A general approach to access 5,6-dihydroindolo-naphthyridine ring system

Article abstract of DOI:10.1016/j.tetlet.2017.02.030

We report a general approach for the synthesis of 5,6-dihydroindolo-naphthyridine ring system via an intramolecular cyclization of the indole NH to an alkene moiety as the key step.

Full text of DOI:10.1016/j.tetlet.2017.02.030

Accepted Manuscript
A General Approach to Access 5,6-dihydroindolo-naphthyridine ring system
Shuwen He, Peng Li, Xing Dai, Hong Liu, Zhong Lai, Dong Xiao, Casey C.
McComas, Chunyan Du, Yuehui Liu, Jingjun Yin, Qun Dang, Nicolas Zorn,
Xuanjia Peng, Ravi P. Nargund, Anandan Palani
PII:
S0040-4039(17)30197-1
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.02.030
TETL 48641
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
26 November 2016
4 February 2017
9 February 2017
Please cite this article as: He, S., Li, P., Dai, X., Liu, H., Lai, Z., Xiao, D., McComas, C.C., Du, C., Liu, Y., Yin,
J., Dang, Q., Zorn, N., Peng, X., Nargund, R.P., Palani, A., A General Approach to Access 5,6-dihydroindolo-
naphthyridine ring system, Tetrahedron Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.02.030
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

A General Approach to Access 5,6-dihydroindolo-naphthyridine
ring system
Shuwen He a , Peng Li b, Xing Dai a, Hong Liu a, Zhong Lai a, Dong Xiao a, Casey C. McComas
c, Chunyan Du b, Yuehui Liu b, Jingjun Yin d, Qun Danga, Nicolas Zorn a, Xuanjia Peng b, Ravi
P. Nargund a, Anandan Palani a
a Discovery Chemistry, Merck Research Laboratories, 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA
b WuXi Apptec Co., Ltd, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, P. R. China
c Discovery Chemistry, Merck Research Laboratories, 770 Sumneytown Pike, West Point, PA 19486, USA
d Discovery Process Chemistry, Merck Research Laboratories, 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA
Abstract— We report a general approach for the synthesis of 5,6-dihydroindolo-naphthyridine ring system via an intramolecuar
cyclization of the indole NH to an alkene moiety as the key step.
Key words— intramolecular cyclization, 5,6-dihydroindolo-naphthyridine ring system, indole, alkene.
©2016 Elsevier Science Ltd. All rights reserved.
Highlights
 A novel intramolecular cyclization gives access to the title ring system.
 Various precursors containing a six-membered azine are tolerated.
 This method affords 2c with a sterically congested C next to indole N.

A General Approach to Access 5,6-dihydroindolo-naphthyridine
ring system
Shuwen He a,*,† , Peng Li b,†, Xing Dai a, Hong Liu a, Zhong Lai a, Dong Xiao a,Casey C.
McComas c, Chunyan Du b, Yuehui Liu b, Jingjun Yin d, Qun Danga, Nicolas Zorn a, Xuanjia
Pengb, Ravi P. Nargund a, Anandan Palani a
a Discovery Chemistry, Merck Research Laboratories, 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA
b WuXi Apptec Co., Ltd, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, P. R. China
c Discovery Chemistry, Merck Research Laboratories, 770 Sumneytown Pike, West Point, PA 19486, USA
d Discovery Process Chemistry, Merck Research Laboratories, 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA
Abstract—We report a general approach for the synthesis of 5,6-dihydroindolo-naphthyridine ring system via an intramolecuar
cyclization of the indole NH to an alkene moiety as the key step.
Key words—intramolecular cyclization, 5,6-dihydroindolo-naphthyridine ring system, indole, alkene.
©2016 Elsevier Science Ltd. All rights reserved.
Indole, a ubiquitious pharmacophore, is present in many
natural products and pharmaceutical molecules. 1 In
Janurary 2016, FDA approved Zepatier to treat patients
with chronic hepatitis C virus (HCV) genotypes 1 and 4
infections. Zepatier is a fixed-dose combination product
containing elbasvir, a hepatitis C virus (HCV) NS5A
inhibitor, and grazoprevir, an HCV NS3/4A protease
inhibitor.2 As shown in Figure 1, elbasvir (MK-8742)
has an indole moiety in the central part of the molecule.3
system reported by Baranova group, who described an
elegant and practical approach to benzo[b]indolo[1,2-
h][1,7]naphthyridine
4 based on the Friedländer
condensation of 7,8-dihydropyrido[1,2-a]indol-9(6H)-
one with 2-aminobenzaldehyde (Figure 3).5 However,
besides the restriction to a benzo fused system, the
scope of this method was limited to the product with a
pyridyl nitrogen atom at the specific position shown in 4.
In this letter, we will disclose our general approach for
the
synthesis
of
5,6-dihydroindolo[1,2-
h][1,7]naphthyridine 2 and related compounds with
pyridyl nitrogen atoms at various positions.
Figure 1 Structure of elbasvir (MK-8742)
Previously, we reported a general approach to access
tetracyclic 6H-pyrido[2',3':5,6] [1,3]oxazino [3,4-
a]indole 1 which has a methylene linker to connect the
indole nitrogen atom with a hydroxyl group on the
Figure 2 Indole containing tetracyclic structures.
4
pyridyl ring (Figure 2). To continue with our SAR
effort, we were interested in exploring a related indole
containing tetracyclic structure, 5,6-dihydroindolo[1,2-
h][1,7]naphthyridine 2, replacing the oxygen atom on
the linker with a methylene group. In the literature,
there is no report so far describing the synthesis of this
class of structures except for a related benzo fused
Figure 3. Reported route to benzo[b]indolo[1,2-h][1,7]naphthyridine
Our strategy focused on a novel intramolecular
*
Corresponding author. Tel.: +1 908 740 0881.
E-mail address: shuwen_he@merck.com (S. He).
†
Both authors contributed equally to this Letter.

cyclization of the alkenyl intermediate 8 leading to the
target structure 2 (Figure 4). This approach was
t-BuOK or LiHMDS only produced very messy
reactions. Sodium carbonate (Na2CO3) or
inspired by
a
patent disclosure reporting the
diisopropylethylamine gave low conversions (< 10%).
Compared to DMAC (dimethylacetamide), DMF
worked equally well. DMSO gave slightly lower
product yields. There was no cyclized product observed
with THF. Acetonitrile gave poor conversions (<10%).
Therefore, in the subsequent work, we used 3.0 eq. of
K3PO4•3H2O in DMAC as the standard conditions.
intermolecular version of this reaction: a cyclization of
NH of a substituted indole onto a vinyl group of another
molecule.6 Alkenyl intermediate 8 should be available
from phenolic intermediate 7, which was prepared
previously from the boronate 5 and iodide 6. Since each
of them could bear a variety of substitutions, this
modular approach would allow rapid SAR for our
medicinal chemsitry program.
We applied this methodology to the construction of
additional cyclic structures from the corresponding
alkene precursors (Table 1). We prepared alkene
precursors with one or two methyl substitutions on the
vinyl group (entries 2 and 3, Table 1). The cyclization
from each precursor completed in about 4 hours with a
high isolated yield of the cyclized product. It is
remarkable that the cyclization from precursor 8c
produced 2c with a sterically congested carbon
connecting the indole nitrogen atom.
We then examined the impact of the position of nitrogen
in the pyridyl ring on the cyclization (entry 4 to 7,
Table 1). Comparing with 8a, precursor 8d also
underwent a smooth cyclization to afford 2d in good
yield indicating that F and Cl substitutions in 8a are not
required for the cyclization. The cyclization seemed to
be sensitive to the electronic environment since 2d and
2g were obtained in good yield while the cyclizations
from substrates 8e and 8f were sluggish affording 2e
and 2f, respectively, in somewhat lower yields.
Figure 4 Strategy to access 2 via an intramolecular cyclization from 8
We successfully demonstrated this strategy during the
synthesis of 2a (Scheme 1). The synthesis commenced
with known intermediate 9, which was converted to
alkene 8a via a standard triflation-Stille coupling
sequence.
Cyclization under slightly modified
conditions based on ref. 6 afforded 2a in a high isolated
yield. The chloro group of 2a would provide a handle
to attach an additional fragment for SAR work.
We further extended this chemistry to precursors
containing diazines (entry 8-10, Table 1). Pyrazinyl,
pyrimidyl and pyridazinyl were all tolerated affording
the corresponding cyclized products in modest to good
yields. The cyclization of precursor 8j was allowed to
react for only 0.5 h and product 2j was isolated in a
modest yield as the starting material and/or the product
seemed to be unstable under the reaction conditions.
In summary, we have described a general method for
the synthesis of 5,6-dihydroindolo-naphthyridine ring
system with a pyridyl nitrogen atom at all possible
positions based on a novel intramolecular cyclization of
the indole NH to an alkenyl tether. This method can be
extended to the diazine precursors as well. The effort
applying this method to the SAR for our medicinal
chemistry program will be disclosed in due course.
Scheme 1 Preparation of compound 2a. Reagents and conditions: (a)
Tf2O (2 eq.), CH2Cl2, 0ºC to rt, 1 h, 83%; (b) PdCl2(PPh3)2 (5 mol%),
tributyl(vinyl)stannane, LiCl, DMF, 60ºC, 1 h, 69%; (c) K3PO4·3H2O (3
eq.), DMAC, 100ºC, 12 h, 85%.
Starting from the conditions originally reported in ref. 6,
we briefly explored alternative bases and solvents. We
found that the amount of K3PO4 can be reduced to 3 eq.
and that K3PO4•3H2O works equally well compared to
the anhydrous salt. In contrast to K3PO4 or K3PO4•3H2O,

Table 1 Synthesis of 2 from 8 via intramolecular cyclization
Conditions
Yield
Condtions
Yield
Entry
1
Alkene 8
Cyclized product 2
Entry
6
Alkene 8
Cyclized product 2
100oC, 12 h
85%
100oC, 12 h
60%
8f
8a
2a
2f
100oC, 4 h
85%
100oC, 12 h
80%
2
3
7
8
8g
2g
8b
2b
100oC, 4 h
92%
100oC, 2.5 h
60%
8h
2h
2c
8c
100oC, 7 h
85%
100oC, 3 h
80%
4
5
9
8d
2d
8i
8j
2i
100oC, 12 h
50%
100oC, 0.5 h
44%
10
8e
2e
2j

Supplementary Material
The supplementary material contains the experimental procedures and characterization data for all new compounds.
References
1
For an excellent review on recent development of indole-containing antiviral agents, see: Zhang, M.-Z.; Chen, Q.; Yang, G.-F. Eur. J.
Med. Chem. 2015, 89, 421.
2
Zepatier™ (elbasvir and grazoprevir) tablets, for oral use, prescribing information, Merck & Co. Inc., 2000 Galloping Hill Road,
Kenilworth, NJ 07033 U.S.A, www.merck.com. Retrieved September 16, 2016.
3 Coburn, C. A.; Meinke, P. T.; Chang, W.; Fandozzi, C. M.; Graham, D. J.; Hu, B.; Huang, Q.; Kargman, S.; Kozlowski, J.; Liu, R.;
McCauley, J. A.; Nomeir, A. A.; Soll, R. M.; Vacca, J. P.; Wang, D.; Wu, H.; Zhong, B.; Olsen, D. B.; Ludmerer, S. W. ChemMedChem
2013, 8, 1930.
4 He, S.; Li, P.; Dai, X.; McComas, C. C.; Huang, H.; Zhan, C.; Chang, L.; Liu, Y.; Chen, S.; Lai, Z.; Liu, H.; Yin, J.; Dang, Q.; Xiao, D.;
Zorn, N.; Peng, X.; Nargund, R. P.; Palani, A. Tetrahedron Lett. 2013, 54, 3755.
5 Baranova, O. V.; Zhidkov, M. E.; Dubovitskii, S. V. Tetrahedron Lett 2011, 52, 2397.
6 Wollowitz, S.; Kataisto, E. W. Methods for preparing pyridylethyl-substituted carbolines, WO 2009111540 A1.