Synthetic approaches to tetrahydro-2,7- and -1,6-naphthyridines

Article abstract of DOI:10.1016/j.tetlet.2020.152194

Three new tetrahydronaphthyridines were prepared starting from readily available 3-bromo-picolines. The key step of the proposed strategy consists of reduction of the imine prepared by intramolecular reaction of the acyl and amine groups. The amine group was introduced via deprotonation of the methyl group in bromopicoline, its reaction with dimethylcarbonate, reduction to the corresponding alcohol and Mitsunobu reaction with phthalamide. The acyl group was placed at the bromine position via the Stille cross-coupling reaction of tributyl(1-ethoxyvinyl)stannane followed by hydrolysis. The proposed chemical sequence allowed the multigram preparation of tetrahydro-2,7- and 1,6-naphthyridines.

Full text of DOI:10.1016/j.tetlet.2020.152194

Journal Pre-proofs
Synthetic Approaches to Tetrahydro-2,7- and -1,6-naphthyridines
Dmytro Sierov, Kostiantyn Nazarenko, Kostiantyn Shvydenko, Tetiana
Shvydenko, Aleksandr Kostyuk
PII:
S0040-4039(20)30659-6
DOI:
Reference:
https://doi.org/10.1016/j.tetlet.2020.152194
TETL 152194
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
23 April 2020
22 June 2020
26 June 2020
Please cite this article as: Sierov, D., Nazarenko, K., Shvydenko, K., Shvydenko, T., Kostyuk, A., Synthetic
Approaches to Tetrahydro-2,7- and -1,6-naphthyridines, Tetrahedron Letters (2020), doi: https://doi.org/10.1016/
j.tetlet.2020.152194
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover
page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version
will undergo additional copyediting, typesetting and review before it is published in its final form, but we are
providing this version to give early visibility of the article. 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.
© 2020 Elsevier Ltd. All rights reserved.

Graphical Abstract
To create your abstract, type over the instructions in the template box below.
Fonts or abstract dimensions should not be changed or altered.
Synthetic Approaches to Tetrahydro-2,7-
and- 1,6-naphthyridines
Leave this area blank for abstract info.
Dmytro Sierov, Kostiantyn Nazarenko, Kostiantyn Shvydenko, Tetiana Shvydenko, Aleksandr Kostyuk
O
R
N
R
O
O
O
N
Br
R
N
or
R
O
N
NH
NH
O
N
Br
N
N
or
N
NH
NH
overall yield: 25% (R=H)
38% (R=CH3)
23%
N
N

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Synthetic Approaches to Tetrahydro-2,7- and -1,6-naphthyridines
a
a
a
Dmytro Sierov a, Kostiantyn Nazarenko , Kostiantyn Shvydenko , Tetiana Shvydenko , and Aleksandr
Kostyuk 
a,
a Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Murmanska Str. 5, Kyiv 02660, Ukraine
———
ARTICLE INFO
ABSTRACT
 Corresponding author. Tel.: +380 44 4994601; e-mail: a.kostyukr@yahoo.com
Article history:
Received
Three new tetrahydronaphthyridines were prepared starting from readily available 3-bromo-
picolines. The key step of the proposed strategy consists of reduction of the imine that was
Received in revised form
Accepted
Available online
prepared by intramolecular reaction of the acyl and amine groups. The amine group was
introduced via deprotonation of the methyl group in bromopicoline, its reaction with
dimethylcarbonate, reduction to the corresponding alcohol and Mitsunobu reaction with
phthalamide. The acyl group was placed at the bromine position via the Stille cross-coupling
reaction of tributyl(1-ethoxyvinyl)stannane followed by hydrolysis. The proposed chemical
sequence allowed the multigram preparation of tetrahydro-2,7- and 1,6-naphthyridines.
Keywords:
Tetrahydro-2,7-naphthyridine
Tetrahydro-1,6-naphthyridine
Stille cross-coupling
Mitsunobu reaction
Reduction
2009 Elsevier Ltd. All rights reserved.
1. Introduction
compounds C1. Cleavage of the phthalimides with hydrazine
afforded transient primary amines, which subsequently cyclized
Partially saturated bicyclic heterocycles are utilized
successfully in drug discovery because as they are structurally
more complex molecules.1 and allow the study of increased They
allow studying more diverse chemical space. Moreover, the
compounds with athe greater fraction of sp3 centers also tend to
be less toxic.2 Various regioisomeric tetrahydronaphthyridines
are the requisite bicyclic saturated heterocycles, but they are
hardly accessible. There are a few reliable synthetic approaches
have been reportedto tetrahydronaphthyridines (Scheme 1).
to ketimines. The ketimines were then reduced with sodium
borohydride to give the target tetrahydronaphthyridines.9 A total
asymmetric synthesis of the tetrahydronaphthyridine alkaloid (-)-
normalindine was accomplished via the addition of a laterally
metalated 4-methyl-3-cyanopyridine D to a sulfinimine as the
key step.10 A route to 5,6,7,8-tetrahydro-1,6-naphthyridines and
related heterocycles was developed using microwave-promoted,
Co-catalyzed [2+2+2] cyclizations of compounds E. Both intra-
and intermolecular approaches were shown to work well.11 1,6-
Naphthyridinium salts F were used to prepare various substituted
tetrahydronaphthyridines via reduction.12,13 This approach was
used for synthesis of blockers of canonical transient receptor
potential channels.14 A series of tetrahydro-1,6-naphthyridine
derivatives were recently described as potential anticancer
agents. The key step was the cyclization of compounds of type
G.15 Although, the above-mentioned methods allow the synthesis
of various terahydronaphthyridine derivatives, it is clear that the
search for new convenient methods is a worthwhile task.
Diverse tetrahydronaphthyridines were prepared via a formal
Pictet−Spengler reaction of electron-poor pyridines of type A.3
The key step of the method is radical addition to imines using
different radical sources and reaction conditions. The method
gives the best results for 1,7-tetrahydronaphthyridines since 2-
pyridyl radicals are more stable compared to the 3- and 4 –
pyridyl radicals. Nevertheless, other isomers such as 1,6- and
2,7-tetrahydronaphthyridines were also prepared, albeit in lower
yields. Predictably, better results were achieved with aromatic
and heterocyclic aldehydes because alkylimines are less stable.
Various 1,5-, 1,6- and 1,8-tetrahydronaphthyridines were
prepared via an inverse-electron demand hetero-Diels−Alder
(ihDA)/retro-Diels−Alder (rDA) sequence in which 1,2,4-
triazines B acted as electron deficient 4π-components. This
sequence
gives
access
to
diversely
substituted
tetrahydronaphthyridines, but it requires less accessible starting
materials.4–8 2,6- and 2,7-Tetrahydronaphthyridines were
synthesized starting from the appropriately substituted
bromoformylpyridines C. Addition of arylmagnesium bromide to
the aldehydes and Heck coupling of the arylbromides with N-
vinylphthalimide gave alcohols. Hydrogenation of the double
bonds followed by oxidation of the alcohols to ketones gave
R'
N
N
N
N
N
Br
(TMS)3SiH
AIBN
R
ihDA

2
Tetrahedron
Our strategy for the synthesis of tetrahydronaphthyridines was
determined by two factors: the use of readily available starting
materials and the possibility to scale up the procedures. We
started from available 3-bromopicolines. Thus, 3-bromo-4-
methylpyridine 1a was deprotonated with 2.1 equivalents of
lithium bis(trimethylsilyl)amide followed by the addition of
dimethyl carbonate to give compound 2b in high yield (Scheme
2). The Ccompound 2b was prepared previously, and we slightly
modified the procedure.16 Compound 2a was prepared
analogously, but after the addition of dimethyl carbonate
followed alkylation with methyl iodide was added, and then the
reaction mixture was quenched with aqueous ammonium
chloride. In both cases, the yields were almost quantitative. In
the case of isomeric 3-bromo-2-methylpyridine 1b, the yield was
slightly lower – (75%). The reduction of compounds 2a-c was
carried out with lithium aluminum hydride in THF at -78 °C to
give 3a-c in 43-78 % yields (Scheme 2). It is important to
maintain a low temperature during the course of the reduction of
the ester group and while quenching the reaction mixture.
Column chromatography was used to purify compounds 3a-c.
Compound 3c was previously prepared by the reduction of ethyl
2-(3-bromopyridin-2-yl)acetate with DIBAL-H in 80% yield. Its
spectral characteristics Our spectroscopic data were identical to
those previously reported.3
The Mitsunobu reaction was selected to transform the
hydroxyl group into an amine group. Phthalimides bearing a
highly acidic NH are known to readily take part in N-alkylation.17
In our case, the reaction proceeded in high yield (85-89%).
Introduction of an acyl group was carried out by the Pd-catalyzed
cross-coupling reaction of bromopyridines 4a-c with 1-
(ethoxyvinyl)tri(n-butyl)stannane in near quantitative yield.18
Next, the reaction mixture was treated with hydrochloric acid
to transform the ethoxyvinyl group into an acyl group. Under
these conditions, the phthalimide group remained intact.
Cleavage of the phthalimide protecting group required overnight
heating under acidic conditions. Cyclisation took place upon
basification. Compound 6a has been described in the literature.19
THowever, the compound was characterized only as its
hydrochloric salt using withits melting point, and no
spectroscopicspectral data were provided.
The final stage of the synthesis was the reduction of
dihydronaphthyridines
6
into tetrahydronaphthyridines 7.
Compounds 6a-c were reduced with sodium borohydride in
methanol in high yields. Compound 7a was prepared as a mixture
of cis:trans isomers in a 1.7:1 ratio which was purified by
gradient column chromatography. The last collected fraction
contained compound 7a in 80% de excess. Its structure was
established by 2D NMR experiments (see ESI).

O
Y
R
R
OMe
OH
3
Br
Br
Br
1. LiHMDS
LiAlH4
Y
Y
O
Y
o
2. (MeO)2CO
R
THF
Br
- 78 C
R
X
X
X
3. MeI
2a
for
OMe
OH
3a,
3b,
3c,
79%
50%
43%
2a,
97%
Br
Br
1. LiHMDS
) X = N, Y = CH
LiAlH
2b,
2c,
95%
76%
4
1a
Y
Y
o
1b
) X = CH, Y = N
2. (MeO)2CO
THF
- 78 C
X
X
X
3. MeI
2a
for
SnBu3
OEt
3a-c
1a,b
2a-c
1.
O
N
O
1a
) X = N, Y = CH
1b
) X = CH, Y = N
R
Pd (dba) (5 mol %)
SnBu
PP2h33 (103mol %)
R
N
O
phthalimide
O
O
1.
C
Br
O
OEt
R
O
N
Y
DEAD/PPh
R
N
Y
3
2. HCl
O
phthalimide
PPh3/Pd2(dba)3
C
X
Br
X
R
O
O
Y
DEAD/PPh3
Y
4a,
4b,
4c,
86%
5a,
5b,
5c,
2. HCl
100%
93%
97%
85%
89%
X
X
4a-c
5a-c
R
HCl, heating
NaBH4
Y
Y
R
R
2 7
for -
HCl, heating
NaBH
N4
Y
Y
2 7
for -
X
X
NH
MeOH
a) R = Me, X = N, Y = CH
b) R = H, X = N, Y = CH
X
N
X
NH
MeOH
a) R = Me, X = N, Y = CH
6a,
6b,
6c,
7a,
7b,
7c,
77%
81%
91%
74%
b) R = H, X = N, Y = CH
c) R = H, X = CH, Y = N
83%
c) R = H, X = CH, Y = N
89%
7a-c
6a-c
Scheme 2. Synthesis of 2,7- and 1,6-naphthyridines 7a-c.
Tetrahydronaphthyridine 7c was previously prepared from 6-
benzyl-1,6-naphthyridin-6-ium bromide.12 It should be noted that
thisits method requires expensive 1,6-naphthyridine as a starting
material.
R
R
Pd/C
10% Pd/C (15 mol%)
6a,b
6a,b
200oC
N
N
N
N
200 oC
8a
8b
, R = CH3, 61%
, R = H, 67%
a
b
) R =Me; ) R=H
8a,b
Scheme 3. Catalytic dehydrogenation of tetrahydronaphthyridines
6a,b.

4
Tetrahedron
9. Horne DB, Tamayo NA, Bartberger MD,
Bo Y, Clarine J, Davis CD, Gore VK,
Kaller MR, Lehto SG, Ma V V, Nishimura
N, Nguyen TT, Tang P, Wang W,
Youngblood BD, Zhang M, Gavva NR,
Monenschein H, Norman MH. J Med Chem.
2014; 57: 2989–3004.
10. Davis FA, Melamed JY, Sharik SS. J Org
Chem. 2006; 71: 8761–8766.
11. Zhou Y, Porco JA, Snyder JK. Org Lett.
2007; 9: 393–396.
12. Shiozawa A, Ichikawa Y, Komuro C,
Kurashige S, Miyazaki H, Yamanaka H,
sakamoto T. Chem Pharm Bull (Tokyo).
1984; 32: 2522–2529.
13. Lowe PA. A. R. Katritzky, and C. W. B. T.-
C. H. C. Rees, Eds.; Pergamon: Oxford,
1984; pp 581–627.
We have also shown that tetrahydronaphthyridine 6a,b can be
converted into naphthyridines 8a,b by catalytic dehydrogenation
at 200 °C inat mesitylene for 3 h (Scheme 3). Naphthyridine 8b
was
previously
prepared
from
the
corresponding
chloronaphthyridine via cross-coupling with MeMgCl using
catalytic CoCl2. The spectroscopic and physical data were
identical to those reported in the literature.20
14. Washburn DG, Holt DA, Dodson J, McAtee
JJ, Terrell LR, Barton L, Manns S,
Waszkiewicz A, Pritchard C, Gillie DJ,
Morrow DM, Davenport EA, Lozinskaya
IM, Guss J, Basilla JB, Negron LK, Klein
M, Willette RN, Fries RE, Jensen TC, Xu
X, Schnackenberg CG, Marino JP. Bioorg
Med Chem Lett. 2013; 23: 4979–4984.
15. Aicher, T. D., Skalitzky, D. J., Toogood,
Peter, L., Vanhuis, C. A.WO2019200120A1
• 2019-10-17 • 2019.
Conclusion.
A
convenient and general approach to
tetrahydro-2,7- and 1,6-naphthyridines has been developed. They
were prepared on a multigram scale from readily available
starting materials - 3-bromopicolines.
References and notes
1. Twigg DG, Kondo N, Mitchell SL,
Galloway WRJD, Sore HF, Madin A,
Spring DR. Angew Chemie Int Ed. 2016; 55:
12479–12483.
2. Lovering F. Medchemcomm. 2013: 515–
519.
16. Hazelden IR, Carmona RC, Langer T,
Pringle PG, Bower JF. Angew Chemie Int
Ed. 2018; 57: 5124–5128.
3. Jackl MK, Kreituss I, Bode JW. Org Lett.
2016; 18: 1713–1715.
17. Swamy KCK, Kumar NNB, Balaraman E,
Kumar KVPP. Chem Rev. 2009; 109: 2551–
2651.
18. Azzouz R, Peauger L, Gembus V, Ţînţaş M-
L, Sopková-de Oliveira Santos J,
Papamicaël C, Levacher V. Eur J Med
Chem. 2018; 145: 165–190.
19. Govindan CK, Taylor G. J Org Chem.
1983; 48: 5348–5354.
20. Greiner R, Ziegler DS, Cibu D, Jakowetz
AC, Auras F, Bein T, Knochel P. Org Lett.
2017; 19: 6384–6387.
4. Jouha J, Buttard F, Lorion M, Berthonneau
C, Khouili M, Hiebel M-A, Guillaumet G,
Brière J-F, Suzenet F. Org Lett. 2017; 19:
4770–4773.
5. Neipp CE, Ranslow PB, Wan Z, Snyder JK.
Tetrahedron Lett. 1997; 38: 7499–7502.
6. Haenel F, John R, Seitz G. Arch Pharm
(Weinheim). 1992; 325: 349–352.
7. Lahue BR, Lo S-M, Wan Z-K, Woo GHC,
Snyder JK. J Org Chem. 2004; 69: 7171–
7182.
7.
8. Buttard F, Berthonneau C, Hiebel M-A,
Brière J-F, Suzenet F. J Org Chem. 2019;
84: 3702–3714.
Supplementary Material
Supplementary materials can be found online at:
☒ The authors declare that they have no known
competing financial interests or personal
relationships that could have appeared to influence
the work reported in this paper.
Declaration of interests

5
☐The authors declare the following financial
interests/personal relationships which may be
considered as potential competing interests:
Highlights



Tetrahydro-2,7- and -1,6-naphthyridines
multigram synthesis
Stille cross-coupling reaction of
bromopicolines
From bromopicolines to 2,7-naphthyridines