Enantioselective N-Heterocyclic Carbene-Catalyzed Cascade Reaction for the Synthesis of Pyrroloquinolines via N-H Functionalization of Indoles

Article abstract of DOI:10.1021/acs.orglett.8b02820

Functionalization of the indole N-H bond for enantioselective synthesis of biologically important pyrroloquinoline derivatives has been reported under oxidative N-heterocyclic carbene catalysis conditions. The interception of catalytically generated chiral α,β-unsaturated acylazoliums with the indole derivatives proceeds in an aza-Michael/Michael/lactonization sequence to deliver the pyrroloquinoline derivatives in good yields, diastereoselectivities, and enantioselectivities. The simultaneous enhancement of reactivity and selectivity observed in polar aprotic solvents is noteworthy.

Full text of DOI:10.1021/acs.orglett.8b02820

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Enantioselective N‑Heterocyclic Carbene-Catalyzed Cascade
Reaction for the Synthesis of Pyrroloquinolines via N−H
Functionalization of Indoles
Subrata Mukherjee,† Sayan Shee, Thomas Poisson,
,‡
§
∥,⊥
Tatiana Besset,∥ and Akkattu T. Biju*,§
†
Organic Chemistry Division, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411008, India
Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
‡
§
∥
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560012, India
Normandie Universite,
́
INSA Rouen, UNIROUEN, CNRS, COBRA (UMR 6014), 76000 Rouen, France
Institut Universitaire de France, 1 rue Descartes, 75231 Paris, France
S Supporting Information
⊥
*
ABSTRACT: Functionalization of the indole N−H bond for enantioselective synthesis of biologically important
pyrroloquinoline derivatives has been reported under oxidative N-heterocyclic carbene catalysis conditions. The interception
of catalytically generated chiral α,β-unsaturated acylazoliums with the indole derivatives proceeds in an aza-Michael/Michael/
lactonization sequence to deliver the pyrroloquinoline derivatives in good yields, diastereoselectivities, and enantioselectivities.
The simultaneous enhancement of reactivity and selectivity observed in polar aprotic solvents is noteworthy.
he indole ring system is a ubiquitous heterocyclic moiety
T
that is present in many biologically active natural
1
products and drugs. Hence, mild and selective functionaliza-
tion of the indole ring has attracted increasing interest among
synthetic organic chemists. Although methods are available for
the selective functionalization of indoles at the C-2 and C-3
positions, the enantioselective functionalization of indoles at
2
the N−H bond is relatively limited. Recently, many methods
have been developed for the synthesis of ring-fused indole
systems. Among the various annulated indoles, pyrroloquino-
lines (1,7-annulated indoles) are important because these
structural motifs are found in many natural products. For
example, the substituted pyrroloquinoline KC 11404 is a
3
promising molecule for the treatment of asthma (Figure 1).
Moreover, DCQTB has been explored as red light-emitting
dopants in organic light-emitting diodes (OLEDs) and PHA-
Figure 1. Selected biologically important pyrroloquinolines.
4
5
29311 is known for its inhibitory activity against herpes virus
5
7
DNA polymerases. In addition, murrayazoline is a carbazole
alkaloid, which is a widely used drug due to its potent
antiplatelet aggregation activity. Consequently, the develop-
(NHC) catalysis has been gaining more interest recently. In
2
2
013, Chi and co-workers developed the NHC-catalyzed [4 +
] annulation of indole 3-carboxaldehydes with trifluoroaceto-
phenones leading to the enantioselective synthesis of tricyclic
6
ment of enantioselective routes to pyrroloquinolines is of great
importance.
Given the importance of indole derivatives, selective
functionalization of this nucleus using N-heterocyclic carbene
Received: September 4, 2018
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02820
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
δ-lactones and that the reaction proceeds via NHC-bound
dienolate intermediates (Scheme 1, eq 1). Independently,
Table 1. Optimization of the Reaction Conditions
8
Scheme 1. NHC-Catalyzed Indole Functionalization
b
c
d
entry (1)
base
solvent
yield 3 (%)
dr
er
1
2
3
4
5
6
7
8
9
1
1
1
1a
1b
1c
1d
1d
1d
1d
1d
1d
1d
1d
1d
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DMSO
DMSO
DMSO
DMSO
toluene
<5
<5
42
60
18
18
40
61
49
47
37
84
nd
nd
nd
nd
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
77:23
95:5
56:44
70:30
73:27
93:7
95:5
95:5
95:5
95:5
CH Cl2
2
THF
DMF
DMSO
DMSO
DMSO
DMSO
K CO3
2
0
1
2
Cs CO3
2
DMAP
DABCO
e
a
Conditions: 1 (0.125 mmol), 2a (0.125 mmol), 4 (10 mol %), 5 (1.0
b
equiv), base (1.0 equiv), solvent (1.0 mL), 25 °C, and 12 h. The
yields were determined by H NMR analysis of crude product using
CH Br as the internal standard. Determined by H NMR
spectroscopy prior to purification. Determined by HPLC analysis
1
c
1
2
2
d
e
on a chiral stationary phase. Using 1.5 equiv each of 2a and 5 and 15
mol % of 4.
Enders and co-workers demonstrated the enantioselective
synthesis of pyrroloindolones by the NHC-catalyzed [2 + 3]
annulation of α-functionalized aldehydes with 2-nitrovinylin-
doles, and the reaction proceeds via the NHC-bound enolate
H acidity. Although the substrate 1b was unreactive under the
present conditions (entry 2), the reaction using 1c afforded the
expected pyrroloquinoline 3c in 42% yield, >20:1 dr, and 77:23
9
intermediates (eq 2). Very recently, Studer and co-workers
13,14
have disclosed the NHC-catalyzed dearomatization of indoles
for the enantioselective synthesis of spirocyclic indolenines (eq
er (entry 3).
Gratifyingly, performing the reaction using
substrate 1d having a COCF group at the 3-position improved
3
10
3
). This reaction proceeds through indole 3-acylation using
the reactivity and selectivity to furnish 3d in 60% yield, >20:1
dr, and 95:5 er (entry 4). A rapid solvent screening revealed
that polar aprotic solvents such as DMF and DMSO were
useful for this cascade reaction (entries 5−8). Among the
various bases screened in DMSO, K CO , Cs CO , and DMAP
afforded 3a in moderate yields, maintaining the high er values
(entries 9−11). Finally, employing 1.5 equiv of both 2a and 5
in DMSO afforded 3d in 84% yield, >20:1 dr, and 95:5 er
the in situ-generated NHC-bound acylazolium intermediates
under oxidative conditions. In light of our interest in the NHC-
catalyzed reactions proceeding via the chiral α,β-unsaturated
1
1
acylazoliums, we envisioned that the reaction of N-
unsubstituted indoles bearing a Michael acceptor at the 7-
position with catalytically generated chiral α,β-unsaturated
acylazoliums under oxidative conditions could result in the
synthesis of tetracyclic δ-lactones. Herein, we report the
enantioselective synthesis of pyrroloquinoline-fused δ-lactones
by the reaction of indole derivatives with enals under oxidative
conditions (eq 4).
2
3
2
3
15
(entry 12).
With these optimized reaction conditions in hand, the scope
and limitations of this tetracyclic δ-lactone synthesis were
studied. Initially, the variation on α,β-unsaturated aldehydes
was evaluated (Scheme 2). The unsubstituted parent system
worked well, and a series of electron-donating/neutral and
-withdrawing groups at the 4-position of the β-aryl ring of enals
was well tolerated, and in each case, the 1,7-annulated indole
(pyrroloquinolines) derivative was formed in a high yield,
excellent dr, and good er values (3d−3k). In the case of the
chloro derivative 3h, the structure and stereochemistry was
unambiguously confirmed by single-crystal X-ray analysis.
Moreover, enals having substituents at the 3- and 2-positions
of the β-aryl ring did not affect the reactivity, and the desired
products were isolated in high yields and selectivities (3l−3p).
In addition, disubstitution at the β-aryl ring of 2 resulted in the
The present studies were initiated by treating the N−H
indole derivative bearing a Michael acceptor moiety at the 7-
position (1a) and cinnamaldehyde 2a in the presence of the
carbene generated from the chiral aminoindanol-derived
1
2
triazolium salt 4 using DABCO and the bisquinone 5 as
the oxidant. Disappointingly, under these conditions, the
desired tetracyclic δ-lactone product 3a was not formed (Table
1
, entry 1). As the reaction design first involved an aza-Michael
addition, we reasoned that the N−H acidity of the indole
substrate was the reason for the inferior reactivity. Hence, we
attempted the reaction with electron-withdrawing groups such
as Cl (1b) and CHO (1c) at the 3-position to increase the N−
B
DOI: 10.1021/acs.orglett.8b02820
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 2. Substrate Scope of the Reaction
A plausible mechanism of the present cascade reaction is
illustrated in Scheme 3. The reaction proceeds via the
Scheme 3. Proposed Mechanism of the Reaction
nucleophilic attack of NHC generated from 4 onto enal 2,
generating the tetrahedral intermediate (I), which on proton
16
transfer generates the nucleophilic Breslow intermediate (II).
In the presence of the bisquinone oxidant 5, intermediate II is
oxidized to the key α,β-unsaturated acyl azolium intermediate
(
III). The nucleophilic attack of 1 to intermediate III via the
N−H indole moiety (aza-Michael addition) provides the
NHC-bound enolate intermediate IV, which undergoes an
intramolecular Michael addition to the vinyl ketone moiety to
give the enolate intermediate V bearing an NHC-azolium
moiety. Finally, intramolecular acylation of V affords the
pyrroloquinoline product 3 with regeneration of the NHC
catalyst.
During the optimization of the reaction conditions, we
observed a simultaneous enhancement in reactivity and
selectivity for the formation of 3d in polar aprotic solvents,
a
General reaction conditions: 1d (0.25 mmol), 2 (0.375 mmol), 4
15.0 mol %), 5 (0.375 mmol), DMSO (2.0 mL), 25 °C, and 12 h.
such as CH CN, DMF, DMSO, and so forth. For this to be
3
(
validated, the reaction was performed in various solvents, and
the dielectric constant (DEC) of the solvent was plotted
Yields of isolated products are given, and the er value was determined
by HPLC analysis on a chiral stationary phase.
15
against the yield/ee of 3d obtained (Figure 2). For instance,
smooth conversion to the products in good yields and
enantioselectivities (3q−3s). Additionally, heterocyclic α,β-
unsaturated aldehydes underwent an efficient cascade reaction,
furnishing the target products in good yields and good er
values (3t, 3u). Furthermore, the dienal having a δ-aryl group
also furnished the tetracyclic indole 3v in 93% yield, >20:1 dr,
and 96:4 er, thus demonstrating the versatility of the present
cascade reaction. Interestingly, the methyl group at the
Michael acceptor moiety could be varied with cyclic and
acyclic alkyl groups without affecting the reactivity/selectivity.
Finally, the presence of Br in the indole ring was also well
tolerated and furnished the corresponding product 3y in 76%
yield, >20:1 dr, and 99:1 er value, thus expanding the scope of
this cascade reaction.
Figure 2. Variation of yield/ee of 3d with polarity of solvent
(dielectric constant).
C
DOI: 10.1021/acs.orglett.8b02820
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
the reaction afforded poor yield/ee when performed in toluene
Details on experimental procedures, characterization,
NMR spectra and HPLC traces of pyrroloquinolines
derivatives (PDF)
(
DEC: 2.38), moderate yield/ee in THF (DEC: 7.58), and
high yield/ee in DMF (DEC: 36.7). Although a general linear
relationship was not observed, the overall trend observed was
that the reactivity/selectivity was improved in polar aprotic
solvents. It should be noted that the reactivity in highly polar
solvents was not only because of the solubility of the reactants,
as the reactants are soluble in THF, but that the reactivity/
selectivity was only moderate. Moreover, polar aprotic solvents
are known to stabilize zwitterionic intermediates.
Accession Codes
CCDC 1863110 contains the supplementary crystallographic
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 Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
Finally, the functionalization of the tetracyclic δ-lactones was
carried out. Ring-opening of the unsaturated lactone moiety in
3
d using MeOH furnished the pyrroloquinoline 6d in 76%
AUTHOR INFORMATION
Corresponding Author
■
yield and 95:5 er value (Scheme 4). Similarly, the ring-opening
*
E-mail: atbiju@iisc.ac.in.
Scheme 4. Functionalization of Pyrroloquinoline 3d
ORCID
Thomas Poisson: 0000-0002-0503-9620
Tatiana Besset: 0000-0003-4877-5270
Akkattu T. Biju: 0000-0002-0645-8261
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Generous financial support by IFCPAR-CEFIPRA (no. 5505-
) is gratefully acknowledged. S.M. thanks UGC for a
■
1
fellowship, and S.H. thanks IISc for a fellowship. We thank
Mr. Rupak Saha (IPC, IISc) for the X-ray data.
REFERENCES
■
(
1) For selected reviews on indoles, see: (a) Zhang, M.-Z.; Chen, Q.;
Yang, G.-F. Eur. J. Med. Chem. 2015, 89, 421. (b) Bartoli, G.;
Bencivenni, G.; Dalpozzo, R. Chem. Soc. Rev. 2010, 39, 4449.
(
c) Kochanowska-Karamyan, A. J.; Hamann, M. T. Chem. Rev. 2010,
of 3d using BnNH2 afforded the corresponding amide
derivative 7d in 81% yield, maintaining the high er value.
Moreover, the selective olefination at the C-4 position of 3d
was achieved by a Rh(III)-catalyzed reaction with methyl
acrylate, leading to the formation of the C-4-functionalized
110, 4489. (d) Bandini, M.; Eichholzer, A. Angew. Chem., Int. Ed.
2009, 48, 9608. (e) Humphrey, G. R.; Kuethe, J. T. Chem. Rev. 2006,
106, 2875.
(2) For selected examples of organocatalytic enantioselective N-H
functionalization of indoles, see: (a) Chen, M.; Sun, J. Angew. Chem.,
Int. Ed. 2017, 56, 4583. (b) Enders, D.; Greb, A.; Deckers, K.; Selig,
P.; Merkens, C. Chem. - Eur. J. 2012, 18, 10226. (c) Xie, Y.; Zhao, Y.;
Qian, B.; Yang, L.; Xia, C.; Huang, H. Angew. Chem., Int. Ed. 2011, 50,
17
product 8d in 79% yield and 97:3 er value. In addition, the
Rh(III)-catalyzed reaction of 3d with N-benzyl maleimide
resulted in the hydroarylation at the C-4 position, affording 9d
as an inseparable mixture of diastereomers in 81% yield, 2:1 dr,
5
682. (d) Cai, Q.; Zheng, C.; You, S.- L. Angew. Chem., Int. Ed. 2010,
9, 8666. (e) Hong, L.; Sun, W.; Liu, C.; Wang, L.; Wang, R. Chem. -
4
18
and 95:5 er (for both diastereomers).
Eur. J. 2010, 16, 440. (f) Cui, H.-L.; Feng, X.; Peng, J.; Lei, J.; Jiang,
K.; Chen, Y.-C. Angew. Chem., Int. Ed. 2009, 48, 5737. (g) Bandini,
M.; Eichholzer, A.; Tragni, M.; Umani-Ronchi, A. Angew. Chem., Int.
Ed. 2008, 47, 3238.
In conclusion, we have developed the enantioselective
synthesis of pyrroloquinolines bearing three contiguous
stereocenters by the NHC catalyzed N−H functionalization
of indoles. The reaction of enals with indole derivatives
proceeded via the generation of the α,β-unsaturated
acylazoliums, and the desired products were formed in a
cascade reaction following the aza-Michael−Michael lactoniza-
tion. Excellent levels of diastereoselectivity and enantioselec-
tivity, atom-economy, and tolerance with a broad range of
functional groups and mild reaction conditions are the notable
features of the present annulation. Further studies on related
cascade reactions are ongoing in our laboratory.
(
3) Paris, D.; Cottin, M.; Demonchaux, P.; Augert, G.; Dupassieux,
P.; Lenoir, P.; Peck, M. J.; Jasserand, D. J. Med. Chem. 1995, 38, 669.
4) Yao, Y. S.; Zhou, Q. X.; Wang, X. S.; Wang, Y.; Zhang, B. W. A.
Adv. Funct. Mater. 2007, 17, 93.
5) Dorow, R. L.; Herrinton, P. M.; Hohler, R. A.; Maloney, M. T.;
Mauragis, M. A.; McGhee, W. E.; Moeslein, J. A.; Strohbach, J. W.;
Veley, M. F. Org. Process Res. Dev. 2006, 10, 493.
(
(
(6) For isolation of racemic murrayazoline, see: (a) Kureel, S. P.;
Kapil, R. S.; Popli, S. P. Tetrahedron Lett. 1969, 10, 3857. (b) Ueno,
A.; Kitawaki, T.; Chida, N. Org. Lett. 2008, 10, 1999.
(
7) For recent reviews on NHC catalysis, see: (a) Murauski, K. J. R.;
Jaworski, A. A.; Scheidt, K. A. Chem. Soc. Rev. 2018, 47, 1773.
b) Zhang, C.; Hooper, J. F.; Lupton, D. W. ACS Catal. 2017, 7,
583. (c) Flanigan, D. M.; Romanov-Michailidis, F.; White, N. A.;
ASSOCIATED CONTENT
Supporting Information
■
(
2
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b02820.
Rovis, T. Chem. Rev. 2015, 115, 9307. (d) Yetra, S. R.; Patra, A.; Biju,
A. T. Synthesis 2015, 47, 1357. (e) Hopkinson, M. N.; Richter, C.;
Schedler, M.; Glorius, F. Nature 2014, 510, 485. (f) Mahatthananchai,
D
DOI: 10.1021/acs.orglett.8b02820
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
J.; Bode, J. W. Acc. Chem. Res. 2014, 47, 696. (g) De Sarkar, S.;
Biswas, A.; Samanta, R. C.; Studer, A. Chem. - Eur. J. 2013, 19, 4664.
(
4
3
h) Ryan, S. J.; Candish, L.; Lupton, D. W. Chem. Soc. Rev. 2013, 42,
906. (i) Grossmann, A.; Enders, D. Angew. Chem., Int. Ed. 2012, 51,
14. (j) Bugaut, X.; Glorius, F. Chem. Soc. Rev. 2012, 41, 3511.
(
k) Izquierdo, J.; Hutson, G. E.; Cohen, D. T.; Scheidt, K. A. Angew.
Chem., Int. Ed. 2012, 51, 11686. (l) Cohen, D. T.; Scheidt, K. A.
Chem. Sci. 2012, 3, 53. (m) Vora, H. U.; Wheeler, P.; Rovis, T. Adv.
Synth. Catal. 2012, 354, 1617. (n) Chiang, P.-C.; Bode, J. W. In N-
Heterocyclic Carbenes; The Royal Society of Chemistry: London, 2011;
p 399. (o) Nair, V.; Menon, R. S.; Biju, A. T.; Sinu, C. R.; Paul, R. R.;
Jose, A.; Sreekumar, V. Chem. Soc. Rev. 2011, 40, 5336. (p) Enders,
D.; Niemeier, O.; Henseler, A. Chem. Rev. 2007, 107, 5606.
(
8) (a) Chen, X.; Yang, S.; Song, B.-A.; Chi, Y. R. Angew. Chem., Int.
Ed. 2013, 52, 11134. See also: (b) Cheng, J.; Sun, J.; Yan, J.; Yang, S.;
Zheng, P.; Jin, Z.; Chi, Y. R. J. Org. Chem. 2017, 82, 13342.
(
9) (a) Ni, Q.; Zhang, H.; Grossmann, A.; Loh, C. C. J.; Merkens,
C.; Enders, D. Angew. Chem., Int. Ed. 2013, 52, 13562. For a related
homoenolate reaction, see: (b) Yang, Y.-J.; Ji, Y.; Qi, L.; Wang, G.;
Hui, X.-P. Org. Lett. 2017, 19, 3271.
(
10) (a) Bera, S.; Daniliuc, C. G.; Studer, A. Angew. Chem., Int. Ed.
2017, 56, 7402. For the pioneering report on the use of 5 in oxidative
NHC-catalysis, see: (b) De Sarkar, S.; Grimme, S.; Studer, A. J. Am.
Chem. Soc. 2010, 132, 1190.
(
11) For reports from our group, see: (a) Mondal, S.; Ghosh, A.;
Mukherjee, S.; Biju, A. T. Org. Lett. 2018, 20, 4499. (b) Mukherjee,
S.; Ghosh, A.; Marelli, U. K.; Biju, A. T. Org. Lett. 2018, 20, 2952.
(
c) Yetra, S. R.; Mondal, S.; Mukherjee, S.; Gonnade, R. G.; Biju, A.
T. Angew. Chem., Int. Ed. 2016, 55, 268. (d) Yetra, S. R.; Mondal, S.;
Suresh, E.; Biju, A. T. Org. Lett. 2015, 17, 1417. (e) Yetra, S. R.;
Bhunia, A.; Patra, A.; Mane, M. V.; Vanka, K.; Biju, A. T. Adv. Synth.
Catal. 2013, 355, 1089. (f) Yetra, S. R.; Roy, T.; Bhunia, A.; Porwal,
D.; Biju, A. T. J. Org. Chem. 2014, 79, 4245. (g) Yetra, S. R.;
Kaicharla, T.; Kunte, S. S.; Gonnade, R. G.; Biju, A. T. Org. Lett. 2013,
1
(
5, 5202.
12) Struble, J. R.; Bode, J. W. Org. Synth. 2010, 87, 362.
(
13) For an organocatalytic synthesis of pyrroloquinolines, see:
Giardinetti, M.; Moreau, X.; Coeffard, V.; Greck, C. Adv. Synth. Catal.
015, 357, 3501.
14) For related reports on NHC-catalyzed aza-Michael reaction,
2
(
see: (a) Zhang, H.-R.; Dong, Z.-W.; Yang, Y.-J.; Wang, P.-L.; Hui, X.-
P. Org. Lett. 2013, 15, 4750. (b) Wu, X.; Hao, L.; Zhang, Y.; Rakesh,
M.; Reddi, R. N.; Yang, S.; Song, B.-A.; Chi, Y. R. Angew. Chem., Int.
Ed. 2017, 56, 4201.
(
(
(
15) For details, see the Supporting Information.
16) Breslow, R. J. Am. Chem. Soc. 1958, 80, 3719.
17) For a related report, see: Lanke, V.; Bettadapur, K. R.; Prabhu,
K. R. Org. Lett. 2016, 18, 5496.
18) For a related report, see: Sherikar, M. S.; Kapanaiah, R.; Lanke,
V.; Prabhu, K. R. Chem. Commun. 2018, 54, 11200.
(
E
DOI: 10.1021/acs.orglett.8b02820
Org. Lett. XXXX, XXX, XXX−XXX