Tandem Claisen rearrangement and ruthenium catalyzed enyne bond reorganization as a route to the synthesis of tricyclic 1,8-naphthyridinones

Article abstract of DOI:10.1016/j.tetlet.2006.01.132

A novel procedure for the synthesis of substituted 1,8-naphthyridinones via tandem Claisen rearrangement and ring-closing enyne metathesis is reported.

Full text of DOI:10.1016/j.tetlet.2006.01.132

Tetrahedron Letters 47 (2006) 2111–2113
Tandem Claisen rearrangement and ruthenium catalyzed
enyne bond reorganization as a route to the synthesis
of tricyclic 1,8-naphthyridinones
K. C. Majumdar,* H. Rahaman, R. Islam and B. Roy
Department of Chemistry, University of Kalyani, Kalyani 741235, WB, India
Received 3 November 2005; revised 18 January 2006; accepted 26 January 2006
Available online 13 February 2006
Abstract—A novel procedure for the synthesis of substituted 1,8-naphthyridinones via tandem Claisen rearrangement and ring-clos-
ing enyne metathesis is reported.
Ó 2006 Elsevier Ltd. All rights reserved.
Naphthyridine derivatives are important due to the
O
OR
exceptionally broad spectrum of their biological activi-
ties. Substituted 1,8-naphthyridine derivatives are used
for diagnostic and therapy of human diseases including
AIDS and for combating exo- and endoparasites in agri-
culture.1 The attractive biological activities of these 1,8-
naphthyridines, for example, the anti-allergic agents2 1
and 2, and the cytoprotective, anti-inflammatory and
anti-allergic activity of some 2,3-fused and 3,4-fused
furo and pyrano tricyclic compounds,3 explains the
great interest in the naphthyridinone moiety as a target
in organic synthesis. However, there is no general syn-
thesis of medium-sized, oxacycle fused, naphthyridinone
derivatives. In recent years, ring-closing enyne metathe-
sis4 has become useful for the synthesis of small and
medium ring dienes5 using the first generation Grubbs
catalyst6 (A). In ring-closing enyne metathesis
(RCEYM), being an intramolecular reaction, catalyst
turnover is usually fast enough to compete with and
overcome coordination by functional groups at the
allylic and propargylic positions. Hence, it appeared to
us that a combination of a Claisen rearrangement and
ring-closing enyne metathesis could be useful to access
hitherto unknown medium-sized, oxacycle-annulated,
1,8-naphthyridinone derivatives.
Pcy3
Ru
Cl
Cl
Ph
Pcy3
(A)
O
O
N
N
N
N
Ph
Ph
1
2 R = -COCH3
3 R =H
Here we report a general methodology for the regiocon-
trolled synthesis of substituted 1,8-naphthyridinones.
4-Allyloxy-1-phenyl-1,8-naphthyridin-2(1H)-one
has
been reported2 earlier. 3-Allyl-4-hydroxy-1,8-naphthy-
ridinone 3 has been prepared2 by refluxing 4-allyloxy-
1,8-naphthyridinone in acetic anhydride followed by
hydrolysis of the resulting acetate 2. We observed that
this two-step protocol for the synthesis of 3 could be
avoided if the Claisen rearrangement of 4-allyloxy-1,8-
naphthyridinone was carried out in refluxing chloroben-
zene. Product 3 was obtained directly under these condi-
tions. The isolation of the product is easy and the yield
of the product is better. Alkylation of 3 with propargyl
bromide (2 equiv) and 1-aryloxy-4-chlorobut-2-yne
(1.5 equiv) in refluxing acetone in the presence of anhy-
drous potassium carbonate for 2–3 h afforded the corre-
sponding ene–yne derivatives 4a–d in good yields
(Scheme 1).
Keywords: 1,8-Naphthyridinones; Enyne metathesis; Oxepine; Claisen
rearrangement; Ring-closing metathesis.
*
When a dichloromethane solution of 4a and 10 mol %
of A was stirred at room temperature for 2 h under a
Corresponding author. Tel.: +91 33 2582 7521; fax: +91 33
25828282; e-mail: kcm_ku@yahoo.co.in
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.01.132

2112
K. C. Majumdar et al. / Tetrahedron Letters 47 (2006) 2111–2113
O
OH
R
(i)
O
O
N
N
N
N
Ph
Ph
3
4
Ar
yields (%)
4a R = H
55%
4b
4-Me-C6H4
52
4b-d R = CH2OAr
4c 2,4-Cl2-C6H3
4d 4-Cl-C6H4
53
50
Scheme 1. Reagents and conditions: (i) propargyl bromide/chloride, dry acetone, K2CO3, reflux, 2–3 h, yields; 50–55%.
nitrogen atmosphere, we found that ring-closing enyne
metathesis proceeded smoothly to afford the oxepine
derivative 5a in 92% yield. The tricyclic compound 5a
was identified from its elemental analysis and spectro-
scopic data. The enynes 4b, 4c and 4d were treated in
a similar manner and the desired RCEYM products
5b, 5c and 5d were obtained in 90%, 95% and 94%
yields, respectively (Scheme 2).
Another simple alkylation was performed on hydroxy-
naphthyridinone 3 with allyl bromide in place of
propargyl bromide and the corresponding diallyl ether
8 was obtained. In fact, during the course of alkylation
of naphthyridinone 6 with allyl bromide we found that a
small amount of the O,C-diallylated product 8 was
formed along with the O-allylated product 7. However,
formation of 8 from 6 in a single step was an advanta-
geous outcome since it could be utilized directly in the
subsequent step. The ring-closing metathesis7 (RCM)
of the O,C-diallylated product 8 using the commercially
available ruthenium carbene complex A under a nitro-
gen atmosphere in dichloromethane solution smoothly
provided the unsubstituted oxepine annulated 1,8-naph-
thyridin-2(1H)-one derivative 9 in an excellent yield
(Scheme 3).
The ring-closing enyne metathesis proceeds through the
formation of a new C–C bond between the triple bond
and the double bond to give the cyclized products 5a–d.
R
O
R
O
Several substituted and fused 1,8-naphthyridin-2(1H)-
ones derivatives have useful levels of biological activities.8
In conclusion, we have developed an efficient route to 1,8-
naphthyridinone-fused polyheterocycles 5 using a Claisen
rearrangement and ring-closing enyne metathesis.
Grubbs' catalyst, A
(10 mol%)
CH2Cl2, r. t.
2-2.5 h
N
N
O
N
N
O
Ph
Ph
4a-d
5a-d
Typical procedure for the ring-closing metathesis reac-
tions: To a solution of substrate 4a (50 mg, 0.158 mmol)
in dry degassed CH2Cl2 (8 ml) under N2 was added cat-
90-95%
Scheme 2.
OH
O
O
Br
+
acetone, K2CO3
O
reflux, 25 h
N
N
N
N
O
N
N
O
Ph
Ph
Ph
6
7
8
20%
46%
O
O
Grubbs' catalyst, A
CH2Cl2, r. t.
2 h
N
N
O
N
N
O
Ph
Ph
8
9
97%
Scheme 3.

K. C. Majumdar et al. / Tetrahedron Letters 47 (2006) 2111–2113
2113
alyst A (10 mol %, 13 mg) and the reaction was stirred at
Acknowledgements
room temperature for 2 h. After the removal of the sol-
vent, the residue was purified by flash column chroma-
tography on silica gel (pet ether/ethyl acetate, 4:1) to
give 5a in 92% yield. Diene 8 and dienynes 4b–d were
treated in a similar manner to give the corresponding
cyclized products in excellent yields.
This work was financially supported by CSIR (New
Delhi). H.R. is grateful to the University of Kalyani
for a fellowship and R.I. is grateful to CSIR for a Senior
Research Fellowship.
References and notes
Compound 5a—Yield 92%; solid; mp 184–186 °C; IR
(KBr) mmax: 2924, 1636, 1585 cmÀ1; UV (EtOH), kmax
:
1. Litvinov, V. P.; Roman, S. V.; Dyachenko, V. D. Russ.
Chem. Rev. 2000, 69, 201.
2. Sherlock, M. H.; Kaminsky, J. J.; Tom, W. C.; Lee, J. F.;
Wong, S. C.; Kreutner, W.; Bryant, R. W.; McPhail, A. T.
J. Med. Chem. 1988, 31, 2108.
1
362, 331, 321, 216 nm; H NMR (400 MHz, CDCl3):
dH 3.75–3.77 (d, J = 6.26 Hz, 2H), 5.11–5.14 (d, J =
10.9 Hz, 1H, exocyclic proton), 5.18 (s, 2H, –OCH2),
5.29–5.33 (d, J = 17.61 Hz, 1H, exocyclic proton),
6.24–6.27 (t, J = 6.26 Hz, 1H), 6.36–6.43 (dd, J =
10.9 Hz, 17.6 Hz, 1H), 7.10–7.13 (dd, J = 4.69 Hz,
7.84 Hz, 1H, ArH), 7.22–7.56 (m, 5H, ArH), 8.22–8.24
(dd, J = 1.36 Hz, 7.8 Hz, 1H, ArH), 8.38–8.39 (dd,
J = 1.32 Hz, 4.29 Hz, 1H, ArH); MS: m/z = 317
(M++1); Anal. Calcd for C20H16N2O2: C, 75.95; H,
5.06; N, 8.86. Found: C, 75.82; H, 5.15; N, 8.79.
3. Sherlock, M. H. U.S. Patent 4596809.
4. For a recent review on RCEYM see: (a) Diver, S. T.;
Giessert, R. T. Chem. Rev. 2004, 104, 1317; (b) Katz, T. J.;
Sivavec, T. M. J. Am. Chem. Soc. 1985, 109, 737; (c) Kim,
S.-H.; Bowden, N.; Grubbs, R. H. J. Am. Chem. Soc. 1994,
116, 10801; (d) Guo, H.; Madhushaw, R. J.; Shen, F.-M.;
Lie, R.-S. Tetrahedron 2002, 58, 5627; (e) Moreno-Manas,
M.; Pleixats, R.; Satamaria, A. Synlett 2001, 1784; (f)
Barrett, A. G. M.; Baugh, S. P. D.; Braddock, D. C.; Flack,
K.; Gibson, V. C.; Procopiou, P. A. Chem. Commun. 1997,
1375; (g) Smulik, J. A.; Diver, S. T. J. Org. Chem. 2000, 65,
1788; (h) Watanuki, S.; Ochifuji, N.; Mori, M. Organomet-
allics 1994, 13, 4129; (i) Trost, B. M.; Tanoury, G. J. J. Am.
Chem. Soc. 1988, 110, 1636.
5. Mori, M.; Kitamura, T.; Sato, Y. Synthesis 2001, 654.
6. Schwab, P.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc.
1996, 118, 100.
7. (a) Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34,
18; (b) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54,
4413; (c) Grubbs, R. H. Tetrahedron 2004, 60, 7117; (d)
Furstner, A. Angew. Chem., Int. Ed. 2000, 39, 3012.
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Med. Chem. 1987, 30, 2270; (b) Litvinov, V. P. Russ. Chem.
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Compound 9—Yield 97%; solid; mp 142–144 °C; IR
(KBr) mmax: 2921, 1646, 1582 cmÀ1; UV (EtOH), kmax
:
1
359, 330, 322, 219 nm; H NMR (400 MHz, CDCl3):
dH 3.70 (d, J = 5.45 Hz, 2H), 4.91–4.93 (d, J = 5.5 Hz,
2H, –OCH2), 6.00–6.05 (m, 1H, @CH), 6.20–6.26 (m,
1H, @CH), 7.11–7.14 (dd, J = 4.7 Hz, 7.8 Hz, 1H,
ArH), 7.23–7.56 (m, 5H, ArH), 8.21–8.23 (dd, J =
1.2 Hz, 7.8 Hz, 1H, ArH), 8.39–8.40 (dd, J = 1.2 Hz,
4.36 Hz, 1H, ArH); MS: m/z = 291 (M++1). 13C
NMR (125 MHz, CDCl3): 25.14, 68.00, 113.64, 114.13,
118.47, 127.00, 128.76, 129.33, 129.85, 132.13, 133.93,
138.00, 149.87, 150.31, 160.04 and 164.72. Anal. Calcd
for C18H14N2O2: C, 74.48; H, 4.82; N, 9.65. Found: C,
74.62; H, 4.98; N, 9.51.