Cascade radical cyclization of N-propargylindoles: Substituents dictate stereoselective formation of N-fused indolines versus indoles

Article abstract of DOI:10.1021/acs.orglett.7b02005

An efficient protocol for the synthesis of pyrrolo[1, 2- a]indole derivatives having sulfide functionality using cascade radical cyclization on propargylindole is described. The nature of the substituents at the propargylic carbon bearing nitrogen of the indole has a profound effect on the rate, yield, and nature of the product obtained by the cascade radical cyclization. An expeditious one-pot route for cascade radical cyclization-desulfurization is also presented. Products obtained were elaborated to the core of the putative structure of the yuremamine and indoline derivative with five contiguous stereocenters.

Full text of DOI:10.1021/acs.orglett.7b02005

Letter
pubs.acs.org/OrgLett
Cascade Radical Cyclization of N‑Propargylindoles: Substituents
Dictate Stereoselective Formation of N‑Fused Indolines versus
Indoles
Santosh J. Gharpure* and Yogesh G. Shelke
Department of Chemistry, Indian Institute of Technology Bombay, Powai, Mumbai 400076, India
S
* Supporting Information
ABSTRACT: An efficient protocol for the synthesis of pyrrolo[1,2-
a]indole derivatives having sulfide functionality using cascade radical
cyclization on propargylindole is described. The nature of the
substituents at the propargylic carbon bearing nitrogen of the indole
has a profound effect on the rate, yield, and nature of the product
obtained by the cascade radical cyclization. An expeditious one-pot
route for cascade radical cyclization−desulfurization is also presented. Products obtained were elaborated to the core of the
putative structure of the yuremamine and indoline derivative with five contiguous stereocenters.
mong annelated indoles, pyrrolo[1,2-a]indole is a priv-
ileged and celebrated scaffold owing to its structural
diversity and analogy to antitumor agents mitomycins (1),
which show the extraordinary ability of cross-linking DNA
(Figure 1).1 Isatisine A (2) is a unique fused indolone alkaloid
Organosulfur compounds, such as sulfides and sulfoxides, are
valuable building blocks in organic synthesis and commonly
found in many natural products and biologically active
compounds.7 In this context, we reasoned that synthesis of N-
fused indoles bearing sulfide functionality incorporated in the
ring would be of interest. In continuation of our interest in the
stereoselective synthesis of ring-fused heterocycles in general and
pyrrolo[1,2-a]indole derivatives in particular, herein we disclose
a cascade thiyl radical cyclization of propargyl indoles for the
rapid construction of N-fused indolines as well as indoles.8 We
also demonstrate that substitution on propargyl indoles has a
profound effect on the rate and outcome of these radical
cyclizations.
A
We envisioned that the pyrrolo[1,2-a]indole/indolines 6/7
could be rapidly assembled using a cascade radical cyclization of
N-propargylindole 8 initiated by an appropriate radical precursor
(X = ArS) via the intermediate 9 (Scheme 1). If the last step of
Scheme 1. Retrosynthetic Analysis for Pyrrolo[1,2-a]indole/-
indoline (6/7)
Figure 1. Natural products bearing pyrrolo[1,2-a]indole core.
with antiviral activity.2 Flinderole C (3) is a pyrrolo[1,2-a]indole
that shows antimalarial properties.3 Callaway and co-workers
isolated yuremamine, a phytoindole alkaloid with hallucinogenic
and psychoactive properties, from the stem bark of Mimosa
hostilis and assigned its structure as pyrrolo[1,2-a]indole
derivative (4).4
During their biomimetic synthesis of the proposed yurem-
amine pyrroloindole (4), Sperry et al. serendipitously found the
true structure of the natural product to be flavonoidal indole
(5).5 Interesting biological activity coupled with the structural
diversity of the pyrrolo[1,2-a]indole scaffold has generated
significant interest among synthetic chemists, and efforts toward
synthesis of these derivatives have been described.6
the radical cascade proceeds in reductive manner, pyrrolo[1,2-
a]indolines 7 should be formed in a stereoselective manner. On
the other hand, if the radical 9 after 5-exo-trig cyclization
undergoes oxidation, pyrrolo[1,2-a]indole 6 would be the
product.
Received: July 1, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02005
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
It was also argued that the latter outcome could be potentially
used to gain access to the putative core structure of yuremamine
(4). To test our strategy, synthesis of propargyl indole 8 was
initiated. While the primary propargyl indole 8a is known,9a the
secondary propargyl indole 8b was prepared in a three-step
protocol (Scheme 2). Thus, copper(I)-catalyzed propargylic
Thus, we started exploring the scope of the radical cascade for the
synthesis of N-fused indolines 7 using thiophenol derivatives.
The scope of the cascade radical cyclization reaction was
studied by changing the substituents on the propargylindole
moiety. The cyclization readily took place with propargylindole
derivatives 8c−e having electron rich as well as electron-deficient
aryl rings on the alkyne to deliver N-fused indoline 7c−e, with
latter giving better yields than former (Scheme 4). The substrate
Scheme 2. Synthesis of the Secondary Propargylindole 8b
Scheme 4. Scope of Synthesis of N-Fused Indoline
a
Derivatives
substitution on acetate 10 using indoline 11 as nucleophile
furnished the terminal alkyne 12b in excellent yield.10
Sonogashira coupling of terminal alkyne 12b followed by
DDQ mediated aromatization gave the requisite secondary
propargylindole 8b in good yield.
Having the primary and secondary propargylindole 8a,b in
hand, attention was turned toward using them in the proposed
cascade radical cyclization for synthesis of N-fused indoles. When
primary propargylindole 8a was subjected to reaction with
thiophenol and AIBN in refluxing benzene, tandem inter-
followed by intramolecular radical cyclization proceeded
smoothly to furnish the N-fused indoline derivative 7a in
moderate yield and excellent diastereoselectivity (Scheme 3).
Interestingly, when the secondary propargylindole 8b was used
as substrate, the pyrroloindoline 7b was obtained with improved
yield.
Scheme 3. Cascade Radical Cyclization for Synthesis of N-
Fused Indoline Derivatives 7a,b
a
In all cases, dr ≥19:1.
8f having a heteroaromatic ring attached to alkyne could be
successfully utilized in this transformation, and N-fused indoline
7f is obtained in good yield and excellent diastereoselectivity. In
the case of propargylindole 8g having no substituent at the third
position of indole, the reaction proceeded smoothly and
furnished the indoline derivative 7g in moderate yield. N-
Fused indoline derivatives 7h−k bearing a cyclohexyl ring and
side chain with free alcohol or a TBS protecting group at the third
position of indole were also synthesized from the corresponding
propargylindoles 8h−k. p-Methoxythiophenol and 2-naphthale-
nethiol led to indolines 7l,m, respectively, in excellent yields. The
stereochemistry of the three stereocenters in N-fused indoline
was assigned by single-crystal X-ray diffraction studies on the
indoline derivatives 7c and 7f.11
The scope of tertiary propargylindoles for cascade radical
cyclization was investigated next. When propargylindole 13a was
subjected to optimized reaction conditions, cascade radical
cyclization took place smoothly but surprisingly resulted in the
formation of N-fused indole derivative 6a rather than the
indoline derivative (Scheme 5). The reaction was found to be
quite general, and alkynes 13b−e bearing electron-donating as
well as electron-withdrawing substituents gave the correspond-
ing pyrrolo[1,2-a]indole derivatives 6b−e in excellent yields.
The presence of free alcohol in propargylindole is tolerated
under reaction conditions, and pyrrolo[1,2-a]indole derivatives
The stereochemistry of the indoline derivatives 7a−b was
assigned on the basis of their spectral data. This was further
unambiguously confirmed by single-crystal X-ray diffraction
studies on the indoline derivative 7b.11
In all of these reactions, formation of the N-fused indolines
7a−b was observed, and none of the pyrrolo[1,2-a]indole
derivative 7′ was formed. Interestingly, this reaction outcome is
at variance with some of the very recent studies from the groups
of Tang, Zhu, and Song who have described silver- and copper-
mediated tandem phosphinoylation/cyclization process to
construct 2-phosphinoyl-9H-pyrrolo[1,2-a]indole derivatives.9
This variation in the outcome can be attributed to neutral
conditions employed in the present study instead of acidic ones
as in the earlier reports, which led to isomerization of initially
formed indole derivatives. While these strategies were useful,
they gave only moderate yields of the products. Further, the
substituent effect on carbon next to nitrogen has not been
studied, which is an important aspect in the context of synthesis
of putative structure of yuremamine (4). Finally, the choice of
thiophenol as radical precursor allows further functionalization
of the products, which in turn enhances the utility of this method.
B
DOI: 10.1021/acs.orglett.7b02005
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 5. Scope of Synthesis of Pyrrolo[1,2-a]indole
Derivatives
Scheme 6. Proposed Mechanism and Rational for
Stereochemical Outcome
Further, the thiol radical cyclization leading to the N-fused
indoline/indole derivative displayed an interesting trend in the
rate and yield of the reaction. Thus, while going from primary
(8a) to secondary (8b) to tertiary (13a) propargylindole
substrates, the reaction time reduced significantly. The yield of
the indoline/indole product was also increased (Table 1). This
Table 1. Substrate-Dependent Radical Cyclization Leading to
Indoline/Indole: Thorpe−Ingold Effect
6f,n were obtained in excellent yield. Propargylindole derivative
13g with a heteroaryl ring underwent reaction smoothly to give
the corresponding pyrroloindole 6g in good yield. The
spirocyclic pyrrolo[1,2-a]indole derivatives 6h−j were synthe-
sized using tandem radical cyclization on propargylindole
precursors 13h−j in good yields. The absence of a substituent
at the third position of the indole or presence of a cyclohexyl ring
did not have any impact on the yield of the reaction, and
pyrrolo[1,2-a]indole derivatives 6k−m were obtained in good
yields. The structure of pyrrolo[1,2-a]indole derivatives was
assigned on the basis of their spectral data and further
unambiguously confirmed by single-crystal X-ray diffraction
studies on N-fused indole derivatives 6h−j,m.11
In cascade radical cyclization, primary and secondary
propargylindoles 8 gave N-fused indoline derivatives 7 in good
yield and as a single diastereomer. On the other hand, tertiary
propargylindoles 13 gave N-fused indoles 6. This substituent-
dependent diverse formation of the products and stereochemical
outcomes can be explained on the basis of the mechanism
depicted in Scheme 6. Intermolecular thiyl radical addition to
alkyne 8 generates the vinyl radical 9, which undergoes a 5-exo-
trig radical cyclization on the indole moiety to furnish the
intermediate 14a. During this cyclization, the bulkier aryl ring in
vinyl radical 9 prefers to occupy the sterically less crowded
convex face (transition state structure A vs B). The reduction of
the radical 14a proceeds through a late transition state, and
hence, the alkyl substituent prefers to be on the sterically less
incumbent convex face via delivery of the hydrogen from the
concave face to furnish the indoline 7. In the case of tertiary
propargylindole 13, due to presence of an alkyl group in the
concave face in the intermediate 14b, the delivery of the
hydrogen from the PhSH, which would lead to the indoline 15, is
slowed down, and instead, a competing hydrogen abstraction by
the PhS leads to the indole derivative 6 with the concomitant
aromatization being the driving force.7f
entry
substrate
R2
R3
time (h)
yield (%)
product
1
2
3
8a
H
H
10
3
40
68
85
7a
7b
6a
8b
Ph
Me
H
13a
Me
1
trend in rate and efficiency could be attributed to the “gem-dialkyl
effect” also referred to as the “Thorpe−Ingold effect” during the
5-exo-trig radical cyclization of the vinyl radical 9 on the indole
moiety (cf. Scheme 6).12 As we increase the size of the
substituents at the propargylic position, the angle between alkyne
and the indole moiety decreases with a reduction in conforma-
tional flexibility, which leads to rate acceleration.
In order to further elaborate these N-fused indole derivatives,
we attempted Raney nickel mediated desulfurization on the
indoline 7b. Product 16 was obtained in good yield via selective
desulfurization, and the olefin reduction was not observed
(Scheme 7). Interestingly, addition of excess of thiophenol
during cyclization of the alkyne 13a also resulted in the formation
of the product 17a. The intermediate vinyl sulfide 6a formed in
this reaction underwent desulfurization through the radical
path.13 The method was general for indole derivatives, and
propargylindoles 13g, 13k also underwent radical cyclization
followed by desulfurization smoothly to furnish the correspond-
ing products 17g, 17k.
Finally, hydroboration of the indole 17a followed by oxidation
gave the alcohol 18a in good yield, which constitutes the
synthesis of core of the putative structure of yuremamine (4)
(Scheme 8). Interestingly, hydroboration−oxidation of pyrro-
loindole 16 gave indoline derivative 19 in a highly regio- and
diastereoselective fashion. This sequence is noteworthy as it
C
DOI: 10.1021/acs.orglett.7b02005
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 7. Desulfurization of N-Fused Indolines 7 and Indoles
6
ACKNOWLEDGMENTS
■
We thank BRNS, Mumbai, the Council of Scientific and
Industrial Research (CSIR), New Delhi, and SERB, New
Delhi, for financial support. We thank Mr. Darshan Mhatre of
the X-ray facility of the Department of Chemistry, IIT Bombay,
for collecting the crystallographic data and IRCC, IIT Bombay,
for funding. We are grateful to CSIR, New Delhi, for the award of
research fellowships to Y.G.S.
REFERENCES
■
(1) (a) Bradner, W. T. Cancer Treat. Rev. 2001, 27, 35. (b) Wolkenberg,
S. E.; Boger, D. L. Chem. Rev. 2002, 102, 2477.
(2) Liu, J.-F.; Jiang, Z.-Y.; Wang, R.-R.; Zheng, Y.-T.; Chen, J.-J.; Zhang,
X.-M.; Ma, Y.-B. Org. Lett. 2007, 9, 4127.
(3) Fernandez, L. S.; Buchanan, M. S.; Carroll, A. R.; Feng, Y. J.; Quinn,
R. J.; Avery, V. M. Org. Lett. 2009, 11, 329.
(4) Vepsalainen, J. J.; Auriola, S.; Tukiainen, M.; Ropponen, N.;
Callaway, J. C. Planta Med. 2005, 71, 1053.
Scheme 8. Synthesis of Core of Putative Structure of
Yuremamine (4)
(5) Calvert, M. B.; Sperry, J. Chem. Commun. 2015, 51, 6202.
(6) (a) Monakhova, N.; Ryabova, S.; Makarov, V. J. Heterocyclic Chem.
2016, 53, 685. (b) Johansen, M. B.; Kerr, M. A. Org. Lett. 2008, 10, 3497.
(c) Patil, D. V.; Cavitt, M. A.; France, S. Org. Lett. 2011, 13, 5820.
(d) Chen, K.; Zhang, Z.; Wei, Y.; Shi, M. Chem. Commun. 2012, 48,
7696. (e) Cui, H.-L.; Feng, X.; Peng, J.; Lei, J.; Jiang, K.; Chen, Y.-C.
Angew. Chem., Int. Ed. 2009, 48, 5737. (f) Liu, W.- B.; Zhang, X.; Dai, L.-
X.; You, S.-L. Angew. Chem., Int. Ed. 2012, 51, 5183. (g) Dethe, D. H.;
Boda, R.; Das, S. Chem. Commun. 2013, 49, 3260. (h) Li, H.; Wang, Z.;
Zu, L. RSC Adv. 2015, 5, 60962. (i) Calvert, M. B.; Sperry, J. Org. Biomol.
Chem. 2016, 14, 5728. (j) Ghosh, A.; Bainbridge, D. T.; Stanley, L. M. J.
Org. Chem. 2016, 81, 7945.
(7) (a) Schaumann, E. Sulfur-Mediated Rearrangements (I-II); Springer:
Berlin, 2007. (b) Cremlyn, R. J. An Introduction to Organosulfur
Chemistry; John Wiley and Sons: Chichester, UK, 1996. (c) Block, E.
Reactions of Organosulfur Compounds; Academic Press: New York, 1978.
(d) Organic Chemistry of Sulfur; Oae, S., Ed.; Plenum: New York, 1977.
(e) Chatgilialoglu, C.; Bertrand, M. P.; Ferreri, C. In S-Centered Radicals;
provides an expeditious access to the N-fused indoline 19
possessing five contiguous stereocenters.
In conclusion, an efficient, cascade thiyl radical cyclization for
the synthesis of N-fused indole and indoline derivatives has been
developed. Primary and secondary propargylindole derivatives
furnish N-fused indoline in a highly diastereoselective manner,
while tertiary propargylindoles gave access to pyrrolo[1,2-
a]indole derivatives. The reaction is found to be very sensitive
with respect to substituents present at carbon next to the
nitrogen of indole, and the “Thorpe−Ingold effect” was observed
in this cascade radical cyclization. We have also shown that the
cascade radical cyclization followed by desulfurization can be
carried out in the same pot. The desulfurized products were
elaborated to the core of the putative structure of the
yuremamine as well as highly stereoselective synthesis of
indoline bearing five contiguous stereocenters.
́ ̀
Alfassi, Z. B., Ed.; John Wiley & Sons: Chichester, 1999. (f) Denes, F.;
Pichowicz, M.; Povie, G.; Renaud, P. Chem. Rev. 2014, 114, 2587.
(g) Capella, L.; Montevecchi, P. C.; Navacchia, M. L. J. Org. Chem. 1996,
61, 6783. (h) Rahaman, H.; Ueda, M.; Miyata, O.; Naito, T. Org. Lett.
2009, 11, 2651. (i) Miyata, O.; Nishiguchi, A.; Ninomiya, I.; Aoe, K.;
Okamura, K.; Naito, T. J. Org. Chem. 2000, 65, 6922.
(8) (a) Gharpure, S. J.; Sathiyanarayanan, A. M. Chem. Commun. 2011,
47, 3625. (b) Gharpure, S. J.; Prasath, V. Org. Biomol. Chem. 2014, 12,
7397. (c) Gharpure, S. J.; Shelke, Y. G.; Kumar, D. P. Org. Lett. 2015, 17,
1926. (d) Gharpure, S. J.; Nanda, S. K. Org. Biomol. Chem. 2016, 14,
5586.
(9) During preparation of our manuscript, the following radical
cyclizations were reported on indole: (a) Chen, S.; Zhang, P. B.; Shu, W.
Y.; Gao, Y. Z.; Tang, G.; Zhao, Y. F. Org. Lett. 2016, 18, 5712. (b) Zhang,
H.; Li, W.; Zhu, C. J. Org. Chem. 2017, 82, 2199. (c) Xu, J.; Yu, X.; Song,
Q. Org. Lett. 2017, 19, 980. (d) Zhang, P.; Gao, Y.; Chen, S.; Tang, G.;
Zhao, Y. Org. Chem. Front. 2017, 4, 1350.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b02005.
■
S
(10) Hattori, G.; Sakata, K.; Matsuzawa, H.; Tanabe, Y.; Miyake, Y.;
Nishibayashi, Y. J. Am. Chem. Soc. 2010, 132, 10592.
(11) CCDC 1555451−1555457 (7b,c,f, 6h−j,m) 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.
Synthetic procedures and characterization data of
products (PDF)
Crystallographic data for 6h−j,m and 7b,c,f (ZIP)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: sjgharpure@iitb.ac.in.
ORCID
(12) Jung, M. E.; Piizzi, G. Chem. Rev. 2005, 105, 1735.
(13) (a) This was confirmed by independently subjecting the sulfide
6a to reaction conditions, which resulted in the formation of the indole
17a. No reaction was observed in the absence of radical initiators.. (b)
For a review on desulfurization, see: Rentner, J.; Kljajic, M.; Offner, L.;
Breinbauer, R. Tetrahedron 2014, 70, 8983.
Santosh J. Gharpure: 0000-0002-6653-7236
Yogesh G. Shelke: 0000-0003-3157-1159
Notes
The authors declare no competing financial interest.
D
DOI: 10.1021/acs.orglett.7b02005
Org. Lett. XXXX, XXX, XXX−XXX