B. P. Bandgar, S. S. Pandit / Tetrahedron Letters 44 (2003) 3855–3858
3857
ester or by using a strong lithium reagent. The desired
References
monoacylated product, 5 can easily be purified by
simple recrystallization or using column chromatogra-
phy (pet. ether:ethyl acetate=8:2) and by-products such
as N-methylmorpholine hydrochloride and the triazine
derivative easily removed by aqueous work-up. Due to
the steric hindrance present in the 4,6-dimethoxy-1,3,5-
triazine intermediate 4, the reaction with a second
amino group is prevented and, therefore, no bisadduct
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1
was detected. H NMR spectroscopy revealed that the
monoacylated piperazine derivatives thus prepared were
the desired products. The methodology was found to be
general, a variety of carboxylic acids such as aliphatic,
unsaturated, aromatic and heterocyclic were smoothly
converted into the corresponding monoacylated piper-
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4
5
. (a) Jung, B.; Schurmann, B. L. Mol. Cryst. Liq. Cryst.
1
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In conclusion, a convenient and straightforward proto-
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product can easily be purified by recrystallization or
column chromatography. Furthermore, this process is
amenable to scale-up. All the chemicals used are com-
mercially available and inexpensive. The selective
preparation of monoacylated piperazine, short reaction
times, mild reaction conditions and the use of inexpen-
sive and easily available reagents are noteworthy
advantages of this method.
6
. (a) Koo, J.; Avakian, S.; Martin, G. J. J. Am. Chem. Soc.
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2
2
N-methylmorpholine (15 mmol) was added at 0–5°C
under continuous stirring. A white suspension was
formed after 30–40 min and to this mixture 2,3-dihy-
drobenzo[1,4]dioxin–carboxylic acid (5 mmol) in
CH Cl (10 ml) was added resulting in the formation of
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(
h) Campell, S. F. US Pat. 4,188,390, 1980; (i) Manoury,
2
2
P. M. US Pat. 4,315,007, 1982; (j) Roteman, R. US Pat.
a clear solution. After stirring the mixture for 1 h,
piperazine (5 mmol) was added at room temperature.
After completion of the reaction (TLC, 10 min), the
4
1
,251,532, 1981; (k) Igarashi, T. Eur. Pat. 0,209,089,
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Konig, J. Ger. Pat. 3,419,223, 1984.
mixture was washed with 10% aqueous NaHCO solu-
3
8
9
. (a) Jacobi, K. Ber. Dtsch. Chem. Ges. 1933, 66, 113; (b)
Cymerman-Craig, J.; Rogers, W. P.; Tate, M. E. Aust. J.
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tion (2×10 ml) followed by H O (3×10 ml). The organic
2
layer was dried over anhydrous sodium sulfate and
removal of the solvent under reduced pressure fur-
nished a crude product which was further purified by
recrystallization or column chromatography (pet.
ether:ethyl acetate=8:2).
N-(2,3-Dihydrobenzo[1,4]dioxin-2-carbonyl)piperazine
1983, 48, 661; (c) Stahl, G. L.; Walter, R.; Smith, C. W.
−
1 1
(
(
5n): mp=85°C; IR (KBr): 1640, 3450 cm ; H NMR
J. Org. Chem. 1978, 43, 2285; (d) Lyon, R. A.; Titler, M.;
McKenney, J. D.; Magee, P. S.; Glenon, R. A. J. Med.
Chem. 1986, 29, 630.
300 MHz, CDCl ): l=2.15 (s, 1H, NH), 2.8–2.9 (m,
3
2
2
H), 2.95–3.00 (m, 2H), 3.5–3.65 (m, 2H), 3.7–3.8 (m,
H), 4.4 (dd, J=12, 8.5 Hz, 1H), 4.5 (dd, J=12, 2.5
1
0. (a) Wang, T.; Zhang, Z.; Meanwell, N. A. J. Org. Chem.
Hz, 1H), 4.9 (dd, J=8.5, 2.5 Hz, 1H), 6.9–7.1 (m, 4H);
1999, 64, 7661; (b) Mesaguer, C. F.; Ravina, E. Tetra-
1
3
C NMR (75 MHz, CDCl ); l=40.2, 45.7, 50.3, 65.1,
hedron Lett. 1996, 37, 5171; (c) Kawakubo, H.; Okazaki,
K.; Nagatani, T.; Takao, K.; Hasimoto, S.; Sugihara, T.
J. Med. Chem. 1990, 33, 3110; (d) Ravina, E.; Fueyo, J.;
Mesaguer, C. F.; Negreira, J.; Cid, J.; Loza, I.; Honrubia,
A.; Tristan, H.; Ferreiro, T.-G.; Fontenla, J. A.; Rosa,
3
7
0.5, 115.1, 120.2, 122.4, 123.9, 144.2, 145.6, 170.2;
+
mass: m/z (%)=248 (M , 25), 111 (100). Anal. calcd for
C H ,N O : C, 62.89; H, 6.50; N, 11.28. Found: C,
13
16
2
3
63.02; H, 6.41; N, 11.35.