An environmentally friendly protocol for oxidative halocyclization of tryptamine and tryptophol derivatives

Article abstract of DOI:10.1039/c7gc01341h

An environmentally friendly and efficient protocol (KX/oxone) for oxidative halocyclization of tryptamine/tryptophol derivatives was developed and demonstrated with 28 examples and concise total synthesis of cyclotryptamine alkaloid protubonines A and B. The distinct advantage of this protocol over all previous methods is that no organic byproduct is generated from a halogenating agent or oxidant, thus greatly reducing the environmental impact of halocyclization and facilitating the post-reaction purification.

Full text of DOI:10.1039/c7gc01341h

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DOI: 10.1039/C7GC01341H
Journal Name
COMMUNICATION
An Environment-Friendly Protocol for Oxidative Halocyclization of
Tryptamine and Tryptophol Derivatives†
Jun Xu and Rongbiao Tong*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
An environmentally friendly and efficient protocol (KX/oxone) for active alkaloid natural products2 (e.g.,chimonanthine,
oxidative halocyclization of tryptamine/tryptophol derivatives was madindine A, vincorine, aspidophylline, conolutinine, etc) and
developed and demonstrated with 28 examples and concise total pharmaceutical compounds (physostigmine is clinically used for
synthesis of cyclotryptamine alkaloid protubonines A and B. The treatment of glaucoma, myasthenia gravis and Alzheimer’s
distinct advantage of this protocol over all previous methods was disease)3 (Figure 1). In addition, the halide at C3 provides an
no organic byproduct arisen from halogenating agent or oxidant, invaluable opportunity for further functionalization with many
thus greatly reducing the environment impact of halocyclization well-established transformations of halides. While recent
and facilitating the post-reaction purification.
efforts have led to remarkable improvements of efficiency and
the development of many elegant asymmetric versions of
of halocyclization,4 less attention has been paid to eliminate or
Among various oxidative
cyclizations1
tryptamine/tryptophol derivatives, halocyclization is one of the reduce the hazardous organic byproducts arisen from the
most widely used reactions for the construction of stoichiometric halogenating agents or terminal oxidants
hexahydropyrroloindolines (HPIs) / tetrahydrofuroindolines employed in all previous protocols. For example, oxidative
(TFIs), which are useful building blocks or cores of biologically
bromocyclization of tryptamine derivatives using PyHBr3,5 NBS,6
PIDA/CuBr2,7 DABCO-derived bromine salts,8 or NBAc9 would
inevitably produce stoichiometric organic wastes (Scheme 1),
which negatively impact the environment and usually require
immediate removal from the desired HPIs/TFIs by
chromatography. Herein, we describe the development of an
environment-benign
oxidative
halocyclization
of
tryptamine/tryptophol derivatives using potassium halide and
oxone, which generates potassium sulfate (K2SO4) as the only
stoichiometric byproduct and greatly facilitate the post-
reaction purification and integration of other transformations.
Figure 1. Selectedindole alkaloids bearing HPI or TFI core
Department of Chemistry, The Hong Kong University of Science and Technology,
Clearwater Bay, Kowloon, Hong Kong, China,E-mail: rtong@ust.hk
Fax: +(852) 23581594; Tel: +(852) 23587357
†Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
Scheme 1. Previous methods for bromocyclization of
tryptamine/tryptophol derivatives and our new hypothesis
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Mechanistic understanding of the halocyclization prompted
us to envision that the complete elimination of the organic
byproducts could be achieved by the use of halogenating agents
generated in situ from oxidation of alkali metal halides with
inorganic oxidants (Scheme 1). The key to successful realization
of this idea is to identify an appropriate inorganic oxidant that
is able to efficiently oxidize the halide but not the readily
oxidized indole. With this consideration we chose oxone
(potassium peroxymonosulfate, 2KHSO5•KHSO4•K2SO4) as the
terminal oxidant coupled with alkali metal halides to explore
the halocyclization of tryptamine/tryptophol derivatives
on the reaction yield (entries 10-12), which suggested that sub-
stoichiometry of oxone (0.50.7 equiv) substantially decreased
the yield and over-stoichiometry did not further improve the
cyclization yield.
To evaluate the potential environmental impact of our
optimized condition with the most widely used method, i.e.,
NBS-promoted bromocyclization, we performed a simple E-
Factor analysis13 (See ESI for details): E-Factor of our system is
1.99, suggesting that 1.99 grams of non-hazardous and non-
toxic K2SO4 waste was generated in the production of 1.0 gram
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DOI: 10.1039/C7GC01341H
because oxone has been a widely used inorganic oxidant for of the HPI 1a. E-Factor of NBS system is 0.54, namely, 0.54
halides to generate halogenating agents due to multifaceted
advantages including cheap, stable, non-toxic, and
air/moisture-insensitive.10 The precedent11 that oxone was able
to oxidize the 2-arylindoles to the corresponding 2-
arylbenzoxainones cast doubt on chemoselective oxidation of
halides over indoles using oxone. Therefore, the reaction
condition for halocyclization of tryptamine/tryptophol
derivatives using halide/oxone12 needs to be identified and
optimized.
We began our studies with screening of solvents for the most
widely used oxidative bromocyclization2 of tryptamine
derivative using 1a as the model compound (Table 1). To our
delight, treatment of tryptamine (1a) with KBr (1.0 equiv) and
oxone (1.0 equiv) in either methanol (polar and protic) or
dichloromethane (unpolar and nonprotic) at room temperature
afforded the 3-bromopyrroloindoline 2a in moderate yields of
grams of toxic succinimide waste produced for synthesis of 1.0
gram of HPI 1a. Nevertheless, the key difference lies on the
nature of the byproducts: organic vs inorganic, and our system
completely eliminates the toxic and hazardous organic
byproducts derived from all previous methods.
With the optimized condition in hand, we set out to examine
the substrate scope (Table 2). Tryptamine derivatives bearing
carbamate, acyl or sulfonate protecting groups on both
nitrogen atoms were excellent substrates for the
bromocyclization to provide the corresponding HPIs (2a
the excellent yields (86–95%). Notably, the electron-donating
substituents on indoles such as methoxy (2j 2k) and methyl
2m and 2o) groups were tolerated without formation of
possible oxindoles.
2p) in

(
Table 2. Substrate scope for halocyclization of tryptamine
and tryptophol derivativesa
63% and 56% (entries 1
DMSO, DMF or H2O did not occur (entries 3

2), respectively, while the reaction in
5). Although

acetone was also a suitable solvent for the bromocyclization to
provide 2a in 86% yield (entry 6), acetonitrile was identified as
the optimal solvent and 93% yield could be obtained (entry 7).
It was noted that the addition of water to increase the solubility
of oxone in acetonitrile significantly reduced the yield (entries
89). Finally, we examined the effect of oxone’s stoichiometry
Table 1. Optimization of conditions for bromocyclization of
tryptamine 1a
Entrya
Solvent
Time(h)
Conv. (%)
Yield(%)b
1
2
3
4
5
6
7
8
MeOH
CH2Cl2
DMF
H2O
DMSO
acetone
MeCN
MeCN/H20 (2:1)
MeCN/H20(10:1)
MeCN
4
4
8
8
8
4
4
4
4
4
4
4
100
100
<5
<5
<5
100
100
100
100
53
63
56
<5
<5
<5
86
93
63
64
46
67
93
9
10c
11d
12e
MeCN
MeCN
72
100
aThe reaction was carried out at rt with tryptamine (0.2 mmol), oxone
(0.2 mmol, 1.0 equiv), KBr (0.2 mmol), solvent (2.0 mL). bIsolated yields.
coxone (0.5 equiv). doxone (0.7 equiv). eoxone (2.0 equiv).
aReaction conditions: tryptamine or tryptophol (0.2 mmol), oxone
(0.2mmol), MeCN (2.0 mL), KX(0.2mmol); Isolated yields by column
chromatography on silica gel. bDetermined by 1H-NMR analysis.
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Unsurprisingly, bromocyclization did not occur for tryptamine
COMMUNICATION
To further highlight the utility of our new green protocol for
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DOI: 10.1039/C7GC01341H
derivatives with the electron-donating group on either the the oxidative halocyclization, we initiated the total synthesis of
indole nitrogen or the side chain nitrogen (A, Table 2). This protubonines A and B, which were isolated from the cultured
might be attributed to the facile oxidation of indoles or marine-derived fungus Aspergillussp. SF-5044.18 The C-11
alkylamines by oxone to oxindoles and alkylamineN-oxide, absolute configuration was originally assigned as (R)-
respectively. To further expand the substrate scope, we configuration but recently revised by de Lera and co-workers by
examined the tryptophol derivatives and found that they were total syntheses of two C-11 epimers.19 Our synthesis (Scheme 3)
also excellent substrates for the bromocyclization to provide began with the protection of the commercially available L-
TFIs 2u2z in excellent yields. Similarly, the electron- tryptophan methyl ester as tert-butyl carbamate followed by
withdrawing group on the nitrogen was key to the successful acetylation to give 11. Removal of the Boc protecting group with
bromocyclization since the cyclization of tryptophol and N- TFA and subsequent amidation with N-Boc-L-Leucine under the
methyltryptophol failed (B, table 2). Finally, we extended our classical amide bond formation condition (EDCI and HOBt)
protocol to the less-explored chloro-,14 fluoro-15 and afforded dipeptide 13 in 71% yield. The oxidative
iodocyclization14 of tryptamine and tryptophol. The bromocyclization of 13 using our newly-established protocol
chlorocyclization proceeded smoothly with slightly lower provided the tricyclic HPI 14 in an excellent yield on a gram-scale,
efficiency than bromocyclization to afford 3-chloro HPIs 2s
,
2t
,
albeit as 3.5:1 mixture of diastereomers that were separated by
2aa and 2ab in 78-85%, while fluoro- and iodocyclization using column chromatography on silica gel. However, the separation
our protocol (KF/oxone or KI/oxone) under otherwise identical of this diastereomeric mixture was much easier after the
conditions unfortunately did not work (
C
, Table 2).
subsequent ring-closure. Therefore, this mixture was carried
forward without separation for the TFA-promoted Boc
deprotection and simultaneous formation of the
diketopiperazine ring to provide the tetracyclic HPI 15 in 87%
To demonstrate the synthetic advantages of our protocol
over previous methods, we showcased the successful
integration of the halocyclization and subsequent aromatic
halogenation in a one-pot manner. As depicted in Scheme 2a,
the one-pot sequential halocyclization/halogenation of
tryptamine/tryptophol derivatives was achieved by addition of
stoichiometric amounts of KX and oxone to the reaction mixture
yield (14
water2b,16i and acetate19 furnished (
and ( )-protubonine B (83% yield), respectively. Our total
→
15). Silver(I)-mediated bromide substitution with

)-protubonine A (85% yield)

synthesis were efficiently completed in total 7 steps with 29%
overall yields. The spectroscopic data including the specific
rotation of our synthetic materials were in good agreement
with those reported for the natural products.18,19
of halocyclization, providing polyhalogenated HPIs (
3 and 5) and
TFIs ( and ) in excellent yields. Importantly, these halides on
4
6
Scheme Sequential halocyclization/halogenation of
2.
tryptamine and tryptophol derivatives and exemplary bromide
functionalization
Scheme 3.Total syntheses of ()-protubonines A and B
the HPIs/TFIs could be further exploited with many well
established transformations to structurally diversify the tricyclic
skeletons of HPIs and TFIs. For example, the aromatic bromide
could undergo Suzuki coupling reaction to provide 7 in 74% yield
(Scheme 2b), while the aliphatic bromide at C3 could undergo a
variety of known substitution reactions (alkylation, arylation,
azidation, homodimerization, hydroxylation and amination)16
Conclusions
In summary, we have developed an environmentally friendly
and efficient protocol for the very important halocyclization of
tryptamine/tryptophol derivatives. The efficiency and utility of
including the interesting reaction that provided
9 through
cyclopropylazetoindoline 817 (Scheme 2c).
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Q. Cai, Q. Yin and S.-L. You, Asian J. Org. Chem., 2014, 3, 408.
9
this new protocol was demonstrated with 1) 28 examples, 2)
successful integration of halogenation as a one-pot reaction,
and 3) 7-step total synthesis of cyclotryptamine alkaloid ()-
protubonines A and B. The most striking advantage of this
protocol over all previous methods using stoichiometric organic
halogenating agents or oxidants is no organic byproduct
generated from the reaction. Additional features of this new
protocol include simple operation (open flask to air and
moisture), facile purification, and broad scope.
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Narender, Synthesis, 2012, 43, 15.
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Acknowledgements
This research was financially supported by Research Grant
Council of Hong Kong (ECS 605912, GRF 605113, and GRF
16305314).
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