6162
M. Sanna et al. / Tetrahedron Letters 49 (2008) 6160–6162
9. (a) Hudson, D. J. Comb. Chem. 1999, 1, 333–360; (b) Hudson, D. J. Comb. Chem.
(i) CDCl3, 18 h, r.t.
H
1999, 1, 403–457.
NCO
NHRR'
(1.2 eq)
N
NRR'
+
10. Krajnc, P.; Brown, J. F.; Cameron, N. R. Org. Lett. 2002, 4, 2497–2500.
11. Tripp, J. A.; Svec, F.; Fréchet, J. M. J. J. Comb. Chem. 2001, 3, 216–223.
12. (a) Arnauld, T.; Barrett, A. G. M.; Cramp, S. M.; Roberts, R. S.; Zecri, F. J. Org. Lett.
2000, 2, 2663–2666; (b) A sample of ROMPGEL was previously provided by
Professor Barrett to Merck Chemicals Ltd.
(ii) 1 (1.5–2 eq),
O
18 h, r.t.
13. Typical procedure for the synthesis of the macroporous cyclic anhydride resin 1:
The poly(methacrylic acid) resin (AmberliteÒ IRC-50, 10 g, ca. 100 mmol) was
washed with 1.0 M HCl(aq) (1 L), distilled H2O (1 L) and MeOH (500 mL) and
subsequently stirred in MeOH (500 mL) for 1 h. The resin was then collected
and washed with MeOH (50 mL), THF (50 mL) and CH2Cl2 (50 mL) and dried in
vacuo overnight to afford the resin material as a white, free-flowing powder
(9.70 g). IR (KBr): 3450 (OH) and 1705 (C@O) cmÀ1. Anal. found C, 58.05; H,
7.77; Cl, 0.38; N, 0.00. The dried resin material (2.00 g, 21.86 mmol;
determined by a back-titration method) was suspended in DMF/CH2Cl2 1:1
(10 mL), to which was added 1,3-diisopropylcarbodiimide (2.39 mL,
15.30 mmol) and the mixture was stirred at 4 °C for 18 h. The resin was then
washed consecutively with warm DMF (500 mL) and CH2Cl2 (500 mL), and
dried in vacuo to afford the desired reagent as off-white granules (1.53 g, 85%).
IR (KBr): 1804 and 1760 cmÀ1 (C(O)–O–C(O)). Anal. found C, 60.02; H, 6.33; N,
0.59.
Cl
H
H
N
H
H
N
N
N
O
O
2
3
(mp 91 ˚C, yield 78%)
(mp 116 ˚C, yield 47%)
O
H
H
N
N
H
NH2
N
N
O
O
4
5
The macroporous cyclic anhydride resin 1 (100 mg, theoretical 0.68 mmol) was
(mp 90 ˚C, yield 63%)
(mp 171 ˚C, yield 78%)
suspended in DMF (0.5 mL).
A sample of 4-chlorobenzylamine (0.412 mL,
3.40 mmol) was added and the reaction was stirred for 16 h. The resin was
filtered and washed consecutively with 1 M HCl(aq), H2O, DMF, and CH2Cl2
(10 mL each), and dried in vacuo to yield poly(methacrylic acid-alt-N-4-
chlorobenzyl methacrylamide) (151 mg, 99%); IR (KBr): 3375 (OH), 1716 (acid
C@O), 1655 (amide I), and 1516 (amide II) cmÀ1. Anal. found C, 59.11; H, 6.72;
N, 5.90; Cl, 12.21; based on chloride content (3.44 mmol gÀ1), the initial
Scheme 3. Parallel synthesis of N-allylureas.
The reactivity per gram of the anhydride resin in fact exceeds that
of benzoic anhydride (4.4 mmol gÀ1). Due to the robustness of the
matrix, we anticipate that the poly(methacrylic anhydride) resin
will have amine scavenging utility in both batch1 and flow16 meth-
ods for parallel synthesis of compound libraries.
anhydride loading was calculated to be 6.72 mmol gÀ1
.
14. 1-Allyl-3-benzylurea, 2. To a solution of 1-allylisocyanate (0.106 mL, 1.20
mmol) in CDCl3 (5 mL) was added benzylamine (0.157 mL, 1.44 mmol). The
mixture was stirred for 18 h (at this stage, a sample of the solution was
typically analyzed by 1H NMR), after which macroporous anhydride resin 1
(244 mg, 1.64 mmol) was added and the resultant suspension was stirred
vigorously for
a further 18 h. The suspension was filtered and the resin
Acknowledgment
material was washed with CDCl3. The combined filtrate was evaporated to
dryness to afford a white solid (202 mg), which on trituration with hexane
gave the compound 2 as a white solid (178 mg, 78%): mp 91 °C, m/z (+ES) 191.3
(MH+), calcd 191.2; dH (250 MHz, CDCl3) 3.55–3.59 (2H, m), 4.13 (2H, d, J
5.8 Hz), 4.93–5.08 (2H, m), 5.59–5.75 (1H, m), 5.85 (1H, t, J 5.3 Hz), 6.10 (1H, t, J
5.7 Hz), 7.18 (5H, m). Anal. Calcd for C11H14N2O: C, 69.44; H, 7.41; N, 14.72.
Found: C, 69.49; H, 7.41; N, 14.79.
M.S. would like to acknowledge Merck Chemicals Ltd. for the
funding of a studentship.
References and notes
1-Allyl-3-(4-chlorobenzyl)urea, 3: Mp 116 °C; m/z (+ES) 225.2 (MH+), calcd.
225.7; dH (250 MHz, CDCl3) 3.68–3.74 (2H, m), 4.22 (2H, d, J 5.9), 5.03–5.17
(2H, m), 5.21 (1H, t, J 5.6), 5.51 (1H, t, J 5.6), 5.70–5.85 (1H, m), 7.12–7.28 (4H,
m). Anal. Calcd for C11H13ClN2O: C, 58.80; H, 5.83; N, 12.42. Found: C, 58.69; H,
5.71; N, 12.33.
1. (a) Kaldor, S. W.; Siegel, M. G.; Fritz, J. E.; Dressman, B. A.; Hahn, P. J.
Tetrahedron Lett. 1996, 37, 7193–7196; (b) Booth, J. R.; Hodges, J. C. J. Am. Chem.
Soc. 1997, 119, 4882–4886; (c) Booth, R. J.; Hodges, J. C. Acc. Chem. Res. 1999, 32,
18–26; (d) Eames, J.; Watkinson, M. Eur. J. Org. Chem. 2001, 1213–1224; (e) Ley,
S. V.; Baxendale, I. R. Nature Rev. Drug Discov. 2002, 1, 573–586.
2. (a) Flynn, D. L.; Crich, J. Z.; Devraj, R. V.; Hockerman, S. L.; Parlow, J. J.; South, M.
S.; Woodard, S. J. Am. Chem. Soc. 1997, 119, 4874–4881; (b) Parlow, J. J.;
Mischke, D. A.; Woodard, S. S. J. Org. Chem. 1997, 62, 5908–5919.
N-Allylpyrrolidine-1-carboxamide, 4: Mp 90 °C; m/z (+ES) 155.2 (MH+) calcd
155.2; dH (250 MHz, CDCl3) 1.85–1.96 (4H, m), 3.34 (4H, t, J 6.6), 3.85–3.90 (2H,
m), 5.05–5.22 (2H, m), 5.82–5.97 (1H, m). Anal. Calcd for C8H14N2O: C, 62.31;
H, 9.15; N, 18.16. Found: C, 61.87; H, 9.06; N, 18.33.
3. (a) Parlow, J. J.; Naing, W.; South, M. S.; Flynn, D. L. Tetrahedron Lett. 1997, 38,
7959–7962; (b) Siegel, M. G.; Hahn, P. J.; Dressman, B. A.; Fritz, J. E.; Grunwell, J.
R.; Kaldor, W. S. Tetrahedron Lett. 1997, 38, 3357–3360.
4. (a) Zhang, W.; Chen, C. H. T.; Nagashima, T. Tetrahedron Lett. 2003, 44, 2065–
2068; (b) Zhang, W. Tetrahedron 2003, 59, 4475–4489.
(S)-2-(3-Allylureido)-3-phenylpropionamide, 5: Mp 171 °C; m/z (+ES) 248.2
(MH+) calcd 248.3; dH (250 MHz, CD3OD) 2.95 (2H, dd, J 6.4 and 13.8), 3.69–
3.72 (2H, m), 4.46–4.52 (1H, m), 5.02–5.15 (2H, m), 5.71–5.86 (1H, m), 7.19–
1
7.32 (5H, m). Anal. Calcd for C13H17N3O2Á MeOH, C, 62.33; H, 7.10; N, 16.40.
4
Found: C, 62.41; H, 6.83; N, 16.34.
5. Rebek, J.; Brown, D.; Zimmerman, S. J. Am. Chem. Soc. 1975, 97, 4407–4408.
6. Frechet, J. M.; Schuerch, C. J. Am. Chem. Soc. 1971, 93, 492–496.
7. Leznoff, C. C.; Dixit, D. M. Can. J. Chem. 1977, 55, 3351–3355.
15. The macroporous polymer-supported cyclic anhydride resin (MP-anhydride
resin) is commercially available from Merck Chemicals Ltd.
16. (a) Baxendale, I. R.; Ley, S. V.; Smith, C. D.; Trammer, G. K. Chem. Commun. 2006,
4835–4837; (b) Ley, S. V.; Baxendale, I. R. Chimia 2008, 62, 162–168.
8. Coppola, G. M. Tetrahedron Lett. 1998, 39, 8233–8236.