SYNTHESIS
Short Papers
1420
3-Chloro-3-(dimethoxyphosphoryl)isobenzofuran-1(3H)-one (1):
Trimethyl phosphite (8.4 g, 8.0 mL, 0.069 mol) was added dropwise
to neat phthaloyl chloride (14 g, 10 mL, 0.069 mol) over 25 min at
such a rate that the temperature was kept below 50°C. The mixture
was stirred at r.t. for 15 min until gas evolution ceased and then excess
trimethyl phosphite was evaporated in vacuo leaving behind a white
solid which could be recrystallized from Et2O, or from benzene/petro-
leum ether (bp 40–60°C); yield: 14.9 g (78%); mp 78–80°C.
1H NMR (CDCl3): δ = 8.0–7.6 (m, 4H, arom), 4.0 (d, 3H, J = 10.5 Hz,
CH3OP), 3.70 (d, 3H, J = 10.5 Hz, CH3OP).
(1) On leave from the Department of Organic Chemistry, Universi-
ty of Copenhagen.
(2) Breuer, E. In The Chemistry of Organophosphorus Compounds,
Vol. 4; Hartley, F. R. Ed.; Wiley: Chichester, 1996; pp 653–
729.
(3) Berlin, K. D.; Burpo, D. H.; Pagilagan, R. U.; Bude, D. J. Chem.
Soc., Chem. Commun. 1967, 1060.
(4) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis, 2nd ed.; Wiley: New York, 1991.
(5) Bodanszky, M.; Bodanszky, A. The Practice of Peptide Synthe-
sis, 2nd ed.; Springer: Heidelberg, 1994.
31P NMR (CDCl3): δ = 7.9 (septet, J = 10.5 Hz).
(6) Kocienski, P. J. Protecting Groups; Thieme: Stuttgart, 1994.
(7) Kamiya, T.; Hashimoto, M.; Nakaguchi, O.; Oku, T. Tetrahe-
dron 1979, 35, 323.
Synthesis of N-Phthaloylamines 2; General Procedure:
Method A: To 1 (0.7 g, 2.5 mmol) dissolved in MeCN (25 ml), was
added an amine (2.8 mmol) and Et3N14 (282 mg, 2.8 mmol). After
10 min 31P NMR showed complete conversion of 1 to dimethyl phos-
phite. The mixture was evaporated in vacuo (50°C/0.026 mbar), the
residue dissolved in CH2Cl2 (50 mL), washed with sat. NaHCO3 (2 ×
20 mL), dried (Na2SO4) and evaporated in vacuo. The phthalimide
was recrystallized from MeOH.
Townsend, C. A.; Nguyen, L. T. Tetrahedron Lett. 1982, 23,
4859.
(8) Breuer, E.; Safadi, M.; Chorev, M.; Gibson, D. Phosphorus,
Sulfur, Silicon 1991, 60, 239.
(9) For a review of phthaloylation methods see ref 10.
(10) Nefkens, G. H. L.; Tesser, G. I.; Nivard, R. J. F. Rec. Trav.
Chim. 1960, 79, 688.
Method B: To 1 (1.38 g; 5 mmol) and the amine (5.25 mmol) dis-
solved in MeCN/H2O (1:1, 25 mL) was added i-Pr2NEt (3.5 mL,
20 mmol) and the mixture stirred at r.t. After 10 min 31P NMR
showed complete conversion of 1 to dimethyl phosphite. The mixture
was concentrated in vacuo to a small volume (50°C/0.026 mbar),
acidified with 2 M HCl, and cooled to 0°C. The white precipitate was
filtered, washed with ice cold 2 M HCl and dried in vacuo over P2O5.
(11) Aguilar, N.; Moyano, A.; Pericàs, M. A. Riera, A. Synthesis
1998, 313.
(12) The salt of monodemethylated 1 is completely inert under the
reaction conditions.
(13) Acylphosphonates have been reported to possess highly reac-
tive carbonyl groups which add rapidly nucleophiles: Katzhend-
ler, J.; Ringel, I.; Karaman, R.; Zaher, H.; Breuer, E. J. Chem.
Soc., Perkin Trans. 2 1997, 341.
(14) A slight excess of an aliphatic tertiary amine or a base of com-
parable strength is essential for the reaction. Only partial con-
version was observed when NaHCO3 was used.
(15) Schindlbauer, H. Monatsh.Chem. 1973, 104, 848.
(16) Gabriel; S. Ber. Dtsch. Chem. Ges. 1891, 24, 3106.
(17) Boyd, G. V.; Monteil, R. L. J. Chem. Soc., Perkin Trans. 1
1978, 1338.
J. K. thanks the Rabin Foundation in Denmark for a generous grant.
E. B. is affiliated with the David Bloom Center for Pharmacy at the
Hebrew University of Jerusalem.