Phthalimides
PhthNR
T. W. Green, P. G. M. Wuts,
Protective Groups in Organic
Synthesis,
Wiley-Interscience,New York, 1999, 564-566, 740-743.
Stability
| H2O: | pH < 1, 100°C | pH = 1, RT | pH = 4, RT | pH = 9, RT | pH = 12, RT | pH > 12, 100°C |
| Bases: | LDA | NEt3, Py | t-BuOK | Others: | DCC | SOCl2 |
| Nucleophiles: | RLi | RMgX | RCuLi | Enolates | NH3, RNH2 | NaOCH3 |
| Electrophiles: | RCOCl | RCHO | CH3I | Others: | :CCl2 | Bu3SnH |
| Reduction: | H2 / Ni | H2 / Rh | Zn / HCl | Na / NH3 | LiAlH4 | NaBH4 |
| Oxidation: | KMnO4 | OsO4 | CrO3 / Py | RCOOOH | I2, Br2, Cl2 | MnO2 / CH2Cl2 |
General
The most important synthesis of phthalimides is the dehydrative condensation of phthalic anhydride at high temperatures with primary amines, when the amine is available. When the amine is not readily accessible, the direct N-alkylation of phthalimides with alcohols under Mitsunobu conditions and of potassium phthalimide with alkyl halides (Gabriel Synthesis) are popular alternative approaches to Phth-protected amines.
In peptide synthesis, the exhaustive substitution of primary amines is desirable to block both hydrogens and avoid racemization of the substrates. Phthalimides are suitable protective groups for this purpose, but beyond the most frequently used methods of hydrazinolysis and basic hydrolysis, there are only a few deprotection methods that are gentle and near-neutral, which is a drawback.
Protection of Amino Groups
An economical and practical method for the synthesis of a wide range of imide
derivatives has been developed by using inexpensive and readily available
reagents under mild conditions.
P. Y. Reddy, S. Kondo, T. Toru, Y. Ueno, J. Org. Chem., 1997,
62, 2652-2654.
A Lewis acid catalyzed and solvent free procedure for the preparation of imides
from the corresponding anhydrides uses TaCl5-silica gel as Lewis acid
under microwave irradiation.
S. Chandrasekhar, M. Takhi, G. Uma, Tetrahedron Lett., 1997,
38, 8089-8092.
Other Syntheses of Phthalimide-protected Amino Groups
A convenient, efficient, and selective N-Alkylation of N-acidic heterocyclic compounds with alkyl halides is accomplished in ionic liquids in the presence of potassium hydroxide as a base. In this
manner, phthalimide, indole, benzimidazole, and succinimide can be successfully
alkylated.
Z.-G. Le, Z.-C. Chen, Y. Hu, Q.-G. Zheng, Synthesis, 2004,
208-212.
An efficient and simple method enables the N-alkylation of aromatic cyclic
imides using cesium carbonate as the base in anhydrous N,N-dimethylformamide
at low temperatures (20-70˚C). The employment of microwave irradiation presents
noteworthy advantages over conventional heating. The method is compatible with
base labile functional groups.
M. I. Escudero, L. D. Kremenchuzky, I. A. Perillo, H. Cerecetto, M. M. Blanco, Synthesis, 2011,
571-576.
Imidoyl chlorides, generated from secondary acetamides and oxalyl chloride,
enable a selective and practical deprotection sequence. Treatment of these
intermediates with propylene glycol enables the rapid release of
amine hydrochloride salts in good yields without epimerization of the amino
center. The hydrochloride salts can be isolated or carried forward for subsequent chemistry.
S. G. Koenig, C. P. Vandenbossche, H. Zhao, P. Mousaw, S. P. Singh, R. P. Bakale, Org. Lett., 2009,
11, 433-436.
The synthesis of isomerically pure allylic amines, including farnesyl amine, is
achieved in excellent yields using a modified Gabriel synthesis.
S. E. Sen, S. L. Roach, Synthesis, 1995, 756-758.
S. Dandapani, D. P. Curran, Tetrahedron,
2002, 58, 3855-3864.
S.-e. Syu, Y.-T. Lee, Y.-J. Jang, W. Lin, J. Org. Chem., 2011,
76, 2888-2891.
Suzuki-Miyaura cross-coupling enables a one-pot primary aminomethylation of aryl
halides, triflates, mesylates, and tosylates via coupling with sodium
phthalimidomethyltrifluoroborate followed by deamidation with ethylenediamine.
N. Murai, M. Miyano, M. Yonaga, K. Tanaka, Org. Lett., 2012,
14, 2818-2821.
Deprotection
Phthalimides are converted to primary amines in an efficient, two-stage,
one-flask operation using NaBH4/2-propanol, then acetic acid.
Phthalimides of α-amino acids are smoothly deprotected with no measurable loss
of optical activity.
J. O. Osby, M. G. Martin, B. Ganem, Tetrahedron Lett., 1984,
25, 2093-2096.
The synthesis of isomerically pure allylic amines, including farnesyl amine,
is achieved in excellent yields using a modified Gabriel synthesis.
S. E. Sen, S. L. Roach, Synthesis, 1995, 756-758.
The synthesis of isomerically pure allylic amines, including farnesyl amine,
is achieved in excellent yields using a modified Gabriel synthesis.
S. E. Sen, S. L. Roach, Synthesis, 1995, 756-758.
Suzuki-Miyaura cross-coupling enables a one-pot primary aminomethylation of aryl
halides, triflates, mesylates, and tosylates via coupling with sodium
phthalimidomethyltrifluoroborate followed by deamidation with ethylenediamine.
N. Murai, M. Miyano, M. Yonaga, K. Tanaka, Org. Lett., 2012,
14, 2818-2821.
Phthalimides in Multi-step Syntheses
While 3,4;5,6-di-O-isopropylidene-N-phthaloyl-D-glucosamine
propane-1,3-diyl dithioacetal underwent fast β-elimination, the corresponding
N-acetyl derivative was easily deprotonated with butyllithium to form the
dilithiated intermediate. Stoichiometry and temperature were crucial factors for
selective C-C coupling with various electrophiles.
Y.-L. Chen, R. Leguijt, H. Redlich, R. Fröhlich,
Synthesis, 2006, 4212-4218.
