Rhodium-Catalyzed Enantioselective Cyclization of 3-Allenyl-indoles: Access to Functionalized Tetrahydrocarbazoles

Article abstract of DOI:10.1021/acs.orglett.9b01721

A highly selective rhodium-catalyzed cyclization of tethered 3-allenylindoles is reported. In a smooth reaction, 1-vinyltetrahydrocarbazoles are obtained in excellent yields and enantioselectivities. Aside from a great functional group tolerance, this method requires neither the Schlenk technique nor the use of anhydrous solvents. Preliminary mechanistic investigations proved that the reaction proceeds via an intermediary formed spiroindolenine which rapidly undergoes an acid-catalyzed stereospecific migration.

Full text of DOI:10.1021/acs.orglett.9b01721

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Rhodium-Catalyzed Enantioselective Cyclization of 3‑Allenyl-
indoles: Access to Functionalized Tetrahydrocarbazoles
Christian P. Grugel and Bernhard Breit*
Institut fur Organische Chemie, Albert-Ludwigs-Universitat Freiburg, Albertrstr. 21, Freiburg 79104, Germany
̈
̈
S
* Supporting Information
ABSTRACT: A highly selective rhodium-catalyzed cycliza-
tion of tethered 3-allenylindoles is reported. In a smooth
reaction, 1-vinyltetrahydrocarbazoles are obtained in excellent
yields and enantioselectivities. Aside from a great functional
group tolerance, this method requires neither the Schlenk
technique nor the use of anhydrous solvents. Preliminary
mechanistic investigations proved that the reaction proceeds
via an intermediary formed spiroindolenine which rapidly
undergoes an acid-catalyzed stereospecific migration.
Scheme 1. Transition-Metal Catalyzed Strategies for the
Synthesis of Enantioenriched 1-Vinyltetra-hydrocarbazoles
he indole framework represents one of the most widely
Tdistributed structural features among heteroaromatic
compounds in nature.1 Given their widespread occurrence in
biologically active agents, tetrahydrocarbazoles (THCs)
represent an important subclass among indole-based natural
products (Figure 1) as they constitute key features in many
alkaloids.2
Figure 1. Selected tetrahydrocarbazole (THC) natural products and
structurally related alkaloids.
In this fashion, Bandini and co-workers recently reported on
an allylic alkylation of allylic alcohols by means of a bimetallic
gold cataylst.5 The You group then progressed on the initial
concept and developed a strategy for an iridium-catalyzed
dearomatization of indoles to obtain 5-membered spiroindo-
lenines. Moreover, they observed a stereospecific migration of
For this, selective functionalizations of indoles have drawn
the attention of synthetic organic chemists for many years. In
this respect, various groups aimed at a selective synthesis of the
tetrahydrocarbazole core. Among different strategies, such as
Friedel−Crafts type arylations,3 a powerful tool for their
synthesis is represented by intramolecular allylic substitution
reactions from 3-functionalized indoles (Scheme 1).4
Received: May 16, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01721
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Letter
a
this intermediate to the corresponding 1-vinyltetrahydrocarba-
zole upon exposure to catalytic amounts of a Brønstedt acid.4c,6
Despite their respective synthetic utility and their excellent
stereoelectivities, these methods represent allylic substitution
reactions and thus violate the principle of atom economy7 by
releasing stoichiometric amounts of a side product in the
course of the reaction. Throughout the last years, we reported
on a series of intermolecular rhodium-catalyzed chemo-, regio-,
and enantioselective coupling reactions involving allenes8,9 and
alkynes10,11 as allylic electrophile precursors with various
pronucleophiles, thus establishing a more atom-economic
alternative to the classic allylic alkylation. Meanwhile, we
were also able to expand this methodology toward asymmetric
intramolecular transformations.12
Addressing this strive for sustainability, Liu and Wiedenhoe-
fer similarly developed a gold(I)-catalyzed strategy that
allowed for the intramolecular hydroarylation of allenes.13
However, despite its synthetic elegance, this method is rather
limited with respect to a synthetic applicability as only N-
methylindoles could serve as nucleophiles and terminal allenes
mostly provided the cyclization product only in moderate
enantioselectivies. That being stated, we sought to disclose a
more general, convenient approach toward functionalized
tetrahydrocarbazoles by making use of our previously
developed rhodium-based strategy. Combined with the
findings of the You group that 5-membered spiroindolenines
rapidly undergo a stereospecific rearrangement to the isomeric
1-vinyltetrahydrocarbazoles,6b we envisioned to develop a
tandem spirocyclization/stereospecific migration procedure
starting from readily available, tethered 3-allenylindoles.
Herein, we report our preliminary results.
We initiated our investigations by drafting 3-allenylindole 1a
as the model substrate for the envisioned cyclization. In an
initial attempt with 2.5 mol % [Rh(cod)Cl]2 and 7.5 mol %
rac-BINAP (L1) in the presence of 50 mol % pyridinium 4-
toluenesulfonate (PPTS) as weakly acidic cocatalyst, the
desired vinyl tetrahydrocarbazole 2a was already formed in
an excellent yield of 89% (Table 1, entry 1). With this outcome
in hand, we subsequently sought to examine the potential for a
development of an enantioselective version thereof.
In light of the high structural diversity of commercially
available and, thus, easily accessible ligands with axial chirality,
we examined a variety of members of this family for their
capability to catalyze the given transformation enantioselec-
tively. To our delight, by making use of (R)-BINAP (L2),
tetrahydrocarbazole 2a was already formed in a quite
promising enantiomeric ratio of 77:23 (entry 2). Unfortu-
nately, the reaction’s enantioselectivity remained almost
unaffected when changing the axial chiral backbone from
BINAP to MeO-BIPHEP (L3) or Segphos (L4)-type ligands
(entries 3 and 4). In light of this outcome, we envisioned to
increase the enantioselectivity of the present cyclization by
selectively modifying the substituents at the ligands’ phosphine
moiety.
Table 1. Optimization of Reaction Conditions
b
c
entry
ligand
yield /%
er
1
2
3
4
5
6
7
8
rac-BINAP (L1)
(R)-BINAP (L2)
(R)-MeOBiphep (L3)
(R)-Segphos (L4)
(R)-Tol-BINAP (L5)
(R)-DM-BINAP (L6)
(R)-DM-Segphos (L7)
(S)-DTBM-Segphos (L8)
(R)-DTBM-Segphos (L8)
89
89
90
98
92
83
81
99
93
77:23
71.5:28.5
62:38
80:20
32.5:26.5
70:30
97:3 (−)
97.5:2.5
d
9
a
Reaction conditions: 1a (0.2 mmol), [Rh(cod)Cl]2 (2.5 mol %),
ligand (7.5 mol %), PPTS (50 mol %), DCE (1.0 mL), 40 °C, 16 h.
Isolated yields. Determined by chiral HPLC. Reaction performed
b
c
d
in DCM.
could replace the toxic solvent 1,2-dichloroethane (DCE) for
more benign DCM without negatively affecting the outcome of
the reaction (entry 9).
With these optimized conditions in hand, we sought to
examine the reaction scope (Scheme 2).
In this respect, we subjected a variety of differently
substituted indoles to the indicated reaction conditions.
Halogen-bearing substrates reacted smoothly and furnished
the desired 1-vinyltetrahydrocarbazoles 2b−e in excellent
yields and enantioselectivities. Notably, even an iodide-
substituted indole could be implemented in the catalysis
without observing any side reactions stemming from a
potential oxidative addition of the Rh(I) catalyst into the
C(sp2)-I bond as 2e was obtained in almost quantitative yield
and 98:2 er.
Indoles with electron-rich residues, such as methoxy groups
(2f−h) or alkyl groups (2i−j) were also found to be excellent
coupling partners as the reaction provided the desired cyclized
products in excellent yields and enantioselectivities regardless
of the respective substitution pattern. On the other hand,
electron-withdrawing groups such as nitrile (2k) or nitro
groups (2l) were also well tolerated in this cyclization.
Next, we examined the influence of different tethers which
link the indole and the allene part (Scheme 3). In this respect,
we exchanged methyl malonate for its ethyl (2m), iso-propyl
(2n), and tert-butyl (2o) analogues, all of which provided the
desired tetrahydrocarbazoles smoothly in a clean reaction
almost quantitatively and up to 99:1 er. In order to highlight
the mildness of the present protocol, we subjected a potentially
acid-sensitive acetal 2p to the reaction conditions. To our
delight, no deprotection occurred during the catalysis as 2p
was isolated in 98% yield and 93.5:6.5 er. Additionally,
malononitrile (2q) also proved to be a decent tether, as did
benzoylacetonitrile (2r).
However, more bulky (R)-Tol-BINAP (L5, entry 5) and
(R)-DM-BINAP (L6, entry 6) showed similar or only slightly
better results than (R)-BINAP. The same held for (R)-DM-
Segphos (L7), which promoted the product formation in a
marginally higher er but at the cost of isolated yield of
tetrahydrocarbazole 2a. Gratifyingly, by increasing the steric
bulk even further by implementing DTBM aryls in the ligand
(L8), not only was the excellent reactivity maintained, but also
2a formed in a drastically improved er of 97:3. Finally, we also
B
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a
Scheme 2. Reaction Scope
Table 2. Demonstration of the Reaction’s Robustness and
Convenience for the Conversion of 1a to 2a
a
entry
modifications to the general procedure
yield/%
er
98:2
96:4
97.5:2.5
97:3
97.5:2.5
1
2
3
4
5
6
1 mol % [Rh], 3 mol % ligand
20 mol % PPTS
analytical grade DCM (stab. with amylene)
no flame drying
no Schlenk technique, only Ar-balloon
aerobic conditions
95
94
95
94
86
n.r.
a
See Table 1.
1) resulted in essentially the same outcome as lowering the
amount of PPTS (entry 2). Performing the reaction in (neither
anhydrous nor degassed) analytical grade DCM or waive
previous flame-drying procedures also showed comparable
results (entries 3 and 4). Interestingly, using the Schlenk
technique is also not required even though the corresponding
yield of the cyclization product is slightly compromised (entry
5). However, rapid catalyst decomposition was observed upon
a reaction under aerobic conditions, most likely owing to
ligand oxidation (entry 6).
With this reduced catalyst loading (Table 2, entry 1), we
perfomed the cyclization of 1d on a gram scale and were able
to isolate 1.14 g of tetrahydrocarbazole 2d in an enantiomeric
ratio of 95.5:4.5, thus highlighting the synthetic utility of this
protocol (Scheme 4).
a
Reaction conditions: 1 (0.2 mmol), [Rh(cod)Cl]2 (2.5 mol %),
ligand (7.5 mol %), PPTS (50 mol %), DCM (1.0 mL), 40 °C, 16 h.
All yields given as isolated yields. The absolute configuration of the
tetrahydrocarbazoles 2 was assigned as (S) by means of a crystal
structure analysis of 2d. For details, see the Supporting Information.
Scheme 4. Gram-Scale Catalysis
a
Scheme 3. Reaction Scope (Continued)
In order to prove our initial assumption of an intermediary
formed spiroindolenine 3, we performed in situ NMR
monitoring experiments and were able to observe the
formation (and consumption) of 3a.14 Furthermore, by
stopping the reaction after 15 min, we could isolate the
aspired intermediate 3a in 44% yield with a 9:1 dr and 99:1 er,
which clearly indicates that the present rhodium-catalyzed
intramolecular hydroarlyation of allenes proceeds via an initial
alkylation of the (more nucleophilic) 3-position followed by a
stereospecific migration rather than a direct allylation of the 2-
position (Scheme 5).
On the basis of these observations and previous studies of
this catalytic system,15 we propose the following mechanism
for this transformation (Scheme 6). After initial catalyst
preformation from [Rh(cod)Cl]2 and (R)-DTBM-Segphos
Scheme 5. Isolation of Sprioindolenine Intermediate 3a
a
Reaction conditions: 1 (0.2 mmol), [Rh(cod)Cl]2 (2.5 mol %),
ligand (7.5 mol %), PPTS (50 mol %), DCM (1.0 mL), 40 °C, 16 h.
All yields given as isolated yields. [b] Reaction performed at 30 °C.
In order to demonstrate the robustness and convenience of
the reaction, we performed several experiments under certain
perturbations to the initial reaction conditions (Table 2).
Reducing the amount of rhodium precatalyst and ligand (entry
C
DOI: 10.1021/acs.orglett.9b01721
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Letter
Scheme 6. Proposed Reaction Mechanism
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: bernhard.breit@chemie.uni-freiburg.de.
ORCID
Bernhard Breit: 0000-0002-2514-3898
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the DFG and the Fonds der
Chemischen Industrie. C.P.G. is grateful for a Ph.D. fellowship
from the Fonds der Chemischen Industrie. Dr. Manfred Keller
and Dr. Daniel Kratzert (both from the University of Freiburg)
are acknowledged for providing highly qualified NMR
measurements and X-ray crystal structure analyses. Technical
support by Gamze Ciplak and Joshua Emmerich (both from
the University of Freiburg), specifically for laboratory
assistance and HPLC separations, is acknowledged.
(L8), a rhodium(III) hydride complex A is generated upon
reaction with PPTS,16 followed by a hydrometalation of the
allene moiety in 1 to give the allylrhodium(III) intermediate B.
Subsequent nucleophilic attack of the indole at its C3-position
releases the spirocycle 3 in its protonated form, while
simultaneously regenerating the Rh(I) catalyst. This observed
regioselectivity is explicable by the greater nucleophilicity at
the C3-position compared to C2, despite its increased steric
hindrance.6b The spiroindoleneine 3 then undergoes an acid-
catalyzed stereospecific migration, after which the better
migrating group (higher lying HOMO of the migrating σ-
bond) is attached to C2 of the indole scaffold. Finally,
elimination of HX then releases the 1-vinyltetrahydrocarbazole
2.
To conclude, we have accomplished a highly enantiose-
lective tandem spirocyclization/stereospecific migration start-
ing from tethered, readily available 3-allenylindoles. The
reaction proceeds with perfect atom economy and only
requires low loadings of a commercially available catalyst.
The mildness of the present protocol is exemplified by a great
functional group tolerance. Further investigations regarding the
expansion of this method to alkynes as coupling partners or
other heteroatom-based tethers as well as its application in
synthesis will be the objective of future research in our
laboratories.
REFERENCES
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ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b01721.
Experimental procedures and analytical data for the
synthesized compounds, including H and 13C NMR
1
spectra (PDF)
Accession Codes
CCDC 1899363 and 1909597 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
D
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Am. Chem. Soc. 2017, 139, 1029. (f) Cruz, F. A.; Zhu, Y.; Tercenio, Q.
D.; Shen, Z.; Dong, V. M. J. Am. Chem. Soc. 2017, 139, 10641.
(12) For recent examples on rhodium-catalyzed diastereo- and
enantioselective cyclizations with allenes, see: (a) Haydl, A. M.;
Berthold, D.; Spreider, P. A.; Breit, B. Angew. Chem. 2016, 128, 5859;
Angew. Chem. Int. Ed. 2016, 55, 5765. (b) Ganss, S.; Breit, B. Angew.
Chem. 2016, 128, 9890; Angew. Chem. Int. Ed. 2016, 55, 9738.
(c) Spreider, P. A.; Haydl, A. M.; Heinrich, M.; Breit, B. Angew. Chem.
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