Synthesis of 7-aryl-1,8-naphthyridines via addition of aryl boronic acids to 1,8-naphthyridine N-oxides

Article abstract of DOI:10.1016/j.tetlet.2011.07.040

Simply combining aryl boronic acids with 1,8-naphthyridine N-oxides and heating at 110 °C in toluene or dimethylformamide affords the corresponding 7-aryl-1,8-naphthyridines. The reaction is not sensitive to air or moisture and the process can be extended

Full text of DOI:10.1016/j.tetlet.2011.07.040

Tetrahedron Letters 52 (2011) 4799–4802
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of 7-aryl-1,8-naphthyridines via addition of aryl boronic acids
to 1,8-naphthyridine N-oxides
⇑
Linsey S. Bennie, Paul M. Burton, James A. Morris
Syngenta Ltd, Jealott’s Hill International Research Centre, Bracknell, Berkshire RG42 6EY, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Simply combining aryl boronic acids with 1,8-naphthyridine N-oxides and heating at 110 °C in toluene or
dimethylformamide affords the corresponding 7-aryl-1,8-naphthyridines. The reaction is not sensitive to
air or moisture and the process can be extended to other electron-deficient heteroaromatic N-oxides.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 19 April 2011
Revised 16 June 2011
Accepted 11 July 2011
Available online 30 July 2011
Keywords:
1,8-Naphthyridines
Boronic acids
N-Oxides
Arylation
1,8-Naphthyridine derivatives show an exceptionally broad
range of biological activities.1 Consequently, new methods that
allow the rapid and late-stage derivatisation of this class of mole-
cule are highly attractive in research and optimisation of new
pharmaceuticals and agrochemicals. Due to our own interest in
1,8-naphthyridines as novel herbicides,2 we sought to prepare a
range of 7-aryl substituted analogues (Fig. 1).
5
4
CO2Et
CF3
X
R
N
8
N
1
Figure 1.
Whilst classic cross-coupling chemistry can be envisaged to
instal the 7-aryl substituents, synthesis of the desired 7-
chloronaphthyridine coupling partners suffered from a tedious
chlorination step affording undesirable mixtures of the 5- and
7-chloronaphthyridines which were difficult to separate by chro-
matography (Scheme 1).3 However, the preceding oxidation to
the naphthyridine N-oxide occurs in good yield for a range of
6-halo-substituents as well as the 6-H parent compound (Scheme
1).4,5 Consequently, our efforts turned toward introducing the aryl
substituents directly from N-oxide.
Recently, Fagnou and co-workers reported the direct arylation
of a range of heteroaromatic N-oxides.6 However, the requirement
for an excess of the N-oxide (1.5–4 equiv) coupling partner in this
methodology was undesirable to us as the naphthyridine N-oxides
were advanced intermediates. The arylation of pyridine N-oxides
via the two-step Grignard addition, dehydration sequence reported
by Almqvist and Olsson offers an alternative approach.7 Inspired by
this methodology and the Petasis reaction,8 we reasoned that addi-
tion of aryl boronic acids to the naphthyridine N-oxides, followed
by dehydration could also offer a plausible route towards the 7-
arylated naphthyridines. As many aryl boronic acids are air and
moisture stable, in addition to being commercially available with
a vast range of aromatic substituents, this approach seemed attrac-
tive.9 We report herein this novel chemistry towards 7-aryl-1,8-
naphthyridines.
Simply combining the naphthyridine N-oxide with the appro-
priate aryl boronic acid in toluene or DMF and heating the mixture
to 110 °C for 16 h afforded the desired 7-aryl-1,8-naphthyridines
(Table 1). In all cases, the aryl addition was completely selective
for the 7-position of the 1,8-naphthyridines. The reactions were
performed open to the air, with solvents used as purchased, mak-
ing this process convenient for the synthesis of chemical libraries.
In general, electron-rich aryl boronic acids afforded the desired
products in good yields (Table 1, entries 1–7). Aryl boronic acids
which contained weak inductively withdrawing groups afforded
the products in low to moderate yields (entries 8–11). Interest-
ingly, the presence of a phenolic OH group caused no detrimental
effect to the reaction (entry 3). Sterically hindered boronic acids
could also be successfully employed in the reaction (entries 2
and 5), although a longer reaction time was needed for the mesityl
analogue (entry 5). Whilst 3-furyl and 3-thienyl boronic acids gave
⇑
Corresponding author.
E-mail address: james.morris@syngenta.com (J.A. Morris).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.07.040

4800
L. S. Bennie et al. / Tetrahedron Letters 52 (2011) 4799–4802
5
POCl3 (1.2 eq.)
urea hydrogen
peroxide
CO2Et
CF3
X
CO2Et
CF3
X
CO2Et
CF3
X
Et3N (1.2 eq.)
Cl
N+
O
N
7
N
N
DCE, reflux
N
N
CH2Cl2, TFAA
RT to 40 oC
60-70%
X = H 75% (9:1 mixture of 7 and 5 isomers)
X = F 50% (3:2 mixture of 7 and 5 isomers)
X= H, F, Cl, Br
Scheme 1.
Table 1
Aryl boronic acid additions to naphthyridine N-oxides
CO2Et
CF3
X
PhMe or DMF,
110 oC, 16 h
CO2Et
X
+
ArB(OH)2
(2 eq.)
N+
O
N
Ar
N
N
CF3
Entry
1
Product
Solvent
Yield (%)a
CO2Et
CF3
DMF
PhMe
DMF
1a:63 (X = H)
1b:60 (X = F)
1c:55 (X = Br)
X
N
N
MeO
X
DMF
DMF
2a:63 (X = H)
2b:60 (X = Cl)
CO2Et
CF3
OMe
2
3
N
N
OMe
CO2Et
CF3
DMF
3:72
N
N
HO
CO2Et
CF3
4
PhMe
PhMe
DMF
4:60
5:43
6:72
N
N
MeS
CO2Et
CF3
CO2Et
F
5b
N
N
Cl
O
O
6
N
N
CF3
CO2Et
CF3
O
O
7
8
9
PhMe
DMF
7:71
8:30
9:50
N
N
CO2Et
CF3
N
N
Cl
F
CO2Et
CF3
F
PhMe
N
N

L. S. Bennie et al. / Tetrahedron Letters 52 (2011) 4799–4802
4801
Table 1 (continued)
Entry
Product
Solvent
Yield (%)a
CO2Et
CF3
Cl
10
PhMe
PhMe
10:35
N
N
F3CO
CO2Et
CF3
Cl
11
12
11:26
N
N
F3C
X
PhMe
DMF
12a:57 (X = F)
12b:52 (X = Br)
CO2Et
CF3
N
N
N
N
S
F
CO2Et
CF3
13
14
PhMe
PhMe
13:34
14:55
O
CO2Et
CF3
F
Ph
N
N
a
Isolated yield.
Reaction time of 40 h.
b
the expected products (entries 13 and 12), 2-thienyl boronic acid
failed under the current reaction conditions. Styryl boronic acid
was also found to couple well (entry 14).
whilst these reactions tended to occur faster in dimethylformam-
ide than toluene, larger amounts of by-product 17 resulted in
dimethylformamide.12
A limited solvent screen showed that
The tolerance of chloro- and bromo-substituents under the
reaction conditions is attractive as further elaboration of the scaf-
fold can be carried out through cross-coupling chemistry. An
example of this is shown in Scheme 2. After isolating the
product from the boronic acid addition to the N-oxide, a Suzuki–
dimethylformamide, toluene and 1,4-dioxane afforded comparable
isolated yields. Performing the reaction in acetonitrile, at reflux, led
to good conversion into intermediate 15, however, dehydration to
the naphthyridine was much slower in this solvent. The reaction
failed completely when N-methyl-2-pyrrolidone or n-butanol
was employed as the solvent. Furthermore, for the sterically hin-
dered mesityl group, (Table 1, entry 5), formation of 15 seemed
to be complete after 16 h, however, the dehydration step was
found to be very slow for this analogue.
In an attempt to broaden the scope of this methodology, a small
screen of other heterocyclic N-oxides was undertaken. Whilst the
N-oxides of pyridine and quinoline resulted in no product or poor
yield (Table 2, entries 1 and 2), the more electron-deficient pyrido-
pyrazine and 1,7-naphthyridine N-oxides afforded the desired
products in moderate yields (Table 2, entries 3 and 4).
Miyaura coupling afforded
a
7,8-biaryl substituted 1,8-
naphthyridine.10
Analysis of these reactions by LC–MS suggests the formation of
the hydroxylamine intermediate 15 (Fig. 2) or its respective boric
acid ester. This presumably eliminates water to afford the desired
product.11 It is possible that boronic acid aids this dehydration,
forming boric acid in the process, although we have no evidence
of this. Furthermore, selective 7-arylation may be a result of intra-
molecular transfer of the aryl group from boronate 16. The only by-
product isolated was the corresponding naphthyridine 17. Notably,
Cl
B(OH)2
Pd(OAc)2 (5 mol%)
S-Phos (10 mol%)
CO2Et
CF3
Br
CO2Et
+
N
N
K3PO4 (1.5 eq.)
CF3
N
N
toluene, 110 o C
Cl
MeO
MeO
98%
Scheme 2.
CO2Et
CF3
X
CO2Et
CF3
X
CO2Et
CF3
X
Ar
N+
O
N
N
N
OH
N
N
H
Ar
B-
16
15
17
HO OH
Figure 2.

4802
L. S. Bennie et al. / Tetrahedron Letters 52 (2011) 4799–4802
Table 2
4-Methoxyphenyl boronic acid additions to heteroaryl N-oxides
B(OH)2
DMF,110 oC,
20 h
+
N
N+
O
MeO
OMe
(2 eq.)
Entry
1
N-oxide
Product
Yield (%)a
0
N+
O
N
N
MeO
MeO
2
3
10
51
N+
O
Ph
Ph
Ph
Ph
N
N
N
N
N
N+
O
MeO
N
CO2Et
CF3
CO2Et
CF3
N+
O-
N
N
4b
32
OMe
a
Isolated yield.
Reaction time of 60 h.
b
7. (a) Andersson, H.; Almqvist, F.; Olsson, R. Org. Lett. 2007, 9, 1335–1337; (b)
Andersson, H.; Banchelin, T. S.-L.; Das, S.; Olsson, R.; Almqvist, F. Chem.
Commun. 2010, 3384–3386.
8. Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc. 1997, 119, 445–446.
9. For a silver-catalysed direct arylation of electron-deficient heterocycles with
boronic acids, see: Seiple, I. B.; Su, S.; Rodriguez, R. A.; Giantassio, R.; Fujiwara,
Y.; Sobel, A. L.; Baran J. Am. Chem. Soc. 2010, 132, 13194–13196.
10. Walker, S. D.; Barder, T. E.; Martinelli, J. R.; Buchwald, S. L. Angew. Chem., Int. Ed.
2004, 43, 1871–1876.
11. Chung, J. Y. L.; Cvetovich, R. J.; McLaughlin, M.; Amato, J.; Tsay, F.-R.; Jensen, M.;
Weissman, S.; Zewge, D. J. Org. Chem. 2006, 71, 8602–8609.
12. A control experiment showed that heating the naphthyridine N-oxide from
Scheme 1 (X = H) in DMF for 16 h led to complete deoxygenation to the
respective naphthyridine.
In summary, a novel and user-friendly process for the arylation
of 1,8-naphthyridine N-oxides is reported that can be extended to
other electron-deficient heterocycles.13 The application of this
methodology to the discovery of novel agrochemicals is ongoing
within our laboratories.
Acknowledgement
We thank Andrew Blackaby (Syngenta) for mass spectrometry
assistance.
13. Typical experimental procedure (Table 1, entry 2): A round bottom flask was
charged with the naphthyridine N-oxide (286 mg, 1 mmol), 2,6-
dimethoxyphenyl boronic acid (364 mg, 2 mmol), DMF (6 mL) and a stir bar.
A reflux condenser was fitted and the reaction heated to 110 °C for 16 h. After
cooling, the solvent was removed under high vacuum and the residue was
purified by flash chromatography (hexane/EtOAc, 8:2) to afford the desired
References and notes
1. Litvinov, V. P. Adv. Heterocycl. Chem. 2006, 91, 189–300.
2. (a) Mitchell, G.; Salmon, R; Bacon, D. P.; Aspinall, I. H.; Briggs, E.; Avery, A. J.;
Morris, J. A.; Russell, C. J. W.O. Patent 2009115788; Chem. Abstr. 2009, 151,
403283; (b) Burton, P. M.; Morris, J. A. Org. Lett. 2010, 9, 2373–2375.
3. For the effect of base on the regioselectivity of pyridine N-oxide chlorination,
see: Jung, J.-C.; Jung, Y.-J.; Park, O.-S. Synth. Commun. 2001, 31,
2507–2511.
4. For the synthesis of the 6-halo-substituted naphthyridines, see: Ref. 2a.
5. Caron, S.; Do, N. M.; Sieser, J. E. Tetrahedron Lett. 2000, 41, 2299–2302.
6. (a) Campeau, L. C.; Rousseaux, S.; Fagnou, K. J. Am. Chem. Soc. 2005, 127, 18020–
18021; (b) Leclerc, J.-P.; Fagnou, K. Angew. Chem., Int. Ed. 2006, 45,
7781–7786.
product,
7-(2,6-dimethoxyphenyl)-2-trifluoromethyl-[1,8]naphthyridine-3-
carboxylic acid ethyl ester (2a), as a pale yellow solid (252 mg, 63%), mp:
145-147 °C. 1H NMR (400 MHz, CDCl3) dH 8.75 (1H, s), 8.31 (1H, d, J = 8.4 Hz),
7.71 (1H, d, J = 8.4 Hz), 7.38 (1H, t, J = 8.4 Hz) 6.67 (2H, d, J = 8.4 Hz), 4.49 (2H,
q, J = 7.2 Hz), 3.72 (6H, s), 1.45 (3H, t, J = 7.2 Hz). 13C NMR (100 MHz, CDCl3) dC
165.2, 162.8, 160.0, 154.6, 147.3 (q, J = 35.7 Hz), 141.0, 136.0, 130.7, 128.5,
124.8, 121.3, 120.8 (q, J = 270 Hz), 117.9, 115.0, 62.6, 55.8, 13.9. MS (ES) m/z
407 [M+H]+. HRMS (ES+) calcd For C20H18N2O4F3 [M+H]+ 406.1140, found
406.1120.