Intramolecular Csp2-Csp2 Friedel-Crafts Arylation: Substrate- and Condition-Controlled Divergent Synthesis of Fused-β-carbolines

Article abstract of DOI:10.1021/acs.orglett.6b02794

A triple cooperative catalysis-mediated multicomponent reaction between 1-formyl-N-substituted-β-carbolines, a terminal alkyne, and a secondary amine allows access to unprecedented polycyclic β-carbolines via sequential A³-coupling and an intramolecular C_sp²-C_sp² Friedel-Crafts arylation reaction. The reaction is successful in a dry inert atmosphere only with substrates bearing a methoxy-substituted benzyl group at the indole nitrogen. Conversely, treating 3-aminoindolizino[8,7-b]indoles (obtained after A³-coupling) with acid in the presence of H₂O in air offers a general route to natural-alkaloid-like products.

Full text of DOI:10.1021/acs.orglett.6b02794

Letter
pubs.acs.org/OrgLett
2
2
Intramolecular Csp −Csp Friedel−Crafts Arylation: Substrate- and
Condition-Controlled Divergent Synthesis of Fused-β-carbolines
Shashikant U. Dighe,†,⊥ Veena D. Yadav,†,⊥ Rohit Mahar,‡ Sanjeev K. Shukla,‡ and Sanjay Batra*,†,§
†Medicinal and Process Chemistry Division and ‡Sophisticated Analytical Instrument Facility, CSIR-Central Drug Research Institute,
Sector 10, Jankipuram Extension, Sitapur Road, Lucknow-226031, India
§Academy of Scientific and Innovative Research, New Delhi-110025, India
S
* Supporting Information
ABSTRACT: A triple cooperative catalysis-mediated multicomponent reaction between 1-formyl-N-substituted-β-carbolines, a
terminal alkyne, and a secondary amine allows access to unprecedented polycyclic β-carbolines via sequential A3-coupling and an
2
2
intramolecular Csp −Csp Friedel−Crafts arylation reaction. The reaction is successful in a dry inert atmosphere only with
substrates bearing a methoxy-substituted benzyl group at the indole nitrogen. Conversely, treating 3-aminoindolizino[8,7-
b]indoles (obtained after A3-coupling) with acid in the presence of H2O in air offers a general route to natural-alkaloid-like
products.
and a terminal alkyne would furnish 3-aminoindolizino[8,7-
b]indole (A), which in the presence of a suitable Lewis acid may
lose the secondary amine to offer the aromatic carbocation that
he ubiquity of the β-carboline core in alkaloids and
Tcompounds of pharmacological interest provides impetus
to develop architectural complexity around it.1 Strategically, the
complexity can be articulated either by placing suitable functional
moieties in the indole unit followed by intramolecular cyclization
of the resulting intermediates with appropriate reagents or by
synthetically decorating the β-carboline-based starting materi-
al.2,3 In one of our research programs, we have been pursuing the
latter approach, wherein we employed 1-formyl-9H-β-carboline
as the advanced intermediate4 for developing general routes to
access annulated β-carbolines which may find utility as anticancer
or antiparasitic agents. In this context, recently we reported the
synthesis of 2-substituted-2,11-dihydroimidazo[1′,5′:1,2]pyrido-
[3,4-b]indoles showing antiproliferative and antimetastatic
activity against human breast cancer cells and triple cooperative
catalysis-mediated enantioselective synthesis of S-(−)-5,6-
dihydrocanthin-4-ones having moderate antiplasmodial activ-
ity.5,6 Earlier we reported the synthesis of several natural product
mimics7 including Maxonine-like analogues which were prepared
via an intramolecular Friedel−Crafts (FC) alkylation involving a
2
2
would undergo intramolecular FC-arylation via Csp −Csp bond
formation to furnish the unprecedented polycyclic β-carboline
(B) (Scheme 1). It may be noted that the FC-arylation involving
2
2
Csp −Csp bond formation is scarcely reported perhaps due to the
instability of the arene carbocation. Siegal et al. activated
2
2
Scheme 1. Comparison with known Csp −Csp Friedel−Crafts
Arylation
2
3
Csp −Csp bond formation from N-benzyl protected Morita−
Baylis−Hillman adducts of 1-formyl-9H-β-carboline.8 With this
background and in continuation of our efforts to prepare fused-β-
carboline systems, we envisaged that the A3-coupling of
substituted 1-formyl-9H-β-carboline bearing the N-benzyl
moiety having a phenyl ring with an electron-donating group(s)
Received: September 16, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02794
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
fluoroarenes via silyl cations for the intramolecular FC-reaction
leading to arene−arene coupling.9 Ren et al. used aryltriazene as
anaryl cation precursor for achieving intramolecular FC-arylation
to prepare polycyclic aromatics.10 Working toward the envisaged
strategy, we have successfully developed a triple cooperative
catalysis mediated cascade protocol wherein the polycyclic β-
carboline scaffold B is readily prepared from 1-formyl-9-
(substituted benzyl)-9H-pyrido[3,4-b]indole-3-carboxylate and
a terminal alkyne. Interestingly, we discovered that the phenyl
group of the N-benzyl unit bearing a methoxy group(s) in the
phenyl ring follows the protocol under dry inert conditions.
However, if the reaction is performed in two steps, i.e., initial
formation of 3-aminoindolizino[8,7-b]indole followed by treat-
ment with acid in the presence of water in air, it results in
unexpected product C containing two β-carboline units. Herein,
we disclose the details of the results of this interesting substrate-
and condition-controlled divergent synthesis of new β-carboline
derivatives.
pyrrolidine or piperazine in place of morpholine, but in both cases
yields of the product were inferior (see SI). Thus, the conditions
best suited for intramolecular Csp −Csp FC-arylation included
treating substrate 4aac (1.0 equiv) with MSA (1.5 equiv) in
dichloromethane at rt for 3 h.
2
2
The successful synthesis of 5,6-dihydrocanthin-4-ones via
triple cooperative catalysis provided impetus to test the
cooperativity of the catalyst system for synthesizing polycyclic
β-carboline starting from the N-protected aldehyde. Therefore, in
a pilot experiment the aldehyde 2aa (1.0 equiv) was treated with
3c (1.1 equiv) in the presence of CuI (10 mol %), morpholine (35
mol %), and MSA (1.5 equiv) in toluene at 85 °C to furnish the
product in 72% yield which was identical to 5aac. In order to
improve the yield of 5aac, an optimization study was undertaken
where an improved yield (82%) of 5aac was observed when the
reaction is performed in the presence of CuI using DCE as the
medium (Table 2 in the SI). Other catalysts though successful
afforded product in inferior yields. Thus, the best conditions for
the synthesis of the polycyclic β-carboline via triple cooperative
catalysis were 2aa (1.0 equiv), 3a (1.1 equiv), morpholine (35
mol %), CuI (10 mol %), and MSA (1.5 equiv) in DCE at 85 °C
for 4 h.
With the optimized conditions in hand, the scope of the
protocol was tested for its generality with respect to alkynes (3)
and N-protected aldehydes (2). Initially, the scope was examined
by reacting the aldehyde 2aa with different alkynes 3. In the first
set of reactions the aromatic alkynes (3a−n) were treated with
2aa under the optimized conditions. It was discovered that except
for the alkyne 3i and 3n all substrates afforded the corresponding
products (5aaa−5aah, 5aaj−5aam) in 64−84% yields (Scheme
3). It was observed that the electronic character of the
To test the success of our design, in the first phase we prepared
a suitable starting material 4aac starting from the aldehyde 1a
following the reported strategy (see Supporting Information (SI)
for details).11 Next to induce intramolecular Csp −Csp FC-
arylation, 4aac was treated with BF3·Et2O for 12 h in
dichoromethane as reported,10 but the reaction was unsuccessful.
Hence we were invoked to assess the reaction in the presence of
different Lewis and Bronsted acids (Table 1 in the SI). The
reaction was completed in 12 h in the presence of Sc(OTf)3,
Bi(OTf)3, and In(OTf)3 to afford the chalcone 6aac instead of
the anticipated 5aac but failed with AlCl3 or FeCl3 (Scheme 2).
2
2
Scheme 2. Synthesis of polycyclic β-carboline via
2
2
intramolecular Csp −Csp Friedel−Crafts Arylation
Scheme 3. Scope of the Triple Cooperative Catalysis Mediated
a
Synthesis of Polycyclic β-Carbolines
Subsequently, Bronsted acids were investigated for their
effectiveness in the transformation. Whereas pTSA produced
the chalcone 6aac, HCl and AcOH were inert in the reaction.
Formation of 6aac may be attributed to preferential attack of the
hydroxy group onto the generated arene carbocation rather than
intramolecular FC-arylation (vide infra). The reaction in TFA
completed within 1 h to offer two products which were isolated
and spectroscopically characterized. We were delighted to
discover that the major product (35%) was established as 5aac
while the minor product (16%) was the chalcone 7ac. Altering
TFA with trifluoromethanesulfonic acid (TFMS) though
completed the reaction in 2 h, increasing the yield of 5aac to
52% together with a minor amount (12%) of 7ac. The reaction
with methanesulfonic acid (MSA) pleasingly improved the yield
of 5aac to 62% without any trace of 7ac in 3 h. Enhancing the
loading of MSA from 1.0 to 1.5 equiv furnished 5aac in 86% yield,
but further loading of MSA was found to be detrimental for
reaction. During the process we also evaluated substrates carrying
a
All reactions were performed using 0.2 g of 2. Isolated yields after
column chromatography. X-ray structure of 5aaa at 35% probability
level
substituents on the phenyl ring did not impact the output, but
reactions of the substrates bearing phenyl ring with multiple
substituents required 6 h for completion. The terminal alkyne 3i
with the phenyl ring bearing the N,N-dimethyl group afforded
only the corresponding chalcone 7ai whereas 2aa reacted with 2-
ethynyl-6-methoxynaphthalene (3n) to yield 1a instead of 5aan.
The X-ray diffraction analysis of a single crystal of 5aaa confirmed
B
DOI: 10.1021/acs.orglett.6b02794
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
the assigned structure. Next, reactions of aliphatic terminal
alkynes 3o−p with 2aa were examined, and though successful,
the corresponding products (5aao−5aap) were isolated only in
moderate yields together with several unidentifiable products.
Subsequently, the reaction was attempted with different
aldehydes bearing a methoxy-substituted N-benzyl group (2ab,
2ac, and 2ad) which were reacted with 3a and 3c to smoothly
obtain 5aba, 5aca, 5acc, and 5ada in excellent yields. To enhance
the scope, we conducted the reaction of 2ba with 3a to obtain the
product 5baa in 75% yield. Similarly, use of 1,3-diethynylbenzene
(3q) resulted in the formation of the product 5aaq inferring that
only one alkyne group participated in the reaction while the other
alkyne group was transformed to the acetyl group (Scheme 4). It
may be noted that very recently Li et al. have disclosed acid-
promoted conversion of terminal alkynes to acetophenones in
HFIP but their protocol failed in DCE.12
suggested to involve a hydrolysis step (vide infra), and therefore,
we added water which to our satisfaction improved the yield of
8aea (86%). An identical reaction of 4aec with MSA resulted in
the formation of 8aec (Scheme 6).
a
Scheme 6. Scope for the Acid-Mediated Synthesis of 8
Scheme 4. Scope of Reaction with 1,3-Diethynylbenzene (3q)
Based on our previous work,11 a plausible mechanism for the
synthesis of 5 is outlined in Scheme 5. Initially, the aldehyde 2
a
All reactions were performed using 0.2 g of 4. The yields are the
Scheme 5. Plausible Mechanism for the Formation of 5
isolated yield after column chromatography.
Buoyed by the success of the protocol we considered
evaluating its scope with substrates (4) bearing different
substituted benzyl groups. As mentioned above, products 4
were not isolated but reacted further with MSA in dichloro-
methane as medium in the same pot. Accordingly, in the first set,
4afa−4afe, 4afh, and 4ahl were treated with MSA in the presence
of water for 6 h resulting in respective products 8afa−8afe, 8afh,
and 8afl in excellent yields. Next, substrates 4aga, 4agc, 4aha,
4aia, and 4aic were reacted with MSA under the standardized
conditions to obtain 8aga, 8agc, 8aha, 8aia, and 8aic in 83−94%
yields. Subsequently, reactions of 4acc, 4ada, and 4aja were
conducted, and they too complied affording 8acc, 8ada, and 8aja,
respectively. Finally, to broaden the substrate scope 4bfa, 4bfc,
and 4bfe prepared from 6-chloro-β-carboline aldehyde 1b were
investigated, and they too followed the protocol to efficiently
afford 8bfa, 8bfc, and 8bfe.
reacts with morpholine and 3 in the presence of CuI to form 4.
Successively, acid protonates the nitrogen of the morpholine
followed by a 1,3-H-shift to offer the intermediate imine D, which
then undergoes intramolecular Csp −Csp FC-reaction to produce
E which loses morpholine to furnish 5.
Next we assessed the reaction of aldehyde 2ae wherein the
indole nitrogen carried a (3,4-methylenedioxyphenyl)methyl
group. Treating 2ae with alkyne 3a under the optimized
conditions resulted in a complex mixture from which the major
product was only in 18% isolated yield. Based on detailed
spectroscopic analysis the structure was established as 8aea
bearing E stereochemistry (refer to SI). Since a single crystal for
the compound could not be obtained, molecular dynamics for the
energy minimized structure of 8aea was assessed to arrive at the
assigned structure. Efforts to induce FC-arylation in 4aea under
different conditions were unsuccessful.
2
2
To explain the formation of the observed products a plausible
mechanism is proposed in Scheme 7. Initially, in the presence of
Scheme 7. Plausible Mechanism for the Formation of 8
Nonetheless, close analogy of one unit of 8aea with fascaplysin
prompted us to optimize conditions for improving its yield. After
initial assessment, we discovered that performing the reaction in
two steps improves the yield of 8aea to 48%. Under the process,
the initial formation of 4aea in toluene is followed by removal of
solvent and treatment of the residue with MSA in dichloro-
methane in the same pot. Mechanistically the formation of 8aea is
C
DOI: 10.1021/acs.orglett.6b02794
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
acid, 4 undergoes protonation to form intermediate F which is
transformed into G via a 1,3-H-shift. Subsequent nucleophilic
attack of water onto G yields the hydroxyl intermediate I, which
reacts with G to produce intermediate J via a concerted
mechanism. A second 1,3-H-shift followed by hydrolysis
transforms J to the intermediate K, which undergoes oxidation
leading to product 8. In order to provide support for the proposed
mechanism a few potential control experiments were performed.
To ascertain the oxidation of the intermediate H, a control
experiment was conducted under an inert atmosphere, and as
expected the yield of 8afa dropped to 32% only. To unequivocally
provide evidence that water is the source of oxygen, compound
8afa was treated with MSA in dry methylene chloride in the
presence of H218O (97%). On completion the reaction mixture
was directly subjected to mass spectral analysis which displayed
the presence of a mixture of 16O (891 amu) and 18O (895 amu)
8afa. We have previously reported that the reaction of pyridine-2-
aldehyde with terminal alkyne in the presence of secondary amine
furnishes the substituted indolizine.11 As a result, in another
control experiment, we treated pyridine-2-carbaldehyde with 3aa
in the presence of CuI, morpholine, and MSA which resulted in
the formation of chalcone 9ac (see SI for details).
data. Prof. Sandeep Verma and his student Mr. B. Mohapatra, IIT
Kanpur are acknowledged for carrying out the X-ray diffraction
analysis of 5aaa. The work was carried out via partial funding to
S.B. from DST, New Delhi and Ministry of Earth Sciences, New
Delhi.
REFERENCES
■
(1) A few recent citations: (a) Samita, F.; Ochieng, C. O.; Owuor, P. O.;
Manguro, L. O. A.; Midiwo, J. O. Nat. Prod. Res. 2016, 1. (b) Wang, K.-B.;
Li, D.-H.; Hu, P.; Wang, W.-J; Lin, C.; Wang, J.; Lin, B.; Bai, J.; Pei, Y.-H.;
Jing, Y.-K.; Li, Z.-L.; Yang, D.; Hua, H.-M. Org. Lett. 2016, 18, 3398−
3401. (c) Quintana, V. M.; Piccini, L. E.; Panozzo Zenere, J. D.;
Damonte; Elsa, B.; Ponce, M. A.; Castilla, V. Antiviral Res. 2016, 134,
26−33. (d) Spindler, A.; Stefan, K.; Wiese, M. J. Med. Chem. 2016, 59,
6121−6135. (e) Wu, J.; Zhao, M.; Wang, Y.; Wang, Y.; Zhu, H.; Zhao, S.;
Peng, S. Bioorg. Med. Chem. Lett. 2016, 26, 4631−4636. (f) Giulietti, J.
M.; Tate, P. M.; Cai, A.; Cho, B.; Mulcahy, S. P. Bioorg. Med. Chem. Lett.
2016, 26, 4705−4708. (g) Du, H.; Gu, H.; Li, N.; Wang, J.
MedChemComm 2016, 7, 636−645. (h) Yang, H.; Luo, Y.; Zhao, H.;
Wu, J.; Chen, Y. Nat. Prod. Res. 2016, 30, 42−45. (i) Manda, S.; Sharma,
S.; Wani, A.; Joshi, P.; Kumar, V.; Guru, S. K.; Bharate, S. S.; Bhushan, S.;
Vishwakarma, R. A.; Kumar, A.; Bharate, S. B. Eur. J. Med. Chem. 2016,
107, 1−11. (j) Lood, C. S.; Koskinen, A. M. P. Chem. Heterocycl. Compd.
(N. Y., NY, U. S.) 2015, 50, 1367−1387. (k) Anouhe, J.-B. S.; Adima, A.
A.; Niamke, F. B.; Stien, D.; Amian, B. K.; Blandinieres, P.-A; Virieux, D.;
Pirat, J.-L.; Kati-Coulibaly, S.; Amusant, N. Phytochem. Lett. 2015, 12,
158−163. (l) Li, X.; Bai, B.; Liu, L.; Ma, P.; Kong, L.; Yan, J.; Zhang, J.;
Ye, Z.; Zhou, H.; Mao, B.; Zhu, H.; Li, Y. Cell Death Discovery 2015, 1,
15033.
In summary, we have developed a triple cooperative catalysis-
mediated cascade approach for the synthesis of unprecedented
2
2
polycyclic β-carbolines via an intramolecular Csp −Csp FC-
arylation. The success of the protocol relies on the presence of
electron-donating substituents (methoxy) on the phenyl ring of
the N-benzyl group and inert conditions. Mechanistically, the
protonation of tertiary amine followed by a 1,3-H-shift offers an
imine intermediate which undergoes nucleophilic attack of the
(2) (a) Shmatova, O. I.; Khrustalev, V. N.; Nenajdenko, V. G. Org. Lett.
2016, 18, 4494−4497. (b) Reddy, B. V. S.; Reddy, B. P.; Reddy, P. V. G.;
Siriwardena, A. Org. Biomol. Chem. 2016, 14, 4276−4282. (c) Over-
voorde, L. M.; Grayson, M. N.; Luo, Y.; Goodman, J. M. J. Org. Chem.
2015, 80, 2634−2640. (d) Danda, A.; Kumar, K.; Waldmann, H. Chem.
Commun. 2015, 51, 7536−7539. (e) Pan, X.; Bannister, T. D. Org. Lett.
2014, 16, 6124−6127.
(3) (a) Nishiyama, D.; Ohara, A.; Chiba, H.; Kumagai, H.; Oishi, S.;
Fujii, N.; Ohno, H. Org. Lett. 2016, 18, 1670−1673. (b) Gehring, A. P.;
Tremmel, T.; Bracher, F. Synthesis 2014, 46, 893−898. (c) Singh, D.;
Devi, N.; Kumar, V.; Malakar, C. C.; Mehra, S.; Rattan, S.; Rawal, R. K.;
Singh, V. Org. Biomol. Chem. 2016, 14, 8154−8166. (d) Devi, N.; Singh,
D.; Honey; Mor, S.; Chaudhary, S.; Rawal, R. K.; Kumar, V.; Chowdhury,
A. K.; Singh, V. RSC Adv. 2016, 6, 43881−43891. (e) Gobe, V.;
Guinchard, X. Org. Lett. 2014, 16, 1924−192. (f) Rajapaksa, N. S.;
McGowan, M. A.; Rienzo, M.; Jacobsen, E. N. Org. Lett. 2013, 15, 706−
709.
2
Csp −H of the electron-rich arene system in a highly concerted
manner to produce polycyclic β-carboline. Conversely in the
presence of water in air the imine intermediate undergoes
nucleophilic attack by the water to yield a hydroxyl intermediate
that reacts with the imine intermediate in situ resulting in the
formation of an unusual β-carboline system via sequential 1,3-H-
shift, hydrolysis, and oxidation.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b02794.
(4) Singh, V.; Batra, S. Curr. Org. Synth. 2012, 9, 513−528.
(5) Dighe, S. U.; Khan, S.; Soni, I.; Jain, P.; Shukla, S.; Yadav, R.; Sen, P.;
Meeran, S. M.; Batra, S. J. Med. Chem. 2015, 58, 3485−3499.
(6) Dighe, S. U.; Mahar, R.; Shukla, S. K.; Kant, R.; Srivastava, K.; Batra,
S. J. Org. Chem. 2016, 81, 4751−4761.
(7) (a) Singh, V.; Hutait, S.; Batra, S. Eur. J. Org. Chem. 2009, 2009,
6211−6216. (b) Hutait, S.; Singh, V.; Batra, S. Eur. J. Org. Chem. 2010,
2010, 6269−6276. (c) Hutait, S.; Batra, S. Tetrahedron Lett. 2010, 51,
5781−5783.
(8) Hutait, S.; Biswas, S.; Batra, S. Eur. J. Org. Chem. 2012, 2012, 2453−
2462.
Experimental details, spectroscopic data, X-ray analysis
data of 5aaa, and copies of 1H and 13C NMR data (PDF)
Crystallographic data for 5aaa (CIF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: batra_san@yahoo.co.uk; s_batra@cdri.res.in.
ORCID
Sanjay Batra: 0000-0002-8980-3592
Author Contributions
⊥S.U.D. and V.D.Y. contributed equally.
(9) Allemann, O.; Duttwyler, S.; Romanato, P.; Baldridge, K. K.; Siegel,
J. S. Science 2011, 332, 574−577.
(10) Zhou, J.; Yang, W.; Wang, B.; Ren, H. Angew. Chem., Int. Ed. 2012,
51, 12293−12297.
Notes
(11) Dighe, S. U.; Hutait, S.; Batra, S. ACS Comb. Sci. 2012, 14, 665−
672.
The authors declare no competing financial interest.
(12) Liu, W.; Wang, H.; Li, C.-J. Org. Lett. 2016, 18, 2184−2187.
ACKNOWLEDGMENTS
■
S.U.D., V.Y., and R.M. gratefully acknowledge financial support
from CSIR, New Delhi in the form of fellowships. The SAIF
Division of CDRI is acknowledged for providing spectroscopic
D
DOI: 10.1021/acs.orglett.6b02794
Org. Lett. XXXX, XXX, XXX−XXX