tert-Butyl hypochlorite mediated diastereoselective oxidative coupling: Access to 1-functionalized tetrahydrocarbazoles

Article abstract of DOI:10.1039/c4ra14092c

A mild and operationally simple protocol for the direct C-H functionalization of the 1-position of tetrahydrocarbazoles is reported. The diastereoselective oxidative coupling process is mediated by tert-butyl hypochlorite, and allows the successful generation of 1-functionalized tetrahydrocarbazoles with good to excellent yields and good functional group tolerance.

Full text of DOI:10.1039/c4ra14092c

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tert-Butyl hypochlorite mediated
diastereoselective oxidative coupling: access to 1-
Cite this: RSC Adv., 2015, 5, 9204
functionalized tetrahydrocarbazoles†
a
a
abc
Received 8th November 2014
Accepted 22nd December 2014
*
Long Jiang, Xiaoni Xie and Liansuo Zu
DOI: 10.1039/c4ra14092c
www.rsc.org/advances
A mild and operationally simple protocol for the direct C–H func- phenyl ring) as substrates, reactivity in terms of functional
tionalization of the 1-position of tetrahydrocarbazoles is reported. The group tolerance and diastereoselectivity, which are key factors
diastereoselective oxidative coupling process is mediated by tert-butyl in complex molecule synthesis, remains unexplored. (2) Most
hypochlorite, and allows the successful generation of 1-functionalized oxidative species that promote the direct C–H functionalization
tetrahydrocarbazoles with good to excellent yields and good func- are generated in situ through the combined use of other
tional group tolerance.
reagents. Mild and operational simple protocols using single
stable oxidant are highly desirable. (3) In most cases, protecting
groups on the nitrogen are essential to govern the reactivity, and
thus the overall synthetic efficiency is diminished.
1-Functionalized tetrahydrocarbazoles have attracted attention
due to their potent and diverse biological activities. For
example, a variety of 1-substituted tetrahydrocarbazoles have
been reported for their therapeutic potential as anti-HPV
agents, NPY-1 antagonists, androgen receptor modulators,
and DP1 antagonists (Fig. 1).1 1-Functionalized (heteroatom
substituted) tetrahydrocarbazoles are also key structural
features of some complex indole alkaloids, such as alstoscho-
larine and gilbertine (Fig. 1).2 Thus, the direct C–H functional-
ization of the 1-position of tetrahydrocarbazoles via an oxidative
coupling approach,3,4 particularly in complex settings, could
provide a shortcut to these medicinally important structures
and offer distinct bond disconnection strategy in natural
product total synthesis.
Recently, the direct C–H functionalization of the 1-position
of tetrahydrocarbazoles via an oxidation process has been
documented using different oxidants.5 Despite the signicance
of these approaches, there are still some limitations that remain
to be addressed: (1) as the majority of the developed approaches
utilize simple tetrahydrocarbazoles (with variations only on the
tert-Butyl hypochlorite is a stable, commercial available and
inexpensive oxidizing reagent. Its ability to promote the
2a-functionalization of 2,3-disubstituted indoles has been
reported, as exemplied by the work of Gassman and
co-workers on 2,3-dimethyl indole6 and the chloroindolenine-
based coupling strategy utilized in the total synthesis of
vinblastine and Iboga alkaloids.7 However, attempts to direct
functionalize the 1-position of tetrahydrocarbazole using this
reagent under various reaction conditions failed,8 indicating
that the highly reactive chloroindolenine intermediate formed
could undergo several competing reaction pathways. To provide
a solution to this unsolved synthetic problem, address some
limitations associated with the existing approaches and develop
a mild, operational simple and diastereoselective protocol for
the preparation of 1-functionalized tetrahydrocarbazoles, we set
out to systematically investigate this C–H functionalization via
an oxidative coupling process using tert-butyl hypochlorite with
the hypothesis that suitable reaction conditions in terms of
solvent, additives and temperature might play important roles
in governing the reactivity.
aDepartment of Pharmacology and Pharmaceutical Sciences, School of Medicine,
Tsinghua University, Beijing, 100084 China. E-mail: zuliansuo@biomed.tsinghua.
edu.cn
bCollaborative Innovation Center for Biotherapy, Tsinghua University, Beijing, China
cCollaborative Innovation Center for Biotherapy, State Key Laboratory of Biotherapy
and Cancer Center, West China Hospital, West China Medical School, Sichuan
University, Chengdu, China
† Electronic supplementary information (ESI) available: Detailed experimental
procedures, characterization data, and copies of 1H and 13C spectra of all
products. See DOI: 10.1039/c4ra14092c
Fig. 1 1-Functionalized tetrahydrocarbazoles.
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A model oxidative coupling reaction between 1a and benzyl tetrahydrocarbazoles, which are difficult to be synthesized by
amine (2a) was carried out rst to identify the optimized reac- conventional methods. Notably, a variety of functional groups,
tion conditions (Table 1). 1a, readily prepared by the thermal including ketone, ester, ketal, lactone, and heterocyclic pyrrole
Diels–Alder reaction between 2-vinyl indole and the corre- (3i), remained intact during the oxidative coupling reactions. In
sponding a,b-unsaturated ketone,9,10 represents a suitable addition, good to excellent diastereoselectivities were observed
substrate to examine the diastereoselectivity and functional with substituents at 3 and/or 4 positions, albeit a 1 : 1 mixture
group tolerance of this oxidative coupling reaction. Indeed, as of two isomers was obtained using 2-methyl tetrahy-
we envisioned, the outcome of the reaction was highly depen- drocarbazole (3l).
ded on the solvent used and the reaction temperature. The
We next examined the usage of other nucleophilic reagents
chloroindolenine 4 (X ¼ Cl) was formed in good yields when in the tert-butyl hypochlorite mediated oxidative coupling
DMF, DCM, and acetonitrile were utilized as the reaction reaction (Scheme 2). In addition to benzyl amine, cyclic and
media; however, the reactivity was completely switched and the acyclic secondary amines (3m, 3n, 3o), and aniline (3p) were
desired product 3a was isolated in good yields when ethyl also effective coupling partners. The characterization data of 3p
acetate and THF was used as the solvent at ꢀ20 ꢁC. It should be is identical with that reported.5f Attempts to induce diaster-
noted that the reaction was promoted by tert-butyl hypochlorite eoselectivity using chiral benzylic amine only resulted in a
as the single activating reagent, without the addition of any mixture of two isomers (3q, 2 : 3). Oxygen based nucleophiles
additive(s), such as acid or base. Moreover, the oxidative (3r, 3s, 3t) could also participate in the oxidative coupling
coupling reaction tolerated both the ketone and ester groups reaction with good yields. The surprisingly high diaster-
and proceeded with excellent diastereoselectivity (>20 : 1). The eoselectivity observed with 3r (compared to that of 3s, 3t) might
reaction yield was further improved by using only 1.0 equiv. of be attributed to the recemizable nature of the newly generated
tert-butyl hypochlorite (entry 6). Other halogenating reagents, stereogenic center and the related dynamic resolution process.
such as NBS, iodine, and NIS were also screened, but none of It should be mentioned that 1-oxygenated tetrahydrocarbazoles
them promoted the formation of 3a.‡
have been demonstrated to serve as effective precursors for the
The generality and substrate scope of the oxidative coupling subsequent acid-promoted coupling reactions with a variety of
reaction was next investigated (Scheme 1). Under optimized different nucleophilic reagents.5b,11 In addition, C–C bond
reaction conditions, a variety of different tetrahydrocarbazoles formation was also successfully achieved using sodium salt of
underwent effective coupling with benzyl amine, generating the malonate diester as the coupling partner, further expanding the
directly 1-fuctionalized products in good to excellent yields. chemical diversity of the products generated. Similarly, the
Substituents on the phenyl rings could be varied, and the reaction of cyclohepta [1,2-b] indole afforded 3v in good yield.
electronic properties did not seem to affect the reaction yields
signicantly (3b–3e). Substituents at the 2,3,4-positions of the
tetrahydrocarbazoles were also well tolerated (3a, 3f–3l),
providing a direct entry to multisubstituted 1-fuctionalized
Table 1 Optimization of reaction conditions
Entry
Oxidant
Solvent
Yield of 3aa (%)
Yield of 4a (%)
1
2
3
4
5
6
7
8
9
t-BuOCl
t-BuOCl
t-BuOCl
t-BuOCl
t-BuOCl
t-BuOCl
t-BuOCl
NBS
DMF
DCM
EtOAc
CH3CN
THF
THF
THF
THF
THF
0
0
71
0
60
81b
65c
0
73
68
0
75
0
0
0
82
0
I2
0
10
NIS
THF
0
0
a
b
Isolated yield. Using 1.0 equiv. of tert-butyl hypochlorite and
c
3.0 equiv. of benzyl amine. Using 1.0 equiv. of tert-butyl hypochlorite
Scheme 1 The generality and scope of the oxidative coupling reac-
tion: different tetrahydrocarbazoles.
and 1.5 equiv. of benzyl amine.
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be possible intermediates, and nucleophilic attack through
either SN20 or conjugate addition are possible pathways. In
either mechanism, the observed diastereoselectivity might be
attributed to the axial attack of the nucleophilic reagents from
the opposite side of the most hindered substituted group.
Conclusions
In conclusion, we have developed a mild and operational simple
protocol for the direct C–H functionalization of the 1-position of
tetrahydrocarbazoles. The diastereoselective oxidative coupling
process is mediated by tert-butyl hypochlorite as the single
oxidant, and allows the successful generation of a diverse array
of 1-functionalized tetrahydrocarbazoles with good to excellent
yields and good functional group tolerance. Our method
provides a solution to an unsolved synthetic problem and
address some limitations of the existing approaches. With the
signicance of 1-functionalized tetrahydrocarbazoles as struc-
tural elements in medicinally important compounds and
complex natural products, we expect this strategy will nd
applications in chemical synthesis and drug discovery.
Acknowledgements
The authors are grateful to Tsinghua University, “1000 Talents
Recruitment Program”, Collaborative Innovation Center for
Biotherapy (Tsinghua University and Sichuan University) and
National Natural Science Foundation of China (Grant no.
21302107) for nancial support.
Scheme
2 The generality and scope of the oxidative coupling
reaction: different nucleophiles.
Notes and references
To probe whether the chloroindolenine 4 was the rst
formed intermediate leading to the desired coupling product
3a, control experiments were carried out (Scheme 3). The reac-
tion between 1a and tert-butyl hypochlorite in dichloromethane
led exclusively to the formation of chloroindolenine 4. When 4
was subjected to the standard reaction condition for the
oxidative coupling with benzyl amine in THF, 3a was isolated in
good yield, indicating that the chloroindolenine 4 was indeed
an intermediate en route to 3a. Presumably both of A and B can
‡ Representative procedure: to a solution of 1a (50.0 mg, 0.15 mmol) in THF
(1.0 mL) at ꢀ20 ꢁC was added t-BuOCl (16.2 mg, 0.15 mmol) dropwisely. Aer
being stirred at ꢀ20 ꢁC for 10 min, benzyl amine (2a) (48.0 mg, 0.45 mmol) was
added. The resulting mixture was stirred at ꢀ20 ꢁC for additional 2 hours and then
quenched by the addition of aqueous sodium bicarbonate (5 mL). Aer warmed to
room temperature, the reaction mixture was extracted with dichloromethane
(3 ꢂ 10 mL). The combined organic layers were dried over anhydrous sodium
sulfate, and concentrated under reduced pressure. The crude residue was puried
by silica gel chromatography (dichloromethane/methanol ¼ 50 : 1) to yield the
desired product 3a (53.3 mg, 81% yield) as a light yellow solid.
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11 1-OAc substituted tetrahydrocarbazole was obtained by
treatment of 3r with acetic acid.
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