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org/OrgLett Letter

Stereoselective Routes to Hexahydropyrroloindoles and

Tetrahydropyrroloquinolines from Activated Aziridines and Electron
Deficient 3H‑Indoles
Imtiyaz Ahmad Wani, Sahid Sk, Abhijit Mal, Arunava Sengupta, and Manas K. Ghorai*
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ABSTRACT: An unprecedented and novel synthetic route to

hexahydropyrrolo[2,3-b]indoles bearing cis-contiguous stereocen-
ters with excellent stereoselectivities (ee of >99%, dr of ≤99:1) has
been disclosed that proceeds through the ring opening of activated
aziridines with electron deficient 4-substituted indoles followed by
a novel cyclization in a domino fashion, thereby obviating the use
of 3-substituted indoles as the prerequisite nucleophile. Another
efficient synthetic route to tetrahydropyrrolo[4,3,2-de]quinolines in
excellent yields (≤93%) and excellent enantioselectivity (ee of
>99%) has been established via ring opening of activated aziridines with 4-bromo-1-methyl-1H-indole at relatively higher
temperatures followed by Cu(I)-catalyzed intramolecular C−N cyclization in the same pot. The stability and the formation of
products at different temperatures are explained by computational studies.

H exahydropyrrolo[2,3-b]indoles make up an important

class of organic compounds exhibiting significant
biological and pharmaceutical activity. 4-Bromohexahydro-
pyrrolo[2,3-b]indole derivatives, including recently isolated
securamines H, J, and E, are found to exhibit cytotoxicity
against human cancer cells.1 Similarly, tetrahydropyrrolo[4,3,2-
de]quinolines make up another class of tricyclic heterocyclic
skeletons with significant pharmacological activity; e.g.,
dehydrobufotenine is a bioactive alkaloid found in South
American toad poison.2 A range of marine alkaloids, viz.,
damirone A and makaluvamine C, act as DNA topoisomerase
II inhibitors2 (Figure 1).
The known synthetic routes to hexahydropyrrolo[2,3-
b]indoles from aziridines, including our previous report3
along with other approaches,4 necessarily require 3-substituted
indoles as the essential substrate;5 on the contrary, the 3-
unsubstituted indoles generally produce ring-opening-aromat-
ized products after Friedel−Crafts-type alkylation with a
variety of electrophiles, including aziridines. Therefore, the
scope of all of the previous methodologies is limited and the
products are obtained with at least one substituent other than
hydrogen at the ring junction.6 However, the hexahydro-
pyrrolo[2,3-b]indoles possessing all hydrogens at ring
junctions have a significant reactivity profile as manifested in
asymmetric catalysis7 and in total syntheses of various natural
products.8 This specific substitution pattern is also conducive
to benzylic bromination that allows the synthetic and
medicinal chemists to perform further synthetic operations
such as reductive dimerization,9 heterodimerization,10 coupling
reactions,11a dehalogenation,11b methanolysis,11c etc.
To overcome the limitations of earlier reports on the
synthesis of hexahydropyrrolo[2,3-b]indoles from aziridines
and to offer a practical solution to this long-standing
conundrum, we anticipated that a change in the direction of
the reaction pathway by controlling the aromatization step
could be achieved by proper substitution of the indole ring
with electron-withdrawing groups (EWGs) to afford

Received: July 12, 2022

Published: September 12, 2022

Figure 1. Hexahydropyrrolo[2,3-b]indole- and tetrahydropyrrolo-

[4,3,2-de]quinoline-containing natural alkaloids.

© 2022 American Chemical Society https://doi.org/10.1021/acs.orglett.2c02354

7867 Org. Lett. 2022, 24, 7867−7872
Organic Letters pubs.acs.org/OrgLett Letter

hexahydropyrrolo[2,3-b]indoles with all hydrogens at ring Table 1. Optimization of the Reaction Conditions for the
junctions. Via proper substitution, intramolecular cyclization in Syntheses of Hexahydropyrrolo[2,3-b]indole
a domino fashion will be favored more than rearomatization
through the stabilization of the iminium ion intermediate for a
longer time (Scheme 1).

Scheme 1. Retrosynthetic Analogy for the Synthesis of

Hexahydropyrrolo[2,3-b]indoles from Activated Aziridines yield of 3aa yield of 4a
and Electron Deficient 3H-Indoles entry reaction conditions (%) (%)
1 LiClO4 (10), CH3CN, 60 °C, 8 h 74 trace
2 Cu(OTf)2 (10), CH2Cl2, reflux, 0 72
1h
3 Zn(OTf)2 (10), CH2Cl2, reflux, 0 54
2h
4 Sc(OTf)3 (10), CH2Cl2, reflux, 1 h 0 80
5 Yb(OTf)3 (10), CH2Cl2, reflux, 0 65
2h
6 LiClO4 (5), CH3CN, 60 °C, 12 h 54 trace
As a continuation of our extensive studies in the area of LA- 7 LiClO4 (20), CH3CN, 60 °C, 6 h 78 0
catalyzed SN2-type ring opening of activated aziridines12 in 8 LiClO4 (10), CH3CN, 85 °C, 6 h 32 64
general and the synthesis of pyrrolo[2,3-b]indoles4 in 9b LiClO4 (10), DMF, 80 °C, 12 h − −
particular, we report herein a novel strategy for the 10b LiClO4 (10), DMSO, 80 °C, 12 h − −
stereoselective synthesis of hexahydropyrrolo[2,3-b]indoles 11 LiClO4 (10), toluene, 60 °C, 6 h 0 76
with all hydrogens cis at ring junctions via an unprecedented 12 LiClO4 (10), THF, 50 °C, 12 h 0 82
dearomative domino ring-opening cyclization (DROC) of a
The diastereomeric ratio of 3a was found to be 95:5 in all cases as
activated aziridines with electron-withdrawing group-substi- determined by 1H NMR analysis of the crude reaction mixture. bNo
tuted indoles. Furthermore, we have also developed another reaction was observed.
simple route to tetrahydropyrrolo[4,3,2-de]quinolines via ring-
opening cyclization (ROC) of activated aziridines with 4-
bromoindoles (Scheme 2). toward cyclic product 3a in terms of better yield and
selectivity. However, use of other metal triflates as Lewis
Scheme 2. Novel Synthetic Routes to acids consistently afforded the corresponding ring-opened
Hexahydropyrrolo[2,3-b]indoles and product 4a in varying yields (entries 2−5). Therefore, we
Tetrahydropyrrolo[4,3,2-de]quinolines considered using LiClO4 as our Lewis acid of choice. The best
result was obtained when the catalytic loading of LiClO4 was
increased to 20 mol %, and 3a was obtained exclusively in
enhanced yield (78%) with 95:5 dr (entry 7). The structure of
product 3a and the relative stereochemistry of the three
contiguous stereocenters were determined as all-cis from the
spectral data and were further confirmed by single-crystal X-ray
analysis.13 The results of the complete optimization are
detailed in Table 1.
To investigate the substrate scope of our protocol, several
racemic 2-aryl-N-tosylaziridines 1a−f with different substitu-
The initial study commenced with the reaction of 1a with 2a tion patterns on the 2-aryl groups were studied under the
in the presence of 10 mol % LiClO4 in acetonitrile at 85 °C for optimized dearomative DROC condition, and the correspond-
6 h, and to our great pleasure, the corresponding product 3a ing hexahydropyrrolo[2,3-b]indole derivatives 3a−f were
was obtained in 32% yield with excellent dr (95:5) via a obtained in excellent yields and diastereoselectivities in all
DROC along with ring-opening-aromatized product 4a in 64% cases (Table 2). When 4-Cl-phenyl-N-tosyl aziridine 1b was
yield (Scheme 3). reacted with 2a under the optimized reaction conditions, the
Inspired by the preliminary results of the discovery, we respective hexahydropyrrolo[2,3-b]indole derivative 3b was
screened various reaction conditions, including Lewis acids, obtained in high yield as a single diastereomer [99:1 dr (Table
solvents, and temperatures (Table 1), to control the 2)].
aromatization step and change the direction of the reaction Next, various 2-phenyl-N-arylsulfonylaziridines 1g−i were
studied with 2a under the optimized dearomative DROC
Scheme 3. Lewis Acid-Catalyzed Ring-Opening condition, and the corresponding hexahydropyrrolo[2,3-b]-
Transformation of Racemic 2-Phenyl-N-tosylaziridine (1a) indole derivatives 3g−i were obtained in good yields and
with 4-Bromo-1-methyl-1H-indole (2a) excellent diastereoselectivities [dr of ≤99:1 (Table 2)]. Highly
substituted hexahydropyrrolo[2,3-b]indole 3j bearing all
substituents cis at positions 2, 3, 3a, and 8a was synthesized
in good yield and excellent diastereoselectivity (dr of 99:1) by
reacting trans-2-methyl-3-phenyl-1-tosylaziridine 1j with 2a
under the optimized reaction condition.13 Interestingly,
DROC of aziridine 1a with 2b (R1 = allyl) proceeds smoothly
7868 https://doi.org/10.1021/acs.orglett.2c02354
Org. Lett. 2022, 24, 7867−7872
Organic Letters pubs.acs.org/OrgLett
Table 2. Substrate Scope for the Synthesis of Racemic
Hexahydropyrrolo[2,3-b]indoles via Lewis Acid-Catalyzed
DROC of Racemic 2-Aryl-N-tosylaziridines 1a−j with
Indoles (2a)a,c
a
The diastereomeric ratios were determined by 1H NMR analysis of
the crude reaction mixtures. bFormation of a trace amount of the
corresponding ring-opened product was observed. cYield of the
isolated product.
to afford 3k in 74% yield with a dr of 90:10. All of the results
are summarized in Table 2.
The methodology was further generalized with other
electron-withdrawing groups like cyano and α,β-unsaturated
ester at position 4 of indoles 2c and 2d. When aziridines 1a
and 1k (2-CF3-C6H4) were reacted with 2c and 2d,
respectively, to our immense pleasure, the corresponding
hexahydropyrrolo[2,3-b]indoles 3l and 3m were obtained with
excellent yields and diastereoselectivities (Scheme 4).
Scheme 4. Synthesis of Racemic Hexahydropyrrolo[2,3-
b]indoles 3l and 3m via Lewis Acid-Catalyzed DROC of
Racemic 2-Aryl-N-tosylaziridines 1a and 1k with Indoles 2c
and 2d
While optimizing the dearomative DROC strategy for the
syntheses of hexahydropyrrolo[2,3-b]indole 3a from 2-phenyl-
N-tosylaziridine 1a and 4-bromo-1-methyl-1H-indole 2a in the
presence of 10 mol % LiClO4 in acetonitrile, we observed the
formation of the corresponding ring-opening product N-[2-(4-
bromo-1-methyl-1H-indol-3-yl)-2-phenylethyl]-4-methylben-
zenesulfonamide 4a in 64% yield at a relatively higher
temperature [85 °C (Table 1, entry 8)]. The reaction
condition was further modified to obtain the ring-opened
product exclusively,13 and it was exploited in synthesizing
another biologically significant and rarely accessed class of
heterocyclic frameworks, viz., tetrahydropyrrolo[4,3,2-de]-
quinolines 5. Due to their interesting biological activity and
intricate structural features, a few synthetic reports of the
construction of such a tetrahydropyrrolo[4,3,2-de]quinoline
7869
Letter
framework are available.1,14,15 When 1a was reacted with 2a in
the presence of 20 mol % LiClO4 in acetonitrile at 90 °C for 12
h, the corresponding ring-opened product 4a was observed in
90% yield as the only product. Subsequently, 4a was subjected
to Cu(I)-catalyzed intramolecular C−N bond formation
following our earlier report,12b and gratifyingly, the corre-
sponding tetrahydropyrrolo[4,3,2-de]quinoline derivative 5a
was formed in 62% yield in 20 h (Scheme 5). The structure of
compound 5a was determined by spectral data and further
confirmed by single-crystal X-ray analysis.13
Scheme 5. Synthesis of Racemic Tetrahydropyrrolo[4,3,2-
de]quinoline 5a via Ring Opening of Racemic 2-Phenyl-N-
tosylaziridine 1a with 4-Bromo-1-methyl-1H-indole 2a
Followed by Cu(I)-Catalyzed C−N Bond Formation
The efficiency and synthetic utility of the strategy to access
the desired tetrahydropyrrolo[4,3,2-de]quinoline derivative 5a
was further enhanced by performing the reaction in one pot.
For this purpose, among the reaction conditions13 screened,
the best result was obtained by reacting aziridine 1a with 2a in
the presence of 20 mol % LiClO4 at 90 °C for 12 h followed by
treatment with 10 mol % CuI and 10 mol % trans-cyclohexyl-
1,2-diamine as the ligand in the presence of 2.0 equiv of
potassium carbonate in DMF at 110 °C in the same pot, and
the corresponding tetrahydropyrrolo[4,3,2-de]quinoline deriv-
ative 5a was formed in excellent yield (83%) after 12 h.13 The
substrate scope of the strategy was generalized by reacting a
wide range of racemic 2-aryl-N-tosylaziridines (1b−f and 1k−
m) with 2a via the optimized one-pot ring-opening/C−N
cyclization, and the corresponding tetrahydropyrrolo[4,3,2-
de]quinoline derivatives 5b−i were furnished in good to
excellent yields (≤91%) (Table 3). To study the electronic
effect of the tosyl group, various racemic 2-phenyl-N-
arylsulfonylaziridines (1g−i, 1n, and 1o) were reacted with
2a via the optimized one-pot/C−N cyclization and the
corresponding tetrahydropyrrolo[4,3,2-de]quinoline deriva-
Table 3. Synthesis of Tetrahydropyrrolo[4,3,2-
de]quinolines via One-Pot Ring-Opening Cyclization of
Racemic 2-Aryl-N-arylsulfonylaziridines 1a−i and 1k−o
with 4-Bromoindoles (2a, 2b, and 2e)
https://doi.org/10.1021/acs.orglett.2c02354
Org. Lett. 2022, 24, 7867−7872
Organic Letters pubs.acs.org/OrgLett Letter

tives 5j−n were furnished in excellent yields (≤92%). When 1- Scheme 7. Scale-up Experiments
allyl-4-bromo-1H-indole (2b) and 1-benzyl-4-bromo-1H-in-
dole (2e) served as the nucleophiles with 2-phenyl-N-
tosylaziridine (1a) under the optimized one-pot ring-open-
ing/cyclization conditions, the corresponding tetrahydro-
pyrrolo[4,3,2-de]quinoline derivatives 5o and 5p, respectively,
were obtained in excellent yields. All of the results are
summarized in Table 3.
Further synthetic significance and the scope of the
dearomative DROC and ROC strategies were demonstrated
by the syntheses of nonracemic hexahydropyrrolo[2,3-b]indole
(3S,3aS,8aS)-3a and tetrahydropyrrolo[4,3,2-de]quinoline (R)-
5a in excellent enantiomeric excess (>99%) from (R)-1a and
2a under the optimized dearomative DROC and ROC
conditions, respectively (Scheme 6).
furnish the corresponding hexahydropyrrolo[2,3-b]indole 3
Scheme 6. Synthesis of Enantioenriched exclusively (Figure 2). In the second case, the reaction initially
Hexahydropyrrolo[2,3-b]indole 3a and
Tetrahydropyrrolo[4,3,2-de]quinoline 5a via Dearomative
DROC and ROC of Enantiopure Aziridine (R)-1a with 4-
Bromo-1-methyl-1H-indole (2a)

Figure 2. Plausible mechanistic pathway to hexahydropyrrolo[2,3-

b]indoles at 60 °C.

proceeds in an identical fashion to produce intermediate A. It

On the basis of the experimental observations, we propose undergoes rearomatization at a higher temperature (90 °C)16
that the following two mechanistic pathways are operative for to generate the corresponding ring-opened product 4, which
the synthesis of hexahydropyrrolo[2,3-b]indoles 3 and then sequentially undergoes Cu(I)-catalyzed C−N bond
tetrahydropyrrolo[4,3,2-de]quinolines 5. For the first case, 2- formation via oxidative addition and dehydrobromination
phenyl-N-tosylaziridine 1 upon activation by the Lewis acid followed by reductive elimination to furnish the corresponding
(LiClO4) undergoes SN2-type ring opening by indole tetrahydropyrrolo[4,3,2-de]quinoline derivatives 5 in excellent
nucleophile 2 to generate intermediate A, losing its aromaticity yields (Figure 3).
in the process. At this point, we surmised that performing the To conclude, we have successfully developed an unprece-
reaction at a low temperature (60 °C) aids in stabilizing the dented temperature-controlled synthetic route to hexahydro-
incipient iminium ion by the electron-withdrawing groups Br, pyrrolo[2,3-b]indoles and tetrahydropyrrolo[4,3,2-de]-
CN, and α,β-unsaturated ester at position 4 of indole to quinolines with structural and functional diversity via one-
generate intermediate B, which is kinetically more stable at a
lower temperature by 5.90 kcal/mol than the thermodynami-
cally stable ring-opening intermediate 4 as substantiated by the
DFT computational studies.16 Intermediate B subsequently
undergoes intramolecular attack by the sulfonamide nitrogen at
a low temperature (60 °C) for 5-exo-trig cyclization to furnish
the corresponding hexahydropyrrolo[2,3-b]indole derivatives 3
as the kinetic product.
Finally, to scale up our reaction methodology, when racemic
aziridine 1a was treated with indole derivative 2a under the
optimized DROC and ROC conditions on a 1.0 mmol scale,
the corresponding racemic products 3a and 5a, respectively,
were obtained in high yields (Scheme 7).
On the basis of DFT studies, it appears that intermediate A
generated after SN2-type ring opening of aziridine 1 with
indole 2 becomes more stabilized probably because of the
EWG at position 4 of the indole. A undergoes 5-exo-trig Figure 3. Plausible mechanistic pathway to tetrahydropyrrolo-[4,3,2-
cyclization at a comparatively lower temperature (60 °C) to de]quinolines at 90 °C.

7870 https://doi.org/10.1021/acs.orglett.2c02354
Org. Lett. 2022, 24, 7867−7872
Organic Letters pubs.acs.org/OrgLett
pot domino ring-opening cyclization and ring-opening
cyclization of activated aziridines, respectively, with electron
deficient 3H-indoles. The development of the DROC method-
ology marks a significant advancement in the synthesis of
hexahydropyrrolo[2,3-b]indoles that obviates the use of 3-
substituted indoles as the prerequisite nucleophile. Further
synthetic explorations and mechanistic investigations involving
electron deficient 3H-indoles are in progress in our laboratory.
■
*
ASSOCIATED CONTENT
sı Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.2c02354.
Experimental procedures, characterization data, compu-
tational data, and HPLC chromatograms of the
compounds (PDF)
Accession Codes
CCDC 2132031−2132033 contain the supplementary crys-
tallographic 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.
■ AUTHOR INFORMATION
Corresponding Author
Manas K. Ghorai − Indian Institution of Technology Kanpur,
Kanpur, Uttar Pradesh 208016, India; orcid.org/0000-
0002-0472-4757; Phone: (+91)-512-2597518;
Email: mkghorai@iitk.ac.in; Fax: (+91)-512-2596806
Authors
Imtiyaz Ahmad Wani − Indian Institution of Technology
Kanpur, Kanpur, Uttar Pradesh 208016, India; Present
Address: I.A.W.: Department of Chemistry, Amar Singh
College, Cluster University, Srinagar 190008, J&K, India
Sahid Sk − Indian Institution of Technology Kanpur, Kanpur,
Uttar Pradesh 208016, India
Abhijit Mal − Indian Institution of Technology Kanpur,
Kanpur, Uttar Pradesh 208016, India
Arunava Sengupta − Indian Institution of Technology Kanpur,
Kanpur, Uttar Pradesh 208016, India
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.2c02354
Notes
The authors declare no competing financial interest.
■ ACKNOWLEDGMENTS
M.K.G. is grateful to the Science and Engineering Research
Board, New Delhi, India, and the Indian Institute of
Technology Kanpur for financial assistance. I.A.W. thanks
UGC, India, and S.S. thanks IIT Kanpur for research
fellowships. M.K.G thanks Mr. Indresh Verma for helpful
discussions about determining X-ray crystal structures. M.K.G.
thanks Diganta Ghorai for designing the Front Cover Art.
■ DEDICATION
Dedicated to Prof. Dr. Michael Schmittel on the occasion of
his 66th birthday.
7871
Letter
■ REFERENCES
(1) (a) Hansen, K. O.; Isaksson, J.; Bayer, A.; Johansen, J. A.;
Andersen, J. H.; Hansen, E. J. Nat. Prod. 2017, 80, 3276−3283.
(b) Rahbæk, L.; Christophersen, C. J. Nat. Prod. 1997, 60, 175−177.
(2) (a) Peat, A. J.; Buchwald, S. L. J. Am. Chem. Soc. 1996, 118,
1028−1030. (b) Hester, J. B., Jr. J. Org. Chem. 1964, 29, 1158−1160.
(c) El-Naggar, M.; Capon, R. J. J. Nat. Prod. 2009, 72, 460−464.
(3) (a) Mal, A.; Sayyad, M.; Wani, I. A.; Ghorai, M. K. J. Org. Chem.
2017, 82, 4−11. (b) Sayyad, M.; Mal, A.; Wani, I. A.; Ghorai, M. K. J.
Org. Chem. 2016, 81, 6424−6432.
(4) (a) Chai, Z.; Zhu, Y.-M.; Yang, P.-J.; Wang, S.; Wang, S.; Liu, Z.;
Yang, G. J. Am. Chem. Soc. 2015, 137, 10088−10091. (b) Huang, Y.-
M.; Zheng, C.-W.; Pan, L.; Jin, Q.-W.; Zhao, G. J. Org. Chem. 2015,
80, 10710−10718.
(5) (a) Crich, D.; Banerjee, A. Acc. Chem. Res. 2007, 40, 151−161.
(b) Zhu, J.; Liang, Y.; Wang, L.; Zheng, Z. B.; Houk, K. N.; Tang, Y. J.
Am. Chem. Soc. 2014, 136, 6900−6903. (c) Liu, K.; Deng, Y.; Song,
W.; Song, C.; Lei, A. Chin. J. Chem. 2020, 38, 1070−1074. (d) Trost,
B. M.; Bai, W. J.; Hohn, C.; Bai, Y.; Cregg, J. J. J. Am. Chem. Soc. 2018,
140, 6710−6717.
(6) (a) Ruchti, J.; Carreira, E. M. J. Am. Chem. Soc. 2014, 136,
16756−16759. (b) Chang, L.; Podoll, J. D.; Wang, W.; Walls, S.;
O’Rourke, C. P.; Wang, X. J. Med. Chem. 2014, 57, 3803−3817.
(c) Wu, K.; Du, Y.; Wang, T. Org. Lett. 2017, 19, 5669−5672.
(d) Zhu, S.; MacMillan, D. W. C. J. Am. Chem. Soc. 2012, 134,
10815−10818. (e) Xie, W.; Jiang, G.; Liu, H.; Hu, J.; Pan, X.; Zhang,
H.; Wan, X.; Lai, Y.; Ma, D. Angew. Chem., Int. Ed. 2013, 52, 12924−
12927. (f) Liang, X.-W.; Liu, C.; Zhang, W.; You, S.-L. Chem.
Commun. 2017, 53, 5531−5534. (g) Liu, C.; Yi, J.-C.; Zheng, Z.-B.;
Tang, Y.; Dai, L.-X.; You, S.-L. Angew. Chem., Int. Ed. 2016, 55, 751−
754. (h) Nelson, H. M.; Reisberg, S. H.; Shunatona, H. P.; Patel, J. S.;
Toste, F. D. Angew. Chem., Int. Ed. 2014, 53, 5600. (i) Xing, S.; Xia,
H.; Wang, C.; Wang, Y.; Hao, L.; Wang, K.; Zhu, B. Adv. Synth. Catal.
2021, 363, 1044−1049. (j) López, C. S.; Pérez-Balado, C.; Rodríguez-
Graña, P.; De Lera, Á . R. Org. Lett. 2008, 10, 77−80.
(7) (a) Xiao, J.; Wong, Z. Z.; Lu, Y. P.; Loh, T. P. Adv. Synth. Catal.
2010, 352, 1107−1112. (b) Xiao, J.; Xu, F.-X.; Lu, Y.-P.; Loh, T.-P.
Org. Lett. 2010, 12, 1220−1223. (c) Xiao, J.; Lu, Y.-P.; Liu, Y.-L.;
Wong, P.-S.; Loh, T.-P. Org. Lett. 2011, 13, 876−879.
(8) (a) Viehrig, K.; Surup, F.; Volz, C.; Herrmann, J.; Abou Fayad,
A.; Adam, S.; Koehnke, J.; Trauner, D.; Mueller, R. Angew. Chem., Int.
Ed. 2017, 56, 7407−7410. (b) Guerrero, C. A.; Sorensen, E. J. Org.
Lett. 2011, 13, 5164−5167.
(9) (a) Movassaghi, M.; Schmidt, M. A. Angew. Chem., Int. Ed. 2007,
46, 3725−3728. (b) Lindovska, P.; Movassaghi, M. J. Am. Chem. Soc.
2017, 139, 17590−17596. (c) Iwasa, E.; Hamashima, Y.; Fujishiro, S.;
Higuchi, E.; Ito, A.; Yoshida, M.; Sodeoka, M. J. Am. Chem. Soc. 2010,
132, 4078−4079. (d) D’Hooghe, M.; Van Brabandt, W.; De Kimpe,
N. J. Org. Chem. 2004, 69, 2703−2710. (e) Catak, S.; D’Hooghe, M.;
De Kimpe, N.; Waroquier, M.; Van Speybroeck, V. J. Org. Chem.
2010, 75, 885−896. (f) Kiss, L.; Mangelinckx, S.; Fulöp, F.; De
Kimpe, N. Org. Lett. 2007, 9, 4399−4402. (g) Vervisch, K.;
D’Hooghe, M.; Rutjes, F. P. J. T.; De Kimpe, N. Org. Lett. 2012,
14, 106−109. (h) Moens, M.; De Kimpe, N.; D'hooghe, M. J. Org.
Chem. 2014, 79, 5558−5568. (i) D’Hooghe, M.; Vanlangendonck, T.;
Törnroos, K. W.; De Kimpe, N. J. Org. Chem. 2006, 71, 4678−4681.
(j) Stanković, S.; Catak, S.; D’Hooghe, M.; Goossens, H.; Abbaspour
Tehrani, K.; Bogaert, P.; Waroquier, M.; Van Speybroeck, V.; De
Kimpe, N. J. Org. Chem. 2011, 76, 2157−2167. (k) Xing, S.; Gu, N.;
Wang, X.; Liu, J.; Xing, C.; Wang, K.; Zhu, B. Org. Lett. 2018, 20,
5680−5683.
(10) (a) Lathrop, S. P.; Movassaghi, M. Chem. Sci. 2014, 5, 333−
340. (b) Lathrop, S. P.; Pompeo, M.; Chang, W.-T. T.; Movassaghi,
M. J. Am. Chem. Soc. 2016, 138, 7763−7769.
(11) (a) Espejo, V. R.; Li, X.-B.; Rainier, J. D. J. Am. Chem. Soc.
2010, 132, 8282−8284. (b) Isley, N. A.; Hageman, M. S.; Lipshutz, B.
H. Green Chem. 2015, 17, 893−897. (c) Chiou, W.-H.; Kao, C.-L.;
Tsai, J.-C.; Chang, Y.-M. Chem. Commun. 2013, 49, 8232−8234.
https://doi.org/10.1021/acs.orglett.2c02354
Org. Lett. 2022, 24, 7867−7872
Organic Letters pubs.acs.org/OrgLett Letter

(12) (a) Wani, I. A.; Sayyad, M.; Ghorai, M. K. Chem. Commun.

2017, 53, 4386−4389. (b) Sayyad, M.; Wani, I. A.; Tiwari, D. P.;
Ghorai, M. K. Eur. J. Org. Chem. 2017, 2369−2378. (c) Sayyad, M.;
Wani, I. A.; Babu, R.; Nanaji, Y.; Ghorai, M. K. J. Org. Chem. 2017, 82,
2364−2374. (d) Mal, A.; Sayyad, M.; Wani, I. A.; Ghorai, M. K. J.
Org. Chem. 2017, 82, 4−11. (e) Mal, A.; Goswami, G.; Ahmad Wani,
I.; Ghorai, M. K. Chem. Commun. 2017, 53, 10263−10266. (f) Sayyad,
M.; Mal, A.; Wani, I. A.; Ghorai, M. K. J. Org. Chem. 2016, 81, 6424−
6432. (g) Pradhan, S.; Shahi, C. K.; Bhattacharyya, A.; Chauhan, N.;
Ghorai, M. K. Org. Lett. 2017, 19, 3438−3441. (h) Pradhan, S.; Shahi,
C. K.; Bhattacharyya, A.; Ghorai, M. K. Chem. Commun. 2018, 54,
8583. (i) Pradhan, S.; Shahi, C. K.; Bhattacharyya, A.; Chauhan, N.;
Ghorai, M. K. Org. Lett. 2017, 19, 3438−3441. (j) Tarannum, S.; Sk,
S.; Das, S.; Wani, I. A.; Ghorai, M. K. J. Org. Chem. 2020, 85, 367−
379. (k) Wani, I. A.; Goswami, G.; Sk, S.; Mal, A.; Sayyad, M.; Ghorai,
M. K. Org. Biomol. Chem. 2020, 18, 272.
(13) See the Supporting Information for further details.
(14) (a) Makosza, M.; Stalewski, J.; Maslennikova, O. S. Synthesis
1997, 1997, 1131−1133. (b) Izawa, T.; Nishiyama, S.; Yamamura, S.
Tetrahedron Lett. 1994, 50, 13593−13600. (c) Nishiyama, S.; Cheng,
J. F.; Tao, X. L.; Yamamura, S. Tetrahedron Lett. 1991, 32, 4151−
4154. (d) Roberts, D.; Venemalm, L.; Alvarez, M.; Joule, J. A.
Tetrahedron Lett. 1994, 35, 7857−7860. (e) Moro-Oka, Y.; Fukuda,
T.; Iwao, M. Tetrahedron Lett. 1999, 40, 1713−1716.
(15) (a) Liu, Y.; Zhang, J.-L.; Song, R.-J.; Qian, P.-C.; Li, J.-H.
Angew. Chem., Int. Ed. 2014, 53, 9017−9020. (b) White, J. D.; Yager,
K. M.; Yakura, T. J. Am. Chem. Soc. 1994, 116, 1831−1838. (c) Inoue,
K.; Ishikawa, Y.; Nishiyama, S. Org. Lett. 2010, 12, 436−439.
(d) Kraus, G. A.; Selva kumar, N. J. Org. Chem. 1998, 63, 9846−9849.
(e) Roberts, D.; Joule, J. A.; Bros, M. A.; Alvarez, M. J. Org. Chem.
1997, 62, 568−577. (f) Lim, H. J.; Gallucci, J. C.; Rajan Babu, T. V.
Org. Lett. 2010, 12, 2162−2165.
(16) See the Supporting Information for a detailed DFT study that
explains the formation of two different products at different
temperatures.

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