7826
P. Mizar, B. Myrboh / Tetrahedron Letters 47 (2006) 7823–7826
12. Touzeau, F.; Arrault, A.; Guillaumet, G.; Scalbert, E.;
Pfeiffer, B.; Rettori, M.-C.; Renard, P.; Merour, J.-Y. J.
Med. Chem. 2003, 46, 1962–1979.
refluxed in toluene with the methyl ester in 56–65% yields;
a catalytic amount of I2 enhanced the rate and increased
the overall yields of these reactions.
13. (a) Combs, D. W.; Rampulla, S. C.; Bell, S. C.;
Klaubert, D. H.; Tobia, A. J.; Falotico, R.; Haertlein,
B.; Lakas-Weiss, C.; Moor, J. B. J. Med. Chem. 1990,
33, 380–386; (b) Iakovou, K.; Kazanis, M.; Vavayannis,
A.; Bruni, G.; Romeo, M. R.; Massarelli, P.; Teramoto,
S.; Fujiki, H.; Mori, T. Eur. J. Med. Chem. 1999, 34,
903–917.
Acknowledgements
P.M. thanks CSIR for a research fellowship, RSIC
Shillong, IISc Bangalore and CIF-IIT Guwahati, for
spectral analysis.
14. Synthesis of 3,4-dihydro-2H-1,4-benzoxazines 1. To a
suspension of 2-aminophenol (46 mmol) and potassium
carbonate (229 mmol) in dry DMF (40 ml), 1,2-dibromo-
ethane (69 mmol) was added. The mixture was heated at
125 °C for 15 h. After cooling, the mixture was treated
with crushed ice and then extracted with ethyl acetate. The
organic extracts were dried over Na2SO4 and evaporated.
The residue was purified by chromatography on a silica gel
column using ethyl acetate and hexane (1:10) as the eluent.
Compound 1a was reddish oil (73% yield) IR (film) m cmÀ1
References and notes
1. Ellis, G. P. Synthesis of fused Heterocycles; John Wiley
and Sons, 1987; pp 55–57.
2. (a) Hietala, P. K.; Virtanen, A. I. Acta Chem. Scand. 1960,
14, 502–506; (b) Coults, R. T.; Hindmarsh, K. W. Can. J.
Pharm. Sci. 1966, 11–15; (c) Chatterjee, A.; Basa, S. C.
Chem. Ind. 1969, 11, 328–331; (d) Hofman, J.; Hofma-
nova, O. Eur. J. Biochem. 1969, 8, 109–114; (e) Nagao, T.;
Otsuka, H.; Kohda, H.; Sato, T.; Yamasaki, K. Phyto-
chemistry 1985, 24, 2959–2963; (f) Otsuka, H.; Hirai, Y.;
Nagao, T.; Yamasaki, K. J. Nat. Prod. 1988, 51, 74–79; (g)
Neimeyer, H. M. Phytochemistry 1988, 27, 3349–3353; (h)
Lyans, P. C.; Hipskind, H. D.; Wood, K. V.; Nicholson,
R. L. J. Agric. Food Chem. 1988, 36, 57–63; (i) Chatterjee,
A.; Sharma, N. J.; Banerji, J.; Basa, S. C. Indian J. Chem.,
Sect. B 1990, 29, 132–137; (j) Ozden, S.; Ozden, T.; Attila,
I.; Kucukislamoglu, M.; Okatan, A. J. Chromatogr. 1992,
609, 402–409; (k) Hartenstein, H.; Sicker, D. Phytochem-
istry 1994, 827; (l) Hartenstein, H.; Klein, J.; Sicker, D.
Indian J. Heterocycl. Chem. 1993, 2, 151–157.
1
3385 (NH). H NMR (DMSO-d6, 400 MHz) d ppm 3.25
(d, 2H, J = 2.7 Hz), 4.07 (t, 2H, J = 8.6 Hz), 5.69 (s, 1H),
6.46–6.65 (m, 4H, ArH). 13C NMR (CDCl3, 100 MHz)
60.2 (NCH2), 73.1 (OCH2), 112.8, 116.8, 117.3, 119.5,
140.1, 130.2. MS (CI) m/z = 136.21. Calcd for C8H9NO:
C, 71.09; H, 6.71; N, 10.36; found: C, 72.12; H, 6.69; N,
10.31.
15. Synthesis of N-alkylated 3,4-dihydro-2H-1,4-benzoxazines
2 by reduction: To a solution of the acid (7 mmol) and
3,4-dihydro-2H-1,4-benzoxazines
(7 mmol),
NaBH4
(73 mmol) was added slowly at 0 °C. The reaction was
highly exothermic and care was taken to maintain the
temperature around 0–5 °C. The reaction was stirred for
2–3 h. On completion, the mixture was neutralized using
NaOH and extracted with ethyl acetate. The organic layer
was dried and evaporated. The residue was chromato-
graphed on silica gel column using ethyl acetate and
hexane as eluents to obtain the desired product in high
yield. Compound 2a was a reddish oil, IR (film) showed
the absence of NH stretching.1H NMR (CDCl3,
400 MHz) d ppm 1.18 (t, 3H, J = 14.2 Hz), 3.30 (q, 2H,
J = 8.7 Hz), 3.34 (t, 2H, J = 14.1 Hz), 4.24–4.26 (t, 2H,
J = 8.8 Hz), 6.6–6.84 (m, 4H, ArH). 13C NMR (CDCl3,
100 MHz); d ppm 14.5, 49.5, 59.1, 72.3, 112.9, 116.9,
117.1, 122.1, 130.1, 143.6. MS (CI) m/z = 164.1. Calcd for
C10H13NO is C, 73.59; H, 8.03; N, 8.58; found: C, 73.12;
H, 8.09; N, 8.6.
3. Heterocyclic congeners of PD 128,907 with a partially
hydrogenated benzomorpholine moiety as potential dopa-
mine D3-receptor ligands Matzanke, N.; Lowe, W.;
Perachon, S.; Sokoloff, P.; Schwartz, J.-C.; Stark, H.
Eur. J. Med. Chem. 1999, 34, 791–798.
4. Fukuda, T.; Setoguchi, M.; Inaba, K.; Shoji, H.; Tahara,
T. Eur. J. Pharmacol. 1991, 196, 299–307.
5. Empfield, J. R.; Russell, K. Potassium Channel Openers.
Ann. Rep. Med. Chem., Vol. 30, Chapter 9, pp 81–89.
6. Hirata, T.; Saito, H.; Tomioka, H.; Sato, K.; Jidoi, J.;
Hosoe, K.; Hidaka, T. Antimicrob. Agents Chemother.
1995, 39, 2295–2301.
16. Synthesis of N-alkylated 3,4-dihydro-2H-1,4-benzoxazines
3 by alkylation: Amine 1 (6 mmol) and dry K2CO3
(15 mmol) were dissolved in dry DMF (15 ml), then an
alkyl halide (8.6 mmol) was added. The reaction mixture
was stirred at room temperature overnight. After comple-
tion of the reaction (TLC monitoring), crushed ice was
added and the product was extracted using ethyl acetate.
The combined organic extracts were dried (Na2SO4) and
concentrated. The crude product was purified over silica
gel eluting with ethyl acetate and hexane (1:20) to obtain
the product. Compound 3a was a reddish oil, IR (film)
7. Matsuoka, H.; Ohi, N.; Mihara, M.; Suzuki, H.; Miya-
moto, K.; Maruyama, N.; Tsuji, K.; Kato, N.; Akimoto,
T.; Takeda, Y.; Yano, K.; Kuroki, T. J. Med. Chem. 1997,
40, 105.
8. (a) Hayakawa, I.; Atarashi, S.; Yokohama, S.; Imamura,
M.; Sakano, K.; Furukawa, M. Antimicrob. Agents
Chemother. 1986, 29, 163–169; (b) Atarashi, S.; Yoko-
hama, S.; Yamazaki, U.; Sakano, K.; Imamura, M.;
Hayakawa, I. Chem. Pharm. Bull. 1987, 35, 1896–1900; (c)
Mitscher, L. A.; Gharma, P. N.; Chu, D. T. W.; Shen, L.
L.; Pernet, A. G. J. Med. Chem. 1987, 30, 2283–2291; (d)
Atarashi, S.; Tsurumi, H.; Fujiwara, T.; Hayakawa, I. J.
Heterocycl. Chem. 1991, 28, 329–335.
9. Kosemura, S.; Yamamura, S.; Anai, T.; Hasegawa, K.
Tetrahedron Lett. 1994, 35, 8221–8224.
10. Largeron, M.; Lockhart, B.; Pfeiffer, B.; Fleury, M. B. J.
Med. Chem. 1999, 42, 5043–5052–5061.
11. Michihiro, O.; Ryoji, H.; Masatumi, I.; Hiroshi, U. PT CT
Int. Appl. Wo 2004, 52, 871–882.
1
showed the absence of NH stretching. H NMR (CDCl3,
400 MHz) d ppm 0.98 (d, 6H, J = 6.6 Hz), 1.62–1.67 (m,
1H), 1.77–1.82 (m, 2H), 3.46 (t, 2H, J = 14.1 Hz), 4.26 (t,
2H, J = 8.1 Hz), 6.5–6.84 (m, 4H, ArH). 13C NMR
(CDCl3, 100 MHz) d ppm 20.3, 28.1, 59.1, 65.8, 72.3,
112.9, 116.9, 117.1, 122.1, 130.1, 143.6; MS (CI) m/
z = 190.13. Calcd for C12H17NO is C, 75.35; H, 8.96; N,
7.32; found: C, 75.12; H, 9.01; N, 7.31.