Convenient preparation of naphthyridines from halopyridines: Sequential Heck coupling and cyclization

Article abstract of DOI:10.1016/S0040-4039(01)00632-3

A simple method for the preparation of 1,7-naphthyridine and 1,6-naphthyridine from the corresponding aminopyridine starting materials is presented.

Full text of DOI:10.1016/S0040-4039(01)00632-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 3963–3965
Convenient preparation of naphthyridines from halopyridines:
sequential Heck coupling and cyclization
Puay-Wah Phuan and Marisa C. Kozlowski*
Department of Chemistry, Roy and Diana Vagelos Laboratories, University of Pennsylvania, Philadelphia, PA 19104, USA
Received 1 April 2001; accepted 9 April 2001
Abstract—A simple method for the preparation of 1,7-naphthyridine and 1,6-naphthyridine from the corresponding aminopy-
ridine starting materials is presented. © 2001 Elsevier Science Ltd. All rights reserved.
The cis-decalin scaffold had been identified as a flexible
framework for the construction of a wide variety of
from 1 (Fig. 1). As such, efficient syntheses of 3 and 5
were sought.
interesting chiral ligands including diamines, diols,
1
5
amino alcohols, phosphites and phosphines. C -Sym-
Although 3 has been prepared by various methods,
2
metric 1,5-diaza-cis-decalin 2 and derivatives have been
most procedures were lengthy and low yielding. The
synthesis by Giam is short and high yielding, but
produces a mixture of 3 and 5. Furthermore, the start-
ing material 2,3-cyclopentenopyridine is no longer com-
6
prepared, resolved, and employed in asymmetric lithia-
2
tion/substitution reactions and asymmetric oxidative
3
biaryl coupling reactions. As a continuation of our
efforts in this area, we would like to investigate the
7
mercially available. Colandrea recently reported a
conformational and ligand properties of non-C -sym-
2
selective seven-step synthesis of 3; however, stoichio-
metric amounts of organotin materials are required.
Herein, a new facile preparation of this seemingly
uncomplicated heterocycle is reported.
4
metric diaza-cis-decalins such as 1,7-diaza-cis-decalin 4
and 1,6-diaza-cis-decalin 6. The most straightforward
preparation of 4 and 6 would be by hydrogenation of
the corresponding aromatic naphthyridines 3 and 5,
respectively following the procedure used to prepare 2
We envisioned that 3 could arise from a 3-amino-4-
iodo-pyridine 7 and an acrolein equivalent via a Heck
8
Figure 1.
Keywords: 1,7-naphthyridine; 1,6-naphthyridine; Heck reaction.
*
Corresponding author.
Scheme 1.
0
040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00632-3

3
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P.-W. Phuan, M. C. Kozlowski / Tetrahedron Letters 42 (2001) 3963–3965
9
coupling followed by an intramolecular condensation
Scheme 1). However, treatment of 7 with acrolein
dimethylacetal in the presence of (o-Tol) P, Pd(OAc) ,
conditions occurred via a multistep sequence involving
Heck coupling, palladium-mediated oxidation of the
allylic alcohol to the aldehyde, double bond isomeriza-
tion, cyclization, and dehydration. With an overall yield
of 38% from commercial 4-aminopyridine, this process
provides 5 in a yield comparable to the reported Skraup
(
3
2
and Et N in MeCN in a sealed tube at 110°C for 16 h
provided none of the expected Heck product 9. Instead,
5% of 3, 9% of 11, and 10% of starting material 7 were
3
2
16
procedure.
isolated. Hydroiodic acid, a byproduct of the reaction,
was postulated to be responsible for the conversion of
the initial Heck adduct 9 into 3 by causing hydrolysis of
the acetal, isomerization of the trans alkene, and con-
densation. Competing b-hydride elimination of the ace-
tal hydrogen in organopalladium 8 explains the
formation of 11 via intermediate 10. Encouraged by
these results, a method was sought to suppress the
formation of 11 and improve the yield of 3.
To examine the general applicability of this approach, a
synthesis of 1,5-naphthyridine was briefly investigated.
However, various Heck reaction conditions with 2-
halo-3-aminopyridines 15 did not yield 1 (Eq. (2)).
After exploring a number of Heck reaction conditions,
1
0
(2)
the Jeffery protocol with heating was found to yield
1
1
9
cleanly (Eq. (1)). After a quick aqueous workup,
crude 9 was treated with DMF and a catalytic amount
of triethylammonium iodide in ethyl ether (generated
In short, a facile synthesis of 1,7-naphthyridine 3 has
been achieved in five steps and 44% overall yield. The
syntheses described for 1,7-naphthyridine 3 and 1,6-
naphthyridine 5 may also be useful for the synthesis of
substituted versions of these interesting heterocycles.
by mixing Et N and HI) and heated to 70°C for 16 h to
3
1
2
cleanly provide 3 in 76% yield over the two steps.
Thus, 3 could be prepared in five steps starting from
commercial 3-aminopyridine in 44% overall yield.
Acknowledgements
Financial support was provided by Merck Research
Laboratories, Pharmacia-Upjohn, and DuPont.
Acknowledgment is made to the donors of the
Petroleum Research Fund, administered by the ACS,
for partial support of this research.
(
1)
We sought to apply this reaction to prepare other
naphthyridines, such as 1,6-naphthyridine. Surprisingly,
1
3
treatment of 4-amino-3-iodopyridine 12 with the con-
ditions developed for 3 did not provide any products
arising from Heck coupling (Scheme 2). The main
complication appeared to arise from the 4-aminopy-
ridine functionality in 12 competing as a ligand for
palladium. A similar problem was observed even with
the less basic N-pivaloyl derivative of 12. However,
when the protocol of Larock using allyl alcohol was
employed, 1,6-naphthyridine 5 could be obtained
directly in 51% yield. Formation of 5 under these
References
1. Kozlowski, M. C.; Evans, C. A., submitted
2. Li, X.; Schenkel, L. B.; Kozlowski, M. C. Org. Lett.
2000, 2, 875–878.
3. Li, X.; Yang, J.; Kozlowski, M. C. Org. Lett. 2001, 3,
1137–1140.
14
1
5
4. Hanus, V.; Turecek, F.; Farag, A. M.; Tichy, M. Org.
Mass. Spectrom. 1984, 19, 450–451.
5. For reviews see: (a) Litvinov, V. P.; Roman, S. V.;
Dyachenko, V. D. Russ. Chem. Rev. 2000, 69, 201–220;
(
1
b) Wozniak, M.; van der Plas, H. C. Heterocycles 1982,
9, 363–405.
6
7
8
. Giam, C. S.; Ambrozich, D. J. Chem. Soc., Chem Com-
mun. 1984, 5, 265–266.
. Colandrea, V. J.; Naylor, E. M. Tetrahedron Lett. 2000,
4
, 8053–8057.
. Compound 7 can be prepared in 59% yield over three
steps: (a) Malm, J.; Rehn, B.; Hornfeldt, A.; Gronowitz,
S. J. Heterocyclic Chem. 1994, 31, 11–15; (b) Estel, L.;
Marsais, F.; Queguiner, G. J. Org. Chem. 1988, 53,
2
740–2744.
. (a) Heck, R. F.; Nolley, Jr, J. P. J. Org. Chem. 1972, 37,
320; (b) Heck, R. F. Palladium Reagents in Organic
Synthesis; Academic Press: London, 1985.
9
2
Scheme 2.

P.-W. Phuan, M. C. Kozlowski / Tetrahedron Letters 42 (2001) 3963–3965
3965
1
0. Jeffery, T. J. Chem. Soc., Chem. Commun. 1984, 5, 1287–
289.
1. A mixture of 7 (1.10 g, 5 mmol), dimethyl acetal acrolein
0.92 mL, 15 mmol), Pd(OAc)2 (50 mg, 0.25 mmol),
NaHCO (1.05 g, 12.5 mmol), nBu NCl (1.39 g, 5 mmol)
8.13 (d, J=8.2 Hz, 1H), 8.60 (d, J=5.6 Hz, 1H), 9.00
(dd, J=1.3, 4.0 Hz, 1H), 9.5 (s, 1H); C NMR (125
13
1
1
MHz, CDCl ): l 120.2, 125.4, 131.5, 135.0, 143.7, 144.1,
3
+
(
152.3, 154.7; MS (ES) m/z 153.1 (MNa )
3
4
13. Produced in 76% yield from 4-aminopyridine, see Ref. 8.
were heated to 70°C in DMF (25 mL) for 8 h. TLC
indicated the disappearance of 7 and clean formation of
1
4. Larock, R. C.; Kuo, M. Y. Tetrahedron Lett. 1991, 32,
69–572.
5. A mixture of 12 (110 mg, 0.5 mmol), allyl alcohol (68 mL,
5
9
. The reaction mixture was cooled to rt, poured into ice
1
water and extracted with EtOAc (3×50 mL). The com-
1
mmol), PdCl (5 mg, 0.025 mmol), NaHCO (126 mg,
2
3
bined extracts were dried over Na SO , and concentrated
2
4
1
.5 mmol), (o-Tol) P (7.6 mg, 0.025 mmol) were heated
1
3
to yield crude 9: H NMR (500 MHz, CDCl ): l 3.37 (s,
3
to 140°C in HMPA (5 mL) for 4 h. The reaction mixture
was cooled to rt, poured into ice water, and extracted
with EtOAc (3 x 50 mL). The combined extracts were
6
6
7
1
1
H), 3.81 (bs, 2 H, NH), 4.97 (dd, J=1.1, 4.3 Hz, 1 H),
.20 (dd, J=4.4, 16.0 Hz, 1H), 6.72 (dd, J=15.9 Hz, 1H),
.11 (d, J=5.0 Hz, 1H), 7.97 (d, J=4.9 Hz, 1H), 8.08 (s,
13
dried over Na
SO and concentrated. The residue was
2 4
H); C NMR (125 MHz, CDCl ): l 52.7, 102.0, 120.7,
3
chromatographed (9:1 CH Cl :MeOH) to afford 5 (33
2
2
26.8, 128.5, 130.8, 138.7, 139.7, 140.1
1
mg) in 51% yield: H NMR (360 MHz, CDCl ): l 7.54
3
1
2. To crude 9 in DMF (25 mL) was added ca. 5 drops of a
(
(
4
2
dd, J=4.2, 8.3 Hz, 1 H), 7.91 (d, J=5.8 Hz, 1H), 8.29
d, J=8.2, 1H), 8.75 (d, J=6.0 Hz, 1H), 9.08 (dd, J=1.6,
preformed 1:1 complex of HI and Et N in Et O. After
3
2
heating at 70°C for 16 h, the reaction mixture was cooled
to rt, poured into ice water and extracted with EtOAc
13
.2 Hz, 1H), 9.27 (s, 1H); C NMR (90 MHz, CDCl ): l
3
2.5, 122.1, 135.7, 146.8, 150.3, 152.8, 154.8; MS (ES)
(3×50 mL). The combined extracts were dried over
+
Na SO4 and concentrated. The residue was chro-
m/z 153.1 (MNa )
2
matographed (9:1 CH Cl :MeOH) to afford 3 (0.50 g) in
16. 1,6-Naphthyridine has been synthesized by a Skraup
reaction from 4-aminopyridine in 40% yield: Kress, T.;
Pavoller, W. J. Chem. Soc., Chem. Commun. 1967, 3.
2
2
1
7
6% overall yield from 7: H NMR (500 MHz, CDCl ): l
3
7
.56 (dd, J=4.10, 8.3 Hz, 1 H), 7.62 (d, J=5.6 Hz, 1H),
.