TfOH catalyzed synthesis of 1-substituted tetrahydrocarbazoles

Article abstract of DOI:10.1016/j.tetlet.2018.07.023

Synthesis of 1-substituted tetrahydrocarbazole is accomplished by TfOH catalyzed reaction of 3-substituted indoles tethered with secondary and tertiary alcohols. The reaction was generalized for a variety of substrates and was extended to the synthesis of

Full text of DOI:10.1016/j.tetlet.2018.07.023

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TfOH Catalyzed Synthesis of 1-Substituted Tetrahydrocarbazoles
Laxmi Narayan Nanda, Vipin Rangari
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S0040-4039(18)30883-9
https://doi.org/10.1016/j.tetlet.2018.07.023
TETL 50132
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Reference:
Tetrahedron Letters
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6 July 2018
8 July 2018
Please cite this article as: Nanda, L.N., Rangari, V., TfOH Catalyzed Synthesis of 1-Substituted
Tetrahydrocarbazoles, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.07.023
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TfOH Catalyzed Synthesis of 1-Substituted Tetrahydrocarbazoles
Laxmi Narayan Nanda*, Vipin Rangari

1
Tetrahedron Letters
journal homepage: www.elsevier.com
TfOH Catalyzed Synthesis of 1-Substituted Tetrahydrocarbazoles
Laxmi Narayan Nanda*, Vipin Rangari
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560012, India
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Available online
Synthesis of 1-substituted tetrahydrocarbazole is accomplished by TfOH
catalyzed reaction of 3-substituted indoles tethered with secondary and tertiary
alcohols. The reaction was generalized for a variety of substrates and was
extended to the synthesis of 2,3,3a,6-tetrahydro-1H-pyrido[3,2,1-jk]carbazole and
carbazoles.
Keywords:
2009 Elsevier Ltd. All rights reserved.
Keyword_1 Brønsted acid catalysis
Keyword_2 Tetrahydrocarbazole
Keyword_3 Carbazoles
Keyword_4 Alkaloids
1. Introduction
Diels-Alder type reactions are also reported for the synthesis
of tetrahydrocrabazoles.5 Török and co-workers used TfOH to
synthesize N-phenylsulfonyl pyrrole, indole and carbazoles in
one pot fashion starting from primary sulfonamides.6oVery
recently, during the preparation of this manuscript, Beeraiah
Tetrahydrocarbazoles and carbazoles are ubiquitous structural
units found in a plethora of bio-active natural products (Fig.
1).1 Tetrahydrocarbazoles also serve as key precursors for the
synthesis of carbazole containing natural products.
and
Tharra
reported
AgOTf/TsOH
catalyzed
cycloisomerization of 3-susbtituted indoles for the synthesis
of carbazoles via the tetrahydrocarbazole. However they
failed in isolating the tetrahydrocarbazole intermediate.6p As
evident from the above metal catalyzed reactions rely on the
use of substrates possessing functionalized alcohols at the 2,3
positions of indole. However use of 3-substituted
indolylbutanols is not explored in literature for the synthesis
of tetrahydrocarbazoles. 6e,7a,b
Figure 1: Natural products having tetrahydrocarbazole and
carbazole frameworks
Traditional way of synthesizing tetrahydrocarbazole is the
Fischer-indole reaction of cyclic ketones with arylhydrazines.2
In recent years, most of the methods for the synthesis of
tetrahydrocarbazoles are based on transition metal catalyzed
reactions that require pre-functionalization, high catalyst
loading, harsh reaction conditions and multi-step sequence for
the preparation of the substrate.2-6 Some of the key methods
for the synthesis tetrahydrocarbazoles include the use of
palladium, platinum, iridium and gold catalyzed reactions
involving carboalkoxylation of 2-susbtituted alkenyl indoles
(Fig. 2).3,4 Similarly organocatalytic Friedel-Craft’s type
alkylation of 2-substituted indolyl-α,β−aldehydes and
transition metal catalyzed allylic alkylation of 2/3-substituted
indoles are shown to yield tetrahydrocarbazoles. Very
recently Nielsen and Zhang groups have reported phosphoric
acid catalyzed synthesis of tetrahydrocarbazoles, limited only
for the synthesis of indole susbstitution.4d-e Application of
Scheme 1: Selected literature reports on tetrahydrocarbazole
synthesis

2
In a solitary example Zheng et al.6e have demonstrated the
synthesis of tetrahydrocarbazole from indolylphenylbutanol
via a three step protocol during their mechanistic investigation
concerning the stereoselective migration of spiroindolenines.
In order to develop a new sophisticated methodology, it was
reasoned that the formation of a carbocation from indole-3-
butanol would lead to the spiroindolenines which would
rearrange to form the tetrahydrocrabazole. Herein, it is
disclosed the efforts concerning the transition metal free,
Brønsted acid catalyzed, Friedel-Craft’s type reaction for the
divergent synthesis of tetrahydrocarbazoles starting from
simple 3-substituted indole butanols 1 (Scheme 1).
quantitative yield. No reaction was observed with camphor
sulphonic acid, acetic acid and trifluoroacetic acid. All the
results are summarised in table 1.
After examining the reaction conditions, TfOH was chosen as
the suitable catalyst since it produced excellent yield of the
tetrahydrocarbazole in shorter reaction time. With this
optimized condition synthesis of various tetrahydrocarbazoles
were attempted.
Alcohols 1b-d were subjected to reaction with catalytic
amount of TfOH in CH2Cl2 and afforded the products 5a-d in
good to excellent yields (Chart 2). Acid sensitive
heteroaromatic (furyl) substitututed alcohol 1e furnished the
tetrahydrocarbazole 5e in almost quantitative yield.
Incidentally, reaction of the alcohol 1f containing the pyridine
group did not yield the desired product. Performing the
reaction with the allylic and propargylic substituted alcohols
1g-h also furnished the tetrahydrocarbazoles 5g and 5h
respectively. It is interesting to note that during the course of
reaction no isomerisation of double bond in presence of TfOH
was observed and the alkyne did not undergo any
hydroalkoxylation. It is worth noting that the
tetrahydrocarbazole 5g was prepared by Bandini et al. in a
multi step sequenece starting from 3-indolylpropanol.6d
Accordingly, the investigations commenced with the
preparation of required alcohols 1a-f from the Weinreb amide
3 synthesized7 from commercially available indole-3-butyric
acid (2). Addition of different Grignard or organolithium
reagents to 3 yielded the ketones 4a-f which on reduction with
NaBH4 rendered the required alcohols 1a-f in good to
excellent yields (Chart 1).
Chart 1: Synthesis of alcohols 1a-f
Chart 2: Synthesis of tetrahydrocarbazoles: Substrate scope
At this stage, we intended to investigate the reaction of
tertiary alcohols derived from 4 in the formation of
tetrahydrocarbazoles.
Accordingly,
addition
of
vinylmagnesium bromide to the phenyl ketone 4a furnished
the tertiary alcohol 1i in quantitative yield. Addition of
vinylmagnesium bromide to the ketones resulting from the
addition of PhMgBr/EtMgBr to N-allyl Weinreb amide 6 gave
the tertiary alcohols 1j-k. Reaction of excess
methylmagnesium bromide with the ester 7 furnished the
known tertiary alcohol 1l in 99% yield (Scheme 2).
Table 1: Synthesis of tetrahydrocarbazole 5a from 1a
Entry
Catalyst
FeCl3⋅6H2O
TfOH
Time (h) % Yield of 5a
1
2
3
4
5
6
7
8
2
0.5
2
82
98
p-TSA
32
O
OH
Ph
2
99
BF3⋅OEt2
TMSOTf
CSA
MgBr
THF, 0 o
Ph
C
NH
4a
NH
1.2
2
99
quant
1i
NR
NR
NR
i) R3MgBr
O
N
OH
R3
THF, 0 o
C
Acetic acid
TFA
2
NaH, THF
0 o
allyl bromide, 90%
then aq. NH4Cl
3
N
OMe
N
C
R1
= R1 = allyl
ii)
MgBr
THF, 0 o
R1
2
R
3 = Ph, 98%
6
C
1j
NR: No Reaction
1k R3 = Et, quant
over 2 steps
O
MeMgBr
After accomplishing the synthesis of the required alcohol 1a-
h, optimization of reaction conditions for the formation of
tetrahydrocarbazole 5a from 1a was examined. Reaction of
the alcohol 1a with 10 mol% of FeCl3.6H2O as catalyst
afforded the product in 82% yield. When the catalyst was
changed from FeCl3.6H2O to Brønsted acid such as triflic
acid, the reaction proceeded with shorter reaction time and an
improved yield of 98% of the product was observed. Reaction
with p-TSA was incomplete and the product was obtained in
32% yield with 64% recovering of starting material. However,
reaction with BF3.OEt2 and TMSOTf afforded the product in
OH
OEt
THF, 0 o
99%
C
NH
NH
1l
7
Scheme 2: Synthesis of tertiary alcohols 1i-l
Tertiary alcohols 1i-l under optimized reaction condition
furnished the corresponding tetrahydrocarbazoles 5i-l in
moderate yields. Yields of these products were found to be
lower compared to other substrates. Structure of the formed
tetrahydrocrabazole 5i was characterized by different
spectroscopic techniques and was further unambiguously
confirmed by X-ray analysis.9

3
Chart 3: Synthesis of tetrahydrocarbazoles comprising a
quaternary centre
and it was observed that the migration to form the
tetrahydrocarbazole is more faster (Fig. 3).
Application of the formed tetrahydrocarbazoles is shown in
the synthesis of 2,3,3a,6-tetrahydro-1H-pyrido[3,2,1-
jk]carbazole and carbazoles frameworks which are found in
many natural products.1b-c DDQ assisted oxidation of
tetrahydrocarabzoles 5a, 5c and 5d gave the carbazoles 8a, 8c
and 8d respectively in good yields. The tetrahydrocarbazole
5j on ring closing metathesis reaction with Grubbs’ second
generation catalyst (G-II) gave the tetracyclic compound 9 a
structural motif present in a number of alkaloids (Scheme 3).
Formation of tetrahydrocarbazoles can be explained by a
mechanism proposed by Zheng et al., Jackson and Smith. 6e,8
Formation of the carbocation ts1 and which reaction in
intramolecular fashion at the 3rd position of indole to forms
the spiro intermediate ts2. The iminium ion of ts2 facilitates
the 1,2 migration of benzylic bond to form
thermodynamically more stable intermediate ts3 which on
further aromatization leads to the tetrahydrocrabazole 5a (Fig.
2).
Scheme 3: Synthesis of carbazoles 8a-c and 2,3,3a,6-
tetrahydro-1H-pyrido[3,2,1-jk]carbazole (9)
In summary, a general route was developed for the synthesis
of tetrahydrocarbazoles starting from commercially available
indole-3-butyric acid via indole-3-butanols. Scope of the
reaction was shown for a variety of substrates. The reaction is
transition metal free with low catalyst loading, easy substrate
preparation and short reaction time. The broad substrate scope
makes this strategy more efficient and general from a
synthetic viewpoint.
Acknowledgement
Figure 2: Plausible mechanism for the formation of
tetrahydrocarbazole 5a
L. N. N. thanks DST, SERB, India, for National Postdoctoral Fellowship and
Prof. K. R. Prasad for providing valuable suggestions and research facilities.
Supporting Information
Yes
References and Notes
1. (a) Campbell, N.; Barclay, B. M. Chem. Rev. 1947, 40, 359; (b) Pelletier,
P. J.; Caventou, J. B. Ann. Chim. Phys. 1818, 8, 323; (c) Janot, M.-M.;
Pourrat, H.; Men, J. Le.; Bull. Soc. Chim. Fr. 1954, 707; (d) Deutsch, H. F.;
Evenson, M. A.; Drescher, P.; Sparwassers, C.; Madsen, P. J. Pharm.
Biomed. Anal. 1994, 12, 1283; (e) Cardellina, J. H.; Kirkup, M. P.; Moore, R.
E.; Mynderse, J. S.; Seff, K.; Simmons, C. J. Tetrahedron Lett. 1979, 4915;
(f) Kato, S.; Kawai, H.; Kawasaki, T.; Toda, Y.; Urata, T.; Hayakawa, Y. J.
Antibiot. 1989, 42, 1879.
5.8
5.6
5.4
5.2
5.0
4.8
4.6
4.4
4.2
4.0
3.8
3.6
3.4
3.2 ppm
Figure 3: (1H) NMR (in CD2Cl2) kinetic study
2. Borch, R. F.; Newell, R. G. J. Org. Chem.1973, 38, 2729.
3. (a) Liu, C.; Widenhoefer, R. A. J. Am. Chem. Soc. 2004, 126, 10250; (b)
Kinetics of the cyclization was studied by 1H NMR
experiment to detect any intermediates based on above
proposed mechanism. The sample was taken in CD2Cl2 and at
Liu, C.; Han. X.; Wang, X.; Widenhoefer, R. A. J. Am. Chem. Soc. 2004,
126, 3700; (c) Han, X.; Widenhoefer, R. A. Org. Lett. 2006, 8, 3801; (d) Liu,
C.; Widenhoefer, R. A. Org. Lett. 2007, 9, 1935.
1
various time interval H NMR was checked. After loading 10
4. (a) Li, C-F.; Liu, H.; Liao, J.; Cao, Y-J.; Liu, X-P.; Xiao, W-J. Org. Lett.
2007, 9, 1847; (b) Bandini, M.; Eichholzer, A. Angew. Chem. Int. Ed. 2009,
48, 9533; (c) Huang, H.; Peters, R. Angew. Chem. Int. Ed. 2009, 48, 604; (d)
Yu, S.; Chen, H.; Xu, X.; Yuan, W.; Zhanga, X.; J. Heterocyclic Chem. 2018,
doi: 10.1002/jhet.3079; (e) Hansen, C.L.; Ohm, R. G.; Olsen, L. B.; Ascic,
E.; Tanner, D.; Nielsen, T. E. Org. Lett. 2016, 18, 5990.
mol% of catalyst, the reaction proceeds very fast and spectra
was not clear and peak broadening was observed. In an
intention to get good spectra, only 1 mol% of catalyst was
1
loaded and H NMR was checked at 6 min to 240 minutes
time interval. The progress of the cyclization was clearly
observed by the change in chemical shift value of proton Ha
that changes from δ 4.75 to 4.23 with increase in time. NMR
monitoring of the reaction always led to the final product
only. The spirocyclic structure intermediate could not be seen
5. (a) Inagaki, F.; Mizutani, M.; Kuroda, N.; Mukai, C. J. Org. Chem. 2009,
74, 6402; (b) Wang, X-F.; Chen, J-R.; Cao, Y-J.; Cheng, H-G.; Xiao, W-J.
Org. Lett. 12, 2010, 1140; (c) Cao, Y-J.; Cheng, H-G.; Lu, L-Q.; Zhang, J-J.;
Cheng, Y.; Chen, J-R.; Xiao, W-J. Adv. Synth. Catal. 2011, 353, 617; (d)
Krishna, N. H.; Saraswati, P.; Sathish, M.; Shankaraiaha, N.; Kamal, A.
Chem. Commun. 2016, 52, 4581; (e) Ren, J-W.; Zhou, Z-F.; Xiao, J-A.;

4
Chen, X-Q.; Yang, H. Eur. J. Org. Chem. 2016, 1264; (f) Zhao, S. Z.;
Andrade, R. B. J. Org. Chem. 2017, 82, 521; (g) Chen, S.; Li, Y.; Ni, P.;
Yang, B.; Huang, H.; Deng, G-J. J. Org. Chem. 2017, 82, 2935; (h) Wu, X.;
Zhu, H-J.; Zhao, S-B.; Chen, S-S.; Luo, Y-F.; Li, Y-G. Org. Lett. 2018, 20,
32; (i) Pirovano, V.; Borri, M.;Abbiati, G.; Rizzato, S.; Rossi, E. Adv. Synth.
Catal. 2017, 359, 1912; (j) Wang, Y.; Tu, M. S.; Yin, L.; Sun, M.; Shi, F. J.
Org. Chem. 2015, 80, 3223; (k) Zhou, L. J.; Xu, B.; Zhang, J. L. Angew.
Chem. Int. Ed. 2015, 54, 9092; (l) Zhao,F.; Li, N.; Zhu, Y. F.; Han, Z. Y.
Org. Lett. 2016, 18, 1506.
6. (a) Cao, Y-J.; Cheng, H-G.; Lu, L-Q.; Zhang, J-J., Cheng, Y.; Chen, J-R.;
Xiao, W-J. Adv. Synth. Catal. 2011, 353, 617 ; (b) Zhu, X-Y.; An, X-L.; Li,
C-F.; Zhang, F-G.; Hua, Q-L.; Chen, J-R.; Xiao, W-J. Chem. Cat. Chem.
2011, 3, 679; (c) Wu, Q-F.; Zheng, C.; You, S-L. Angew. Chem. Int. Ed.
2012, 51, 1680 ; (d) Bandini, M.; Bottoni, A.; Chiarucci, M.; Cera, G.;
Miscione, G. P. J. Am. Chem. Soc. 2012, 134, 20690; (e) Zheng, C.; Wu, Q-
F.; You, S-L.; J. Org. Chem. 2013, 78, 4357; (f) Gimeno, A.; guez-Gimeno,
A. R.; Cuenca, A. B.; de Arellano, C. R.; Medio-Simo´n, M.; Asensio, G.
Chem. Commun. 2015, 51, 12384; (g) Liu, Q-J.; Yan, W-G.; Wang, L.;
Zhang, X. P.; Tang, Y. Org. Lett. 2015, 17, 4014; (h) Liu, Q. J.; Yan, W.
G.;Wang, L. J.; Zhang, X. P.; Tang, Y. Org. Lett. 2015, 17, 4014; (i)
Pirovano, V.; Arpini, E.; Dell’Acqua, M.; Vicente, R.;Abbiati, G.; Rossi, E.
Adv. Synth. Catal. 2016, 358, 403; (j) Zhao, F.; Li, N.; Zhu, Y-F.; Han, Z-Y.
Org. Lett. 2016, 18, 1506; (k) Mishra, U. K.; Yadav, S.; Ramasastry, S. S. V.
J. Org. Chem. 2017, 82, 6729; (l) Williams, D. R.; Bawel, S. A.; Schaugaard,
R. N.; Org. Lett. 2017, 19, 5098; (m) Yang, R-Y.; Sun, J.; Tao, Y.; Sun, Q.;
Yan, C-G. J. Org. Chem. 2017, 82, 13277; (n) Garayalde, D.; Rusconi, G.;
Nevado, C. Helv. Chim. Acta. 2017, 100, e1600333; (o) Abid, M.; Teixeira,
L.; Török, B. Tetrahedron Lett., 2007, 48, 4047; (p) Tharra, P.; Baire, B. Org.
Lett. 2018, 20, 1118.
7. (a) Gillard, R. M.; Sperry, J. J. Org. Chem. 2015, 80, 2900.
8. A solitary example of simple indolylbutanol comprising a tritium affording
.
the tetrahydrocarbazole using BF3 OEt2 as catalyst is reported in literature as a
part of the mechanistic study for the Pictet-Spengler reaction. See: (a)
Jackson, H. A.; Smith, P. Chem. Comm. 1967, 264; (b) Jackson, A. H.;
Naidoo, B.; Smith, P. Tetrahedron 1968, 6119.
9. CCDC 1826833 (5i) contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.

5
Efficient synthesis of tetrahydrocarbazoles
Broad substrate scope
Transition metal free
Low catalyst loading