCA) and N-
bromosuccinimide (NBS) have also been found effective in
21
22
The β-carboline skeleton is one of the most intriguing indole-
23
based heterocycles, its basic ring system being found in many
1
24
natural products and pharmaceutical drugs.
β-Carboline
derivatives have long been known to exhibit excellent antitumor,
promoting dehydrogenative aromatization of tetrahydro-β-
carboline. Beyond that, few alternative strategies to access
2
3
4
5
antiparasitic,
antibacterial, and antiviral activities.
In
addition, some β-carboline derivatives are potential candidates
for the treatment of neurodegenerative disorders such as
Alzheimer's and Parkinson's disease, due to their inhibition of
acetylcholinesterase 6 and human monoamine oxidase. 7
aromatic β-carbolines involved elimination of N-tosyltetrahydro-
25
β-carbolines by strong bases,
gold (III)-catalyzed
26
cycloisomerization
and palladium (II)-catalyzed direct-
27
dehydrogenative annulation. Despite these fruitful efforts for
the synthesis of β-carbolines, some of the reported methods
suffer from certain drawbacks such as strong oxidants, toxic
transition metal reagents, multi-step starting materials, etc..
Therefore, simple and efficient reaction conditions with
inexpensive and commercially available reagents for the
synthesis of β-carbolines are of considerable challenge.
In view of their important pharmacological properties, a
number of synthetic methods have been developed to access
8
these β-carboline derivatives. The classical approach involves
the Pictet-Spengler reaction between a tryptamine derivative and
an aldehyde to generate the tetrahydro-β-carboline precursor,
followed by decarboxylative/dehydrogenative aromatization to
yield the corresponding β-carboline (Scheme 1). The traditional
decarboxylative aromatization of tetrahydro-β-carboline are
carried out at high temperatures with reagents like potassium
9
10
dichromate (K2Cr2O7), selenium dioxide (SeO2),
persulfate
with catalytic silver (Ag+/S2O8
)
11 or copper chloride (CuCl2). 12
2-
Recently, transformations of this type have been achieved by
employing N-chlorosuccinimide in the presence of
13
trimethylamine (NCS/TEA) or iodine in presence of hydrogen
14
peroxide (I2/H2O2).
Another strategy to construct the β-
carboline moiety is dehydrogenative aromatization of a suitable
tetrahydro-β-carboline unit; these reactions are generally
mediated by stoichiometric oxidants, such as potassium
15
16
18
permanganate (KMnO4),
manganese dioxide (MnO2),
Scheme 1. Literature reports and the present work for synthesis
of β-carbolines from tetrahydro-β-carbolines.
17
palladium on carbon (Pd/C), lead tetraacetate (Pb(OAc)4),
———
 Corresponding author. E-mail: chendongyin@njmu.edu.cn (D. Chen), kldlf@njmu.edu.cn (F. Li), YLT1964@sina.com (Y. Tang).

2
Tetrahedron
9-11, 14-16, 20-22, 25
According to the reported methods,
the
conversion of tetrahydro-β-carbolines into their corresponding β-
carbolines was generally accomplished under the basic or
oxidizing reaction condition. On the other hand, simple oxygen,
especially air, as the terminal oxidant is always the ultimate goal
of oxidation reaction, because it is readily available and
environmentally friendly. Based on above idea, a new “smart”
strategy of basic solvent-promoted aromatization of tetrahydro-β-
carbolines under air atmosphere should provide a greener and
more practical approach for the preparation of β-carboline
derivatives. Hence, we describe an efficient organic base-
promoted dehydrogenative/decarboxylative aromatization for the
conversion of tetrahydro-β-carbolines into β-carbolines that
utilizes air as a terminal oxidant (Scheme 1). In addition, this
method has been successfully applied for the gram-scale
synthesis of natural β-carboline alkaloids such as eudistomin U
(7) and harmane (10) in moderate yields.
Entry
1
Base/Atm
TEA/air
T (oC)
90
Additive
Yield (%) b
/
trace
7
2
DIPEA/air
TMEDA/air
NMPRZ/air
NMM/air
DBU/air
DBN/air
DBU/air
DBN/air
DBN/air
DBN/air
DBN/O2
DBN/air
DBN/air
DBN/air
DBN/N2
130
125
140
120
100
100
110
110
120
90
/
3
/
4
4
/
6
5
/
7
6
/
33
46
39
78
77
trace
78
75
74
75
trace
7
/
8
/
9
/
10
11
12
13 c
14 d
15 e
/
In the beginning of our research, tetrahydro-β-carboline 1a
was chosen as the model substrate (Table 1). Initially, as a test
reaction, the effect of various organic bases on 1a was
investigated under air atmosphere from room temperature to
reflux temperature. To our surprise, we obtained β-carboline 2a
in 46% yield when 1a was treated with 1,5-
diazabicyclo[4.3.0]non-5-ene (DBN) for 12 h at 100 °C under air
(Table 1, entry 7). 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU)
was another efficient organic base to afford 33% yield of 2a after
refluxing for 12 h (Table 1, entry 6). Other basic solvents such as
triethylamine (TEA), N,N-diisopropylethylamine (DIPEA),
N,N,N',N'-tetramethylethylenediamine (TMEDA), and N-
methylpiperazine (NMPRZ) were also tested, but the reactions in
all these solvents were much slower and gave 2a only in poor
yields (Table 1, entries 1-5). It is obvious that DBN and DBU are
stronger organic bases with the amidine structure owing to their
/
110
110
110
110
110
/
H2O2
TBHP
K2S2O8
/
16
a
Unless otherwise noted reaction conditions are as follows: 1a (1.0
mmol), organic base (5 mL), refluxing under air atmosphere for 12 h.
b Isolated yields.
c Extra 30% H2O2 (1.0 mmol) was added.
d Extra 70% aq. TBHP (1.0 mmol) was added.
e Extra K2S2O8 (1.0 mmol) was added.
conjugate acids stabilized by the resonance structure between the
28
two nitrogen atoms.
Subsequently, further investigation of
temperature revealed that DBN was more effective than DBU,
and the reaction temperature is a very important effect factor
(Table 1, entries 8-11). When using DBN as the basic solvent
o
under air, increasing the reaction temperature to 110-120 C led
to a significantly improved yield of 2a (Table 1, entries 9 and
10); whereas decreasing reaction temperature to 90 °C almost
failed to yield 2a with the main intermediate I (3,4-dihydro-β-
carboline) remaining in the reaction (Table 1, entry 11). In order
to investigate the reaction process, high performance liquid
chromatography (HPLC) was utilized to monitor the conversion
of 1a to 2a. As shown in Figure 1, after treating 1a with DBN for
o
Figure 1. The conversion of 1a to 2a in the presence of DBN at
2 h at 110 C, two new peaks appeared. These new components
indicated time point.
were identified as I (Rt = 9.6 min) and 2a (Rt = 10.7 min) by
comparison of their retention times (Rt) with corresponding
standard compounds. It was observed that along with peak 2a
growing up gradually, the peaks of 1a and I initially declined and
then diminished at 12 h. Moreover, the reaction yield was not
improved by changing from air to an oxygen balloon, and even if
adding stoichiometric peroxides such as hydrogen peroxide
(H2O2), t-butylhydroperoxide (TBHP), and potassium persulfate
(K2S2O8) (Table 1, entries 12-15). However, the reaction carried
out under nitrogen instead of air almost did not afford 2a, and I
was founded to be the sole product (Table 1, entry 16). This
result indicated that air was essential and powerful enough for the
dehydrogenation reaction. Finally, of the reaction conditions
screened in Table 1, entry 9 was chosen as the best condition.
With the optimal reaction conditions in hand, we turned our
attention to explore the substrate scope. A wide array of 1-
substituted tetrahydro-β-carbolines 1a-1w were obtained easily
via the Pictet−Spengler reaction in which tryptamine or 5-
methoxytryptamine undergone condensation with various
aldehydes followed by ring closure. Then, the dehydrogenative
aromatization of these tetrahydro-β-carbolines was conducted
under the optimized conditions, and the results were depicted in
Table 2. When the 1-position was substituted with aromatic
substituents, the nature of groups on the benzene ring
considerably influenced the yields of the products. For example,
the steric effect of 2-methyl and 2-methoxy on the benzene ring
hindered the DBN-mediated dehydrogenation, and the
corresponding β-carbolines 2b-2c were provided in poor yields.
It was also apparent that the electronic nature of groups had some
effect on the product yields; the strong electron-donating groups
(e.g., 2-hydroxyl, 3-methoxy and 4-methoxy) afforded noticeably
Table 1. Optimization of the reaction conditions a

3
higher yields compared to strong electron-withdrawing groups
(e.g., 2-fluoro, 3-nitro, 3-chloro and 4-bromine). The
corresponding β-carbolines 2d, 2f and 2i could be obtained in >
75% yields, meanwhile, 2e, 2g, 2h and 2j could be afforded only
in 45-66% yields. In addition, substrates with fused-ring and
heteroaromatic substituents proceeded smoothly to afford the
corresponding products 2k-2n in good to excellent yields (75-
87%), however the aliphatic-substituted substrates were observed
to achieve this reaction in moderate yields (2o, 47%; 2p, 67%).
Subsequently, 1-substituted 6-methoxy tetrahydro-β-carbolines
1q-1w were investigated, and the corresponding β-carboline
products 2q-2w were obtained in moderate to good yields (45-
79%). It is important that the steric and electronic effects of
substituents at 1-position to this conversion was consistent to that
of 1a-1p.
Remarkably, the halogen, hydroxyl, nitro and methoxy groups
of these desired β-carboline products would be useful handles for
further modifications to gain other pharmacologically active
molecules.
Table 3. DBN-promoted conversion of tetrahydro-β-carboline
acids into β-carbolines a
Entry Substrate R1
Product
Yield
(%) b
58
1
2
3
4
5
6
3a
3b
3c
3d
3e
3f
Phenyl
4a (2a)
4b (2d)
4c (2f)
4d (2g)
4e
2-Hydroxyl phenyl
3-Methoxy phenyl
3-Nitro phenyl
60
Table 2. DBN-promoted conversion of tetrahydro-β-carbolines
into β-carbolines a
52
45
3-Hydroxyl-4-methoxy phenyl
2-Hydroxyl-5-fluoro phenyl
45
4f
51
a Reaction conditions: compounds 3a-3f (1.0 mmol) and DBN (5 mL) at
110 °C under air for 12 h.
Entry Substrate
R1
R2
Product
Yield
(%)b
78
35
30
76
65
79
66
50
78
45
75
81
79
87
47
67
70
50
79
45
73
65
60
b Isolated yields.
1
1a
1b
1c
1d
1e
1f
Phenyl
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
2a
2b
2c
2d
2e
2f
Furthermore, to apply this method to a wide scope, we
attempted the synthesis of natural β-carboline alkaloids like
eudistomin U (7) and harmane (10), which were reported to
2
2-Methyl phenyl
2-Methoxy phenyl
2-Hydroxyl phenyl
2-Fluoro phenyl
3-Methoxy phenyl
3-Nitro phenyl
3-Chloro phenyl
4-Methoxy phenyl
4-Bromine phenyl
1-Naphthyl
3
29
exhibit anticancer activity due to their DNA-binding ability.
4
Synthesis of eudistomin U (7) began with the acid catalyzed
Pictet-Spengler condensation of tryptamine (5) with indole-3-
carboxaldehyde to give the corresponding tetrahydro-β-carboline
5
6
30
(6). The synthesis of harmane (10) started with tryptophan (8),
7
1g
1h
1i
2g
2h
2i
which underwent
a
Pictet-Spengler condensation with
8
acetaldehyde to provide the corresponding tetrahydro-β-carboline
31
acid (9).
Then, 6 and 9 were subjected to the optimized
9
reaction conditions, and furnished the target alkaloids 7 and 10 in
47% and 50% yield, respectively (Scheme 2). Much to our
10
11
12
13
14
15
16
17
18
19
20
21
22
23
1j
2j
1k
1l
2k
2l
satisfaction,
the
DBN-promoted
dehydrogenative/decarboxylative aromatization can be reliably
run on gram scale.
2-Pyridyl
1m
1n
1o
1p
1q
1r
1s
2-Thienyl
2m
2n
2o
2p
2-Furyl
Isopropyl
Cyclohexyl
2-Hydroxyl phenyl
2-Fluoro phenyl
3-Methoxy phenyl
3-Nitro phenyl
1-Naphthyl
OMe 2q
OMe 2r
OMe 2s
OMe 2t
OMe 2u
OMe 2v
OMe 2w
1t
Scheme 2. Synthesis of eudistomin U (7) and harmane (10) via
DBN-promoted dehydrogenative/decarboxylative aromatization.
1u
1v
1w
2-Pyridyl
25b, 32
On the basis of above results and reported literature,
we
Cyclohexyl
proposed a possible reaction mechanism for DBN-promoted
dehydrogenative/decarboxylative aromatization process under air,
with substrates 1a and 3a as an example. As outlined in Scheme
3, DBN acting as a strong organic base abstracts the proton
localized on the nitrogen atom in the piperidine ring, to form
nitrogen anion A. The newly produced A is oxidized by air (O2)
to the corresponding nitrogen radical B via single-electron
transfer (SET), meanwhile, delivering a single electron to O2 can
a Reaction conditions: compounds 1a-1w (1.0 mmol) and DBN (5 mL) at
110 °C under air for 12 h.
b Isolated yields.
Next, we turned our attention to explore the scope and
generality of decarboxylative aromatization with tetrahydro-β-
carboline acids 3a-3f as reaction substrates under the optimized
conditions. As depicted in Table 3, a series of substituents at 1-
position were tolerated in the reaction, and the corresponding β-
carbolines 4a-4f were formed in moderate yields (45-60%).
·-
generate oxygen radical anion (O2 ). Then, the highly activated
·-
-
O2 rapidly reacts with 1a to give HO2 and nitrogen radical B,
which is abstracted a hydrogen atom from the benzylic C (sp3)-H

4
Tetrahedron
·-
2. (a) Zhang, M.; Sun, D. Anticancer Agents Med. Chem. 2015, 15, 537-
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bond by O2 , to afford a stable intermediate I. On the other
·-
hand, hydrogen abstraction of A by previously formed O2 gives
a radical anion C, that is readily oxidized by air (O2) to afford the
key intermediate I. The structure of I was confirmed by 1H NMR
and MS (see the supporting information for details). Additionally,
oxidative decarboxylation of substrate 3a could be easily
achieved in the DBN/air (O2) reaction system, and lead to the
formation of radical D, which would give an unstable
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·-
intermediate II after further oxidation by O2 . Finally,
intermediates I and II could go through a double-bond
isomerization process (from I, II to III), followed by oxidative
dehydrogenation again in the DBN/air (O2) reaction system, to
yield the desired product 2a (4a).
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Scheme 3. Plausible reaction mechanism.
In conclusion, we have developed a highly efficient protocol for
the
synthesis
of
β-carbolines
via
DBN-promoted
dehydrogenative/decarboxylative aromatization of tetrahydro-β-
carboline precursors under air. The method possessed the advantages
of being metal-free, operational simplicity and broad substrate scope,
which could serve as a milder alternative to the traditional methods.
Additionally, the utility of the process was highlighted in the gram-
scale synthesis of β-carboline alkaloids such as eudistomin U (7) and
harmane (10). Further utilizations of this protocol are underway to
construct more complex β-carbolines in our laboratory.
Acknowledgments
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This work was supported by the National Natural Science
Foundation of China (Grant No. 81602957), the Natural Science
Foundation of Jiangsu Province, China (Grant No.
BK20161035), and the China Postdoctoral Science Foundation
(Grant No. 2016M601853).
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Supplementary data
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Supplementary data associated with this article can be found
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Tetrahedron
Highlights
 An efficient organic base-promoted synthesis
of β-carbolines was accomplished.
 This method was successfully applied for the
gram-scale synthesis of natural β-carboline
alkaloids.
 The method possessed the advantages of being
metal-free, operational simplicity and broad
substrate scope.