Blue LED Mediated Intramolecular C-H Functionalization and Cyclopropanation of Tryptamines: Synthesis of Azepino[4, 5-b]indoles and Natural Product Inspired Polycyclic Indoles

Article abstract of DOI:10.1021/acs.orglett.0c01559

We report a novel blue LED mediated intramolecular C-H functionalization of tryptamine derivatives to generate azepino[4, 5-b]indoles (4) in moderate to good yields. By altering the substitution at the tryptamine nitrogen, intramolecular cyclopropanation is achieved in high yields under the same reactions condition to provide natural product inspired polycyclic indoles (6), which are further transformed to spiropiperidino (5 and 8) indoles in decent yields. The mechanism of formation of the compounds was investigated through DFT studies.

Full text of DOI:10.1021/acs.orglett.0c01559

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Letter
Blue LED Mediated Intramolecular C−H Functionalization and
Cyclopropanation of Tryptamines: Synthesis of Azepino[4,
5‑b]indoles and Natural Product Inspired Polycyclic Indoles
Jyoti Chauhan, Mahesh K. Ravva, Ludovic Gremaud, and Subhabrata Sen*
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ABSTRACT: We report a novel blue LED mediated intramolecular C−H functionalization of tryptamine derivatives to generate
azepino[4, 5-b]indoles (4) in moderate to good yields. By altering the substitution at the tryptamine nitrogen, intramolecular
cyclopropanation is achieved in high yields under the same reactions condition to provide natural product inspired polycyclic indoles
(6), which are further transformed to spiropiperidino (5 and 8) indoles in decent yields. The mechanism of formation of the
compounds was investigated through DFT studies.
a lack of efficient strategies to access azepino[4, 5-b]-
y virtue of their ubiquitous presence in various natural
Bproducts, receptors, proteins, and drug molecules, indole indoles.8−10 As a part of our ongoing investigation on blue
LED catalyzed carbene reactions, we herein report the first
intramolecular C−H functionalization of unsubstituted or N-
methyl tryptamines to afford azepino[4, 5-b]indole (Scheme
1d). This was achieved through blue LED (5−6 W Micro
Photochemical Reactor (ALDKIT001) with blue LED lights
[435−445 nm] source). Acyl substitution on the tryptamine
nitrogen (1c,d) facilitated intramolecular cyclopropanation to
provide polycyclic indole molecules (6a−h).
We began by the proof of concept study where tryptamine
1a was reacted with phenyl acetate in acetonitrile under reflux
(Scheme 1d). Once 1a was completely consumed, the reaction
mixture was cooled to room temperature followed by
sequential addition of p-acetamido benzenesulfonyl azide (p-
ABSA) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). The
reaction was stirred for three more hours at room temperature,
derivatives are essential building blocks and hold a niche
position among the synthetic organic chemists and pharma-
ceutical scientists.1,2 Transition metal catalyzed C2/C3−H
activation and cyclopropanation of indoles are robust synthetic
strategies to afford functionalized indoles from simple
substrates (Scheme 1a).3−5 However, there are only few
reports involving the photocatalytic version of this reaction on
indoles (Scheme 1b,c).6,7 Among them there is an in situ
generation of diazoalkane via Bamford-Stevens reaction of
tosyl hydrazone (in Cs2CO3), which reacts with various N-
substituted indoles in the presence of blue LED to provide
either C3 substituted or cyclopropanated product based on the
N-substitution (Scheme 1b).6 A ruthenium (Ru(bpy)3Cl2)
catalyzed blue LED reaction of diazoalkanes with substituted
indole was also reported to afford mixtures of C2/C3
substituted products (Scheme 1c).7 Amidst these efforts, it
was also interesting to observe that there is a dearth of similar
experiments on C2/C3 substituted indoles or on indole
derivatives like tryptamine and the application of this
methodology (be it transition metal or blue LED catalyzed)
to generate biologically active molecular scaffolds. It is
noteworthy that despite being biologically interesting there is
Received: May 7, 2020
https://dx.doi.org/10.1021/acs.orglett.0c01559
© XXXX American Chemical Society
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Scheme 1. Previous Reports for C2/C3 Functionalization of Indoles and Our Proof of Concept Study
after which the TLC indicated complete formation of the diazo
intermediate 3a. At this point, any effort (precipitation, column
chromatography, or crystallization) to isolate 3a from the
reaction mixture led to its decomposition. We realized that
maybe 3a is unstable under standard condition; hence, the
reaction mixture was immediately subjected to blue LED. The
reaction was monitored by LC−MS, and both the carbene 2a′
and final product 4a were detected (Scheme 1d and related
mass spectrum). After nearly 24 h, intermediates were
completely consumed. The reaction mixture was diluted with
water and extracted with ethyl acetate to provide the crude
product, which was further purified to afford compound 4a in
61% overall yield. Further screening of the reaction in various
solvents (viz. ethanol, dichloroethane, trifluoroethanol, etc.)
and in a range of LEDs (such as green, red, white) (see et al.)
established that reaction in acetonitrile and blue LED at r.t. is
currently the most appropriate condition to generate the
desired azepino[4, 5-b]indoles 4.
Utilizing the optimal reaction condition, we assessed
tryptamine 1a, N-methyl tryptamine 1b, and serotonin 1c in
the intramolecular C2−H functionalization under blue LED to
provide azepino[4, 5-b]indole compounds 4b−g by reacting
with a bevy of alkyl aryl acetates 7a−e containing electron
withdrawing and electron donating groups at the ortho-, meta-,
and para-position of the aryl moiety (Scheme 2). The average
yield of the products obtained from this one pot sequence of
amidation-diazotization−C2-H functionalization ranged from
52 → 71% (Scheme 2). The amidation and the diazotization
reaction went smoothly with complete conversion of the
starting material to the product. We envision that the unstable
nature of the diazo intermediate may be the reason for the
moderate yield of the products. However, the yield remained
consistent irrespective of the nature of substitution on the aryl
moiety of the alkyl aryl acetates. The reaction condition was
also amenable to thiophene substituted diazo moiety to
provide 4e and 4g in 71 and 69% yield, respectively. Generally
simple arenes are higher yielding than hetero arenes. Herein,
B
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The highly active donor−acceptor type polycyclic com-
pounds 6 provide opportunities for further transformation
(Scheme 4). Accordingly, deacetylation of 6a in the presence
Scheme 2. Synthesis of Azepino Indole Molecules 4a−h
Scheme 4. Synthesis of Spiropiperidino Indoles 8a and 5a,b
the intermediate carbene 3 (Scheme 5) is electron deficient;
hence, the high electron density of the thiophene could have
provided stability to it, and consequently, 4e and g were high
yielding compared to the arene analogs. The fact that
azepino[4, 5-b] indoles were isolated as the desired products
indicated exclusive C2 substitution in the indole ring without
any. Interestingly, no keto enol tautomerism was observed
during the formation of 4.
Next, intramolecular cyclopropanation of aryl diazoacetates
derived from N-acetyl and N-Boc tryptamine 1d and 1e
afforded the library of polycyclic indole molecules 6a−i
(Scheme 3). It was remarkable how the alteration in the
of methanol and potassium carbonate afforded the spiropyrro-
lidinone indole molecule 8a albeit in a poor yield of 25%
(Scheme 4a). We expected indoleamine 5a but realized that
deacetylation prompted the cyclopropane ring opening of 6a
to the indoleamine 5a, which was subsequently attacked by the
methanol to provide 8a. Despite few other bases (sodium
hydroxide, potassium hydroxide) and acid (dilute hydrochloric
acid) mediated deacetylation efforts, the reaction yield could
not be further improved. To solve this, it was envisaged that
deboc of 6h will be simpler and high yielding and could
provide the indoleamine 5a. Accordingly, Boc-deprotection of
6h in the presence of 10% trifluoroacetic acid in dichloro-
methane afforded 5a in 91% yield (Scheme 4b). Similarly, 6i
afforded 5b.
Scheme 3. Synthesis of Cyclopropane Fused Polycyclic
Compounds 6a−h
On the basis of experimental results and density functional
theory calculation, a putative mechanism of transformation is
derived (Scheme 5). All optimized geometries of local minima
and transition states were optimized using ωB97XD/6-
31g(d,p) level of theory, and stationary point geometries of
reactants, intermediates, products, and transition states were
characterized by harmonic vibrational frequencies. The
transition states and corresponding reactants and products
they connect were confirmed by following the intrinsic
reaction coordinate (IRC) method. All calculations were
carried out using Gaussian 16 software package.11 Mechanis-
tically, the syntheses of compounds 4, 5, and 6 are interrelated.
Compounds 4 and 6 are generated under blue LED (as
depicted in Scheme 5), and the calculated free energies for
their formation are depicted in plots a and b of Scheme 5,
respectively. Compound 5 is obtained by deprotection of 6 (R
= tert-BuO) in with 10% TFA-DCM at r.t. According to the
mechanism, the diazo intermediate 2 under blue LED provided
the carbene 3, which underwent cyclopropanation with the
indole moiety to afford A through TS1 (Scheme 5). The
calculated free energy from ωB97XD/6-31g(d,p) level of
theory revealed that the process is barrierless and highly
exothermic (−58.26 kcal/mol) (plot b, Scheme 5). When R =
H or Me, in A, the lone pair of electrons on the indole nitrogen
destabilizes the cyclopropyl ring, which opens up to provide B
(plot b, Scheme 5). The hydride transfer from C2 of indole to
the adjacent carbocation afforded compound 4 with reaction
energy −78 kcal/mol (Scheme 5). With acyl substitution on A,
the cyclopropane formation is barrierless and highly energonic
(−63.2 kcal/mol) (plot a, Scheme 5). Since the lone pair on
substitution type (from H/methyl → acyl) on the tryptamine
nitrogen influenced the change in the course of the reaction,
ultimately providing a different product. Typically the aryl
diazoester from 1d and a series of alkyl aryl acetate (7b−g)
under the blue LED in acetonitrile provided the desired
compounds 6a−g in 48 to 69% yield (Scheme 3). Generally
the reactions with electron withdrawing functionalities on the
aryl moiety such as 4-fluoro and 3-fluoro (6b and 6c) were
better yielding (yield: 62 and 67%) compared to the electron
donating substituents such as 4-methyl, 3-methoxy, and 3-
bromo (6e, 6f, and 6g) (yield: 46 → 55%) (Scheme 3). In a
similar fashion, N-boc tryptamine 1e afforded 6h and 6i in 66
and 69% yield, respectively.
C
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a
Scheme 5. Mechanism of Formation of 4, 5, and 6
a
Free energy profile of the reaction (formation of 4a) calculated at ωB97XD/6-31G(d,p) level of theory. All values are given in kcal/mol.
the indole nitrogen here is in conjugation with the acyl moiety,
the cyclopropane ring is more stable to provide 6.
Ludovic Gremaud − School of Engineering and Architecture,
Institute of Chemical Technology at University of Applied
Sciences and Arts of Western Switzerland, CH-1700 Fribourg,
Switzerland; orcid.org/0000-0002-0630-932X
In summary, we accomplished intramolecular C−H
functionalization and cyclopropanation of tryptamine deriva-
tives by blue LED to afford azepino[4, 5-b]indole and
polycyclic indoles in moderate to good yields under mild
reaction condition. The donor−acceptor type polycycles
allowed further transformation to spiropiperidino indoles in
excellent yield. These natural product like molecules generated
through this strategy are presently being screened against
various phenotypes to identify their biological activity.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01559
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
ASSOCIATED CONTENT
■
We thank Shiv Nadar University and Leading House South
Asia and Iran, Zurich University of Applied Sciences for the
financial support. M.K.R. would like to thank SRM Super-
computer Center, SRM Institute of Science and Technology
for providing the computational facility to conduct the DFT
calculations
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The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01559.
Optimization details, mechanistic experiments, exper-
imental procedures, characterization data for all new
compounds (PDF)
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AUTHOR INFORMATION
■
Corresponding Author
Subhabrata Sen − Department of Chemistry, School of Natural
Sciences, Shiv Nadar University, Chithera, Uttar Pradesh
201314, India; orcid.org/0000-0002-4608-5498;
Email: subhabrata.sen@snu.edu.in
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Authors
Jyoti Chauhan − Department of Chemistry, School of Natural
Sciences, Shiv Nadar University, Chithera, Uttar Pradesh
201314, India
Mahesh K. Ravva − Department of Chemistry, SRM University
AP, Neerukonda, Andhra Pradesh 522502, India;
orcid.org/0000-0001-9619-0176
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