A versatile annulation route to primary-amino-substituted naphthyridine esters

Article abstract of DOI:10.1055/s-0033-1340111

A straightforward four-step synthesis of primary-amino-substituted naphthyridine esters from commercially available cyano-pyridines was described. The route makes use of a condensation reaction between pyridinyl acetates with N,N-dimethylformamide dimethylacetal (DMF-DMA) to form ortho-cyano vinylogous carbamates. These intermediates can undergo facile cyclization with ammonium acetate in acetic acid to generate the corresponding naphthyridine esters in good synthetic yields. The synthesis of -primary-amino-substituted 7-azaquinoxaline was also described. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0033-1340111

LETTER
▌89
lAetteVr ersatile Annulation Route to Primary-Amino-Substituted Naphthyridine
Esters
Annulation Route to Primary-Amino-Substituted Naphthyridine Esters
Jinhua Chen,a Zijin Xu,a Tao Wang,a Joseph P. Lyssikatos,b Chudi O. Ndubaku*b
a
Wuxi AppTec, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, P. R. of China
b
Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA
Fax +1(650)7424943; E-mail: chudin@gene.com
Received: 16.08.2013; Accepted after revision: 09.10.2013
O
N
O
F
OH
N
O
Abstract: A straightforward four-step synthesis of primary-amino-
substituted naphthyridine esters from commercially available cyano-
pyridines was described. The route makes use of a condensation re-
action between pyridinyl acetates with N,N-dimethylformamide
dimethylacetal (DMF-DMA) to form ortho-cyano vinylogous car-
bamates. These intermediates can undergo facile cyclization with
ammonium acetate in acetic acid to generate the corresponding
naphthyridine esters in good synthetic yields. The synthesis of
primary-amino-substituted 7-azaquinoxaline was also described.
F
N
OH
N
H
N
S
H
N
N
F
O
H2N
O
H
L-870,810 (1)
HIV-1 integrase inhibitor
F
trovafloxacin (2)
broad-spectrum antibiotic
Key words: naphthyridine, annulation, vinylogous carbamates,
heterocycles, scaffold
O
OH
NH2
N
The naphthyridine scaffold has found some utility as a
template in medicinally active compounds.1 It has been
shown to be a rigid replacement for diketo acids, compris-
ing the central architecture of antiviral drug L-870,810 (1)
and the antibiotic trovafloxacin (2) (Figure 1).2,3 In addi-
tion, it can serve as a suitable core for phosphodiesterase-
4 inhibitors such as NVP-ABE171 (3)4 as well as several
known kinase inhibitors.
R
N
N
N
O
OEt
N
4
N
O
this work
NVP-ABE171 (3)
PDE-4 inhibitor
As a part of a program that sought to utilize various regio-
isomeric primary-amino-substituted naphthyridine esters
4, we required a facile route for the preparation of such
compounds. Previously, this type of heterocycle had been
prepared in lengthy and low-yielding chemical routes.5,6
We sought instead to develop a more concise and general
strategy for preparing various naphthyridine isomers in a
controlled fashion. Herein we report one such approach
that proved to be useful for the construction of several pri-
mary-amino-substituted naphthyridine esters (Scheme 1).
The key transformation in this approach is the annulation
of 2-cyano-substituted vinylogous carbamates 10 with
ammonium acetate under mildly acidic conditions. The
method described makes use of readily available haloge-
nated azine heterocycles (pyridines or pyrazine) bearing
an ortho-substituted nitrile group 5. These can be trans-
formed into the bicyclic ring makeup of the naphthyri-
dines in a few iterative steps. Pirnat et al. have previously
reported a similar approach, although their method was
only demonstrated to work for 2,7-naphthyridin-1-ones.7
Figure 1 Examples of naphthyridine-containing compounds
In one example, SNAr reaction of 3-cyano-4-fluoropyri-
dine (5a) with the sodium salt of diethyl malonate was
used to generate 7a (Scheme 1). Krapcho decarboxylation
of 7a provided the pyridinyl acetate 8a. Condensation
with DMF-DMA then generates the cyclization precursor
10a. With 10a in hand, three screening conditions were at-
tempted to effect the transformation to the naphthyridine
ester 4a (Table 1). We observed that subjecting the sub-
strate 10a to an ammonia solution in water–ethanol (10:1)
resulted only in a minimal amount of the naphthyridine
product 4a being generated (Table 1, entry 1). Next, we
found that using ammonium chloride and hydrochloric ac-
id, a strong acid, resulted predominantly in undesired ni-
trile-group hydrolysis (Table 1, entry 2). Finally,
employing ammonium acetate and a milder acid (acetic
acid) at slightly elevated temperatures yielded 60–70% of
the desired product 4a (Table 1, entry 3).
Encouraged by the latter result, the substrate scope was
then examined (Table 2). A variety of commercially avail-
able regioisomeric halogenated pyridines were employed
in the two-step conversion into the precursor pyridinyl ac-
etates 8b–e. As exemplified by 8f, this methodology was
also applicable to the synthesis of pyrazine-derived ana-
SYNLETT 2014, 25, 0089–0092
Advanced online publication: 02.12.2013
DOI: 10.1055/s-0033-1340111; Art ID: ST-2013-R0792-L
© Georg Thieme Verlag Stuttgart · New York
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6

90
J. Chen et al.
LETTER
O
O
EtO
OEt
CN
CN
CN
X
6
LiCl
R
N
R
R
N
N
CO2Et
CO2Et
NaH, THF
DMSO–THF
5
CO2Et
7
8
MeO
H
OMe
NMe2
NH2
CN
9
NH4OAc
AcOH
N
R
N
R
N
DMF
NMe2
CO2Et
CO2Et
10
4
Scheme 1 General synthetic route for the preparation of naphthyridine isomers
Table 1 Reaction Screening for Effective Cyclization Conditions
NH2
CN
conditions
N
N
N
NMe2
CO2Et
CO2Et
10a
4a
Entry
Conditions
Results
1
2
3
NH3, H2O–EtOH (10:1), reflux
NH4Cl, HCl, EtOH, reflux
<5% desired product + complex mixture of undesired products
0% product; extensive nitrile hydrolysis to amide
60–70% yield of 4a
NH4OAc, AcOH (1:5), 80–100 °C
logues. As with the screening substrate 10a, the condi- 5). Unfortunately, an electron-rich methoxy-substituted
tions for the annulation step using ammonium acetate in precursor could not be prepared as the SNAr reaction
hot acetic acid were applied to each of the vinylogous car- proved unsuccessful.
bamate substrates in the final step of the transformation.
Two plausible reaction mechanisms for the annulation
All substrates were converted in reasonable isolated
step are shown in Scheme 2. Under the acidic reaction
yields to the respective naphthyridines (or 7-azaquinoxa-
conditions employed, ammonium acetate can add to the
line, Table 2, entry 6) from the corresponding acetate in-
nitrile to form an incipient amidine 11. This compound
can then undergo facile conjugate cyclization to generate
the corresponding naphthyridine heterocycle 12. Finally,
termediate. Even the electron-poor substrate bearing a
trifluoromethyl group was successful in generating the
naphthyridine in 16% yield over two steps (Table 2, entry
extrusion of dimethylamine proceeds to furnish the de-
NH2
N
NH
pathway A
R
N
NH2
NMe2
R
– NHMe2
N
NMe2
OEt
HO
CO2Et
NH2
11
12
N
NH4OAc
AcOH
CN
R
N
R
N
NMe2
NH
CO2Et
CO2Et
4
CN
NH2
10
NH
– NHMe2
R
N
R
N
CO2Et
CO2Et
14
pathway B
13
Scheme 2 Proposed reaction mechanisms for cyclization leading to naphthyridine ester 4
Synlett 2014, 25, 89–92
© Georg Thieme Verlag Stuttgart · New York

LETTER
Annulation Route to Primary-Amino-Substituted Naphthyridine Esters
91
7-azaquinoxaline was described. By making use of easily
accessible 2-halocyanopyridines, these various naphthyri-
dines were derived in a four-step sequence that provides
the desired products in synthetically useful yields. As a
demonstration of the broader utility of this method, we
were able to prepare an entire set of regioisomeric primary
amino naphthyridine esters. Further application of this
method in a more complex setting such as the synthesis of
active pharmaceuticals is currently under way.
Table 2 Isolated Yields for Two-Step Annulation from Pyridinyl
Acetate to Naphthyridines
Entry
Substrate
Product
Yield (%)a
NH2
CN
N
N
N
1
43
CO2Et
CO2Et
8a
4a
Diethyl 2-(3-Cyanopyridin-4-yl)malonate (7a)
NH2
N
N
CN
To a stirred solution of NaH (289 mg, 7.22 mmol, 60%) in THF (5
mL) was added diethyl malonate (1.16 g, 7.22 mmol) in THF (5
mL) dropwise at 0 °C under N2 atmosphere. After the reaction mix-
ture was stirred at 0 °C for 10 min, compound 5a (500 mg, 3.61
mmol) in THF (5 mL) was added. The reaction mixture was heated
at reflux for 4 h under N2 and was quenched with aq NH4Cl (20 mL)
and extracted with EtOAc (3 × 20 mL). The organic layer was
washed with brine (2 × 10 mL), dried over Na2SO4, and concentrat-
ed to give 7a as a crude product, which was used for the next step
without further purification.
N
2
3
4
5
6
41
23
48
16
33
CO2Et
CO2Et
8b
4b
NH2
N
CN
N
N
Ethyl 2-(3-Cyanopyridin-4-yl)acetate (8a)
CO2Et
CO2Et
To a solution of crude compound 7a (1.0 g, 3.61 mmol) in DMSO
(30 mL) were added H2O (1 mL) and LiCl (459 mg, 10.82 mmol),
and the resulting mixture was stirred at 100 °C overnight. After the
reaction mixture was cooled to r.t., it was extracted with EtOAc (3
× 20 mL), washed with brine (10 × 2 mL), dried over Na2SO4, and
concentrated. The residue was purified by column chromatography
(PE–EtOAc = 8:1) to give 8a as white solid (300 mg, 43% over two
steps). 1H NMR (400 MHz, DMSO-d6):  = 8.82 (s, 1 H), 8.70 (d,
J = 6.4 Hz, 1 H), 7.37 (d, J = 6.4 Hz, 1 H), 4.19 (q, 2 H), 1.24 (t, 3 H).
8c
4c
NH2
N
CN
N
N
CO2Et
CO2Et
8d
4d
Ethyl 2-(3-Cyanopyridin-4-yl)-3-(dimethylamino)acrylate
(10a)
A solution of compound 8a (100 mg, 0.526 mmol) and DMF–DMA
(157 mg, 1.31 mol) in DMF (5 mL) was heated at 80 °C overnight.
The mixture was evaporated to dryness and carried on to the next
step without further purification.
CF3
CF3 NH2
CN
N
N
N
CO2Et
CN
CO2Et
Ethyl 1-Amino-2,7-naphthyridine-4-carboxylate (4a)
8e
8f
4e
N
A mixture of crude compound 10a from the previous step (150 mg)
and NH4OAc (1.0 g, 13.15 mmol) in AcOH (5 mL) was heated at
80–100 °C overnight. The mixture was cooled to ambient tempera-
ture and poured into ice water. The mixture was extracted with
EtOAc (3 × 20 mL). The combined organic phase was concentrated
to give the crude product, which was purified by preparative TLC
(PE–EtOAc = 1:1) to give the desired product 4a (50 mg, 43% over
two steps). 1H NMR (400 MHz, DMSO-d6):  = 9.19 (s, 1 H), 8.87
(s, 1 H), 8.75 (d, J = 6.0 Hz, 1 H), 8.68 (d, J = 6.0 Hz, 1 H), 5.78 (br,
2 H), 4.35 (q, 2 H), 1.37 (m, J = 6.8 Hz, 1 H), 1.20 (t, 3 H).
NH2
N
N
N
N
CO2Et
CO2Et
4f
a Final two steps.
sired product 4 (pathway A). Alternatively, early expul- Acknowledgment
sion of dimethylamine can lead to 13, which upon rapid
The authors thank Drs. Charles Ding and Kevin Chen (Wuxi) as
well as Dr. Bing-Yan Zhu (Genentech) for helpful discussions du-
ring the course of this work.
cyclization onto the pendant nitrile provides 14. This in-
termediate can then tautomerize to generate the desired
product 4 (pathway B). We speculate that pathway B is
more feasible because formation of the amidine 11 in
pathway A is an energetically disfavored process. More-
over, in the work reported by Pirnat et al.,7 they failed to
observe any amidines among the various intermediates
that were isolated.
References
(1) The Naphthyridines, In The Chemistry of Heterocyclic
Compounds; Vol. 63; Brown, D. J.; Ellman, J. A.; Taylor, E.
C., Eds.; J. Wiley and Sons: Hoboken, 2007.
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P.; Egbertson, M. S.; Vacca, J. P.; Huff, J. R.; Felock, P. J.;
In summary, a unified approach to the preparation of
primary-amino-substituted naphthyridines as well as a
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 89–92

92
J. Chen et al.
LETTER
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Synlett 2014, 25, 89–92
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