LETTER
Facile One-Pot Three Component Synthesis of Macrocyclic Imidazolidines
1129
Table 2 Solvent Effects on Cycloaddition of Macrocyclic Dipolarophiles with Paraformaldehyde and Sarcosine
Product
Benzene, reflux
Time (h)
Acetonitrile, reflux
Time (h)
Toluene, reflux
Time (h)
Yield (%)
Yield (%)
Yield (%)a
6
7
48
46
40
43
42
45
19
17
15
12
11
8
56
58
54
57
60
55
12
11
12
10
7
24
23
22
23
25
26
68
63
65
69
62
60
1
1
1
0a
0b
1a
1b
1
9
a
Based on recovered starting material.
(
2) (a) Chang-Fong, J.; Benamour, K.; Szymonski, B.;
MeCN (20 mL) was refluxed overnight. After completion of
the reaction MeCN was distilled off under vacuum. The
Thomasson, F.; Morand, J. M.; Cussac, M. Chem. Pharm.
Bull. 2000, 48, 729. (b) Sage, C. R.; Michelistich, M. D.;
Stout, J.; Biermann, D.; Nissen, R.; Finer-Moore, N.; Stroud,
R. M. Biochemistry 1998, 37, 13893.
reaction mixture was then washed with H O and extracted
2
with CHCl . The organic layer was concentrated by
3
distillation under reduced pressure to give the required
dialdehyde in an excellent yield (97%).
(
3) (a) Sharma, V.; Crankshaw, C. L.; Piwnica-Worms, D.
J. Med. Chem. 1996, 39, 3483. (b) Sage, C. R.; Michelitsch,
M. D.; Stout, T. J.; Blermann, D.; Nissen, R.; Finer-Moore,
J.; Stroud, R. M. Biochemistry 1998, 37, 13893. (c) Olmos,
G.; Rinera, J.; Varcia-Sevilla, H. A. Eur. J. Pharm. 1996,
(16) Representative Experimental Procedure for the
Synthesis of Imine Derivative 2: A mixture of dialdehyde
1 (1 mmol), 1,2 diamino ethane (1 mmol), and EtOH (100
mL) was refluxed for 12 h. After completion of the reaction
the solvent was carefully removed under reduced pressure to
give the required bisimine 2.
310, 273. (d) Chang-Fong, J.; Benamour, K.; Szymonski,
B.; Thomasson, F.; Morangd, J. M.; Cussac, M. Chem.
Pharm. Bull. 2000, 48, 729. (e) Sakuta, H.; Okamotto, K.
Eur. J. Pharm. 1994, 259, 223.
(17) Arumugam, N.; Raghunathan, R. Tetrahedron Lett. 2006,
47, 8855.
(
(
(
4) (a) Sharma, V.; Khan, M. S. Y. Eur. J. Med. Chem. 2001, 36,
(18) (a) Simon, A.; Simon, C.; Kanda, T.; Nagashima, S.;
Mitoma, T.; Yamada, T.; Mimura, K.; Tashiro, M. J. Chem.
Soc., Perkin Trans. 1 2001, 2071. (b) Armstrong, L. G.;
Lindoy, L. F. Inorg. Chem. 1975, 14, 1322.
651. (b) Kalyaham, N.; Sparthasarathy, P. C.; Ananthan, L.;
Manjunatha, S. G.; Likhate, M. A. Indian J. Chem. Sect. B:
Org. Chem. Incl. Med. Chem. 1992, 31, 243.
5) (a) Van Hook, J. O.; Craig, W. E. U.S. Patent, 2675387,
(19) Representative Procedure for the Synthesis of
Bisimidazolidine Derivatives 6, 7, 10, 11: A mixture of
sarcosine (4.0 equiv), paraformaldehyde (12 equiv) and the
corresponding macrocyclic diimine (1 equiv) was heated
under reflux in toluene in a Dean–Stark apparatus (10 mL for
1 mmol of dipolarophile). After completion of the reaction
as evidenced by TLC the reaction mixture was filtered
through a pad of Celite and the solvent was removed under
reduced pressure. The crude product was subjected to
column chromatography using petroleum ether–EtOAc (3:2)
as eluent to get the pure product.
1
955; Chem. Abstr. 1955, 49, 4729. (b) Craig, W. E.;
Van Hook, J. O. U.S. Patent, 2675381, 1956; Chem. Abstr.
956, 50, 411.
1
6) (a) Li, X.; Bera, M.; Musie, G. T.; Powell, D. R. Inorg.
Chim. Acta 2007. (b) Li, J.; Wang, S.; Hu, J.; Chein, H.
Tetrahedron Lett. 1999, 40, 1961.
(
(
(
7) Erkizia, E.; Aldaba, E.; Vara, Y.; Arrieta, A.; Gornitzka, H.;
Cossio, F. P. ARKIVOC 2005, (ix), 189.
8) Saegusa, T.; Taka-ishi, N.; Tamura, I.; Fujii, H. J. Org.
Chem. 1969, 34, 1145.
9) Northrop, R. C.; Russ, P. L. J. Org. Chem. 1975, 40, 558.
(20) Macrocyclic Schiff Base 8b: R = 0.6 (Hex–EtOAc, 3:1);
f
1
(
10) Wanzlick, H. W.; Lochel, W. Chem. Ber. 1963, 86, 1463.
pale yellow solid; yield: 95%; mp 126–129 °C. H NMR
(
11) Katritzky, A. R.; Suzuki, K.; He, H. Y. J. Org. Chem. 2002,
(300 MHz, CDCl ): d = 4.12 (s, 4 H), 5.22 (s, 4 H), 6.78–7.80
3
1
3
67, 3109.
(m, 12 H), 8.78 (s, 2 H). C NMR (75 MHz, CDCl ): d =
3
(12) (a) 1,3-Dipolar Cycloaddition Chemistry, Vol. 1; Padwa, A.,
60.6, 68.1, 112.1, 120.8, 123.6, 125.2, 125.5, 128.3, 128.6,
+
Ed.; Wiley: New York, 1984. (b) 1,3-Dipolar
131.4, 137.7, 159.3. MS: m/z = 366 [M ]. Anal. Calcd for
Cycloaddition Chemistry, Vol. 2; Padwa, A., Ed.; Wiley:
New York, 1984. (c) Pandey, G.; Banerjee, P.; Gadre, S. R.
Chem. Rev. 2006, 106, 4484.
C H N O : C, 77.79; H, 5.99; N, 7.56; Found: C, 77.84; H,
6.04; N, 7.48.
2
4
22
2
2
(21) Macrocyclic Imidazolidine 6: R = 0.5 (Hex–EtOAc, 3:2);
f
1
(
(
13) Grigg, R.; Sridharan, V. In Advances in Cycloaddition, Vol.
yellow liquid; yield: 68%. H NMR (300 MHz, CDCl ): d =
3
3
; Curran, D. P., Ed.; Jai Press: London, 1993, 161.
14) (a) Suresh Babu, A. R.; Raghunathan, R. Tetrahedron Lett.
007, 48, 6809. (b) Subramaniyan, G.; Raghunathan, R.;
Martin Castro, A. M. Synthesis 2002, 2440.
c) Jayashankaran, J.; Rathna Durga, R. S. M.; Raghunathan,
2.33 (s, 6 H), 2.56 (dd, J = 7.2, 7.5 Hz, 4 H), 3.24 (d, J = 6.3
Hz, 2 H), 3.32 (d, J = 6.3 Hz, 2 H), 4.17–4.29 (m, 4 H), 4.33
(q, J = 4.8 Hz, 4 H), 5.12–5.18 (m, 2 H), 6.77–7.43 (m, 8 H).
2
1
3
C NMR (75 MHz, CDCl ): d = 40.71, 60.52, 65.60, 71.30,
3
(
87.69, 109.85, 120.13, 124.59, 126.98, 130.23, 154.03. MS:
m/z = 422.32 [M ]. Anal. Calcd for C H N O : C, 70.54; H,
+
R. Tetrahedron Lett. 2004, 45, 7303. (d) Suresh Babu,
A. R.; Raghunathan, R. Tetrahedron Lett. 2008, 49, 4487.
15) Representative Procedure for Dialdehyde 1: A mixture of
freshly distilled salicylaldehyde (2 mmol), dibromoethane (1
mmol), anhyd K CO (2 mmol) and KI (0.1 mmol) in anhyd
2
4
32
4
2
7.89; N, 13.72; Found: C, 70.68; H, 7.98; N, 13.84.
(
(22) Macrocyclic Imidazolidine 10a: R = 0.5 (Hex–EtOAc,
f
1
3:2); yellow liquid; yield: 65%. H NMR (300 MHz,
CDCl ): d = 2.35 (s, 6 H), 2.60 (dd, J = 7.2, 7.5 Hz, 4 H), 2.83
2
3
3
Synlett 2009, No. 7, 1126–1130 © Thieme Stuttgart · New York