Synthesis and regioselective alkylation of 1,6- and 1,7-naphthyridines

Article abstract of DOI:10.1016/S0040-4039(00)01400-3

A regioselective alkylation of naphthyridines 4a-d, through the action of ethylchloroformate and benzylstannane 5, afforded the benzyl substituted dihydronaphthyridines 3a-d. These key intermediates 3a-d were transformed into the desired targets 2a-d in seven steps. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01400-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 8053–8057
Synthesis and regioselective alkylation of 1,6- and
1,7-naphthyridines
Vincent J. Colandrea* and Elizabeth M. Naylor
Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA
Received 4 April 2000; revised 1 August 2000; accepted 9 August 2000
Abstract
A regioselective alkylation of naphthyridines 4a–d, through the action of ethylchloroformate and
benzylstannane 5, afforded the benzyl substituted dihydronaphthyridines 3a–d. These key intermediates
3a–d were transformed into the desired targets 2a–d in seven steps. © 2000 Elsevier Science Ltd. All rights
reserved.
It has been established by these laboratories that 1,2,3,4-tetrahydroisoquinoline 1 acts as a
novel b3 adrenergic receptor (AR) agonist, which may be useful in the treatment of obesity.1 As
a result of our work with 3-pyridylethanolamines as b3 AR agonists,2 we envisioned that
5,6,7,8-tetrahydro-(1,6)- or -(1,7)-naphthyridines 2a–d may serve as bioisosteric replacements for
1. Thus, we were interested in preparing compounds 2a–d for biological evaluation (Fig. 1).
Figure 1.
Alkylation of pyridines via pyridinium salts is well documented.3 Recently, this methodology
has been extended to the alkylation of isoquinoline, using methylchloroformate and substituted
benzylstannanes.4 Inspired by these results, we planned to prepare compounds 2a–d from
* Corresponding author.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01400-3

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dihydronaphthyridines 3a–d (Fig. 2). Intermediates 3a–d were proposed to arise from a
regioselective alkylation of naphthyridines 4a–d with benzylstannane 5.
Figure 2.
To test this synthetic approach, we prepared benzyltrimethylstannane 6 and 1,6-naphthyridine
4a by literature methods.4,5 Treatment of naphthyridine 4a and stannane 6 with ethylchloro-
formate gave one dihydronaphthyridine product (Scheme 1).6 This material was tentatively
1
assigned as 7, but due to carbamate rotamers in the H NMR spectrum, additional proof of
structure was needed. Reduction of the olefin, followed by hydrolysis of the ethyl carbamate and
1
HCl salt formation yielded a tetrahydronaphthyridine product in 83% overall yield. Through H
NMR coupling constants, we were able to unequivocally assign this product as 8, proving that
alkylation had occurred at the 5-position.7
Scheme 1.
We next prepared 4-benzyloxybenzyltrimethylstannane 5 from commercially available 4-ben-
zyloxybenzyl chloride 9. Reaction of chloride 9 under Barbier conditions provided stannane 5 in
92% yield (Scheme 2). To our satisfaction, reaction of stannane 5 with 1,6-naphthyridine 4a and
ethylchloroformate vide supra gave rise to dihydronaphthyridine 3a in 51% yield.
Scheme 2.
Having demonstrated that dihydronaphthyridine 3a can be prepared via the acyl iminium salt
of 4a, we turned our attention toward the preparation of naphthyridines 4b–d. A concise
synthesis of 1,7-naphthyridine 4c has been reported; however, we were unable to repeat this
procedure.8 Instead, an alternative route outlined in Scheme 3 was developed based upon an
earlier naphthyridine synthesis.9 The action of acetyl chloride on 2-bromo-3-hydroxypyridine 10
afforded acetate 11, which underwent smooth palladium-catalyzed vinylation (Scheme 3).10

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Deprotection of the crude reaction product with potassium carbonate afforded 3-hydroxy-2-
vinylpyridine 12 in 81% overall yield. Treatment of 12 with triflic anhydride and pyridine gave
triflate 13, in 65% yield. Allylation of 13 under Stille conditions gave 3-allyl-2-vinylpyridine 14.
Ozonolysis of 14 under reductive conditions, followed by treatment with aqueous ammonia
afforded 1,7-naphthyridine 4c in 44% overall yield from 13.
Scheme 3.
The synthesis of BOC-protected 2-aminonaphthyridines 4b (X%=NHBOC, Y%=H) and 4d
(X%=H, Y%=NHBOC) was accomplished by a Curtius rearrangement of the appropriate
naphthyridine carboxylic acids 16 and 19, respectively (Scheme 4).11 Following the work of
Chan, we prepared 2-carboxy-(1,6)-naphthyridine 16 from 4-aminopyridine 15.12 Rearrangement
of acid 16 using diphenylphosphoryl azide (DPPA) in t-butanol yielded naphthyridine 4b in 46%
yield. The synthesis of naphthyridine 4d started with the nicotinic acid 17. Using chemistry
described by Venuti, aldehyde 18 was prepared in two steps from acid 17.13 Removal of the
BOC moiety, followed by an aldol condensation with sodium pyruvate provided 2-carboxy-
(1,6)-naphthyridine 19 in 55% overall yield. Treatment of 19 with DPPA in t-butanol at reflux
afforded the naphthyridine 4d in 51% yield.
Scheme 4.
With substrates 4b–d in hand, conversion to dihydronaphthyridines 3b–d was accomplished
using the aforementioned alkylation conditions in moderate to good yields (Scheme 5 and Table
1). Phase transfer hydrogenolysis of dihydronaphthyridines 3a–d effected concomitant removal
of the benzyl group and hydrogenation of the olefin to give phenols 20a–d, respectively.
Treatment of phenols 20a–d with triflic anhydride and pyridine gave the corresponding triflates,
which were purified by chromatography. The triflates were then subjected to a palladium
catalyzed biaryl cross-coupling with boronic ester 21, as described by Miyaura.14 The resulting
biaryls 22a–d were isolated in good overall yields from phenols 20a–d.

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Scheme 5.
Table 1
Substrate
W
X%
Y%
Z
% Yield
3a–da
20a–da
22a–da
4a
4b
4c
4d
N
N
CH
CH
H
H
H
H
CH
H
N
51
50
43
61
90
99
90
95
82
50
42
62
NHBOC
H
H
NHBOC
N
a Isolated yields.
The syntheses of compounds 2a–d were realized in four steps from biaryls 22a–d (Scheme 6).
Reduction of 22a–d with hydrazine hydrate and potassium hydroxide in ethylene glycol at 150°C
with concomitant cleavage of protecting groups led to the amines 23a–d, respectively.15
A
selective protection of the secondary amine was accomplished with di-tert-butyldicarbonate at
low temperature to furnish anilines 24a–d. Sulfonamide formation with sulfonyl chloride 25,
followed by removal of the BOC group with trifluoroacetic acid in dichloromethane afforded the
desired targets 2a–d16 (Table 2).
Scheme 6.
Table 2
Substrate
W
X
Y
Z
% Yield
23a–da
24a–da
2a–da
21a
21b
21c
21d
N
N
CH
CH
H
NH2
H
H
H
H
NH2
CH
H
N
38
51
86
76
91
98
97
90
74
39
79
39
H
N
a Isolated yields.

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In conclusion, we have established that the acyl iminium salts of naphthyridines 4a–d undergo
a regioselective alkylation with benzylstannanes 5 and 6 to give dihydronaphthyridines 3a–d and
8. These key intermediates 3a–d have been transformed into the desired targets 2a–d in seven
steps.
References
1. Brockunier, L.; Parmee, E.; Weber, A. PCT Application, WO9944609-A.
2. Naylor, E. M.; Colandrea, V. J.; Candelore, M. R.; Cascieri, M. A.; Colwell, L. F.; Deng, L.; Feeney, W. P.;
Forrest, M. J.; Hom, G. J.; MacIntyre, D. E.; Strader, C. D.; Tota, L.; Wang, P.-R.; Wyvratt, M. J.; Fisher, M.
H.; Weber, A. E. Bioorg. Med. Chem. Lett. 1998, 8, 3087–3092.
3. Comins, D. L.; O’Connor, S. Adv. Heterocycl. Chem. 1988, 44, 199–267.
4. Deline, J. E.; Miller, R. B. Tetrahedron Lett. 1998, 39, 1721–1724.
5. Kress, T. J.; Paudler, W. W. J. Chem. Soc., Chem. Commun. 1967, 3–4.
6. General procedure for alkylation of naphthyridines 4a–d: to a solution of naphthyridines 4a–d (1.0 mmol) and
stannane 5 or 6 (1.1 mmol) in 2 mL of dry CH2Cl2 at 0°C, ethylchloroformate (1.1 mmol) was added dropwise.
The reaction mixture was allowed to warm to ambient temperature and stirred for three days. Concentration in
vacuo and purification by flash chromatography (eluent: 10–30% EtOAc/hexanes) on SiO2 gave products 3a–d
and 7.
1
7. Compound 8: H NMR (CD3OD, 400 MHz), l 3.31–3.36 (m, 1H), 3.47–3.66 (m, 4H), 3.79–3.83 (m, 1H), 5.13
(t, J=7.7 Hz, 1H), 7.37–7.42 (m, 5H), 7.84 (dd, J=5.8, 8.2 Hz, 1H), 8.08 (d, J=8.2 Hz, 1H), 8.81 (dd, J=1.3,
5.8 Hz, 1H).
8. Numata, A.; Kondo, Y.; Sakamoto, T. Synthesis 1999, 306–311. We were unable to prepare intermediate 12c in
the yield reported.
9. Giam, C. S.; Ambrozich, D. J. Chem. Soc., Chem. Commun. 1984, 5, 265–266.
10. Attempted vinylation of pyridinol 10 resulted in recovered starting material.
11. The conversion of benzyl substituted dihydronaphthyridines 3a and 3c to their amino derivatives 3b and 3d,
respectively, was unsuccessful.
12. Chan, L.; Jin, H.; Stefanac, T.; Lavallee, J.-F.; Falardeau, G.; Bedard, J.; May, S.; Yuen, L. J. Med. Chem. 1999,
42, 3023–3025.
13. Venuti, M. C.; Stephenson, R. A.; Alvarez, R.; Bruno, J. J.; Strosberg, A. M. J. Med. Chem. 1988, 31, 2136–2145.
14. Ishiyama, T.; Murata, M.; Miyaura, N. J. Org. Chem. 1995, 60, 7508–7510.
15. Shono, T.; Matsumura, Y.; Uchida, K.; Tsubata, K.; Makino, A. J. Org. Chem. 1984, 49, 300–304.
1
16. All compounds were characterized H NMR and HPLC/MS.
.