Reactions >> Protecting Groups >> Stability

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.

A highly efficient transamidation of several primary, secondary, and tertiary amides with aliphatic and aromatic amines (primary and secondary) is performed in the presence of a 5 mol % concentration of different hydrated salts of Fe(III). The methodology was also applied to urea and phthalimide to demonstrate its versatility and wide substrate scope. A plausible mechanism explains the crucial role of water.
L. Becerra-Figueroa , A. Ojeda-Porras, D. Gamba-Sánchez, J. Org. Chem., 2014, 79, 4544-4552.

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.

Transition-metal-free multicomponent reactions involving arynes, isocyanides, and CO₂ as the third component resulted in the formation of N-substituted phthalimides in good yields, whereas the use of water as the third component furnished benzamide derivatives in good yields. These reactions took place under mild conditions with broad scope.
T. Kaicharla, M. Thangaraj, A. T. Biju, Org. Lett., 2014, 16, 1728-1731.

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.

A safe alternative to the Curtius rearrangement, that employs a copper catalyst in combination with blue-LED irradiation, achieves a decarboxylative coupling of readily available aliphatic N-hydroxyphthalimide esters to afford protected amines under mild conditions. This C-N bond-forming process is compatible with a wide array of functional groups, including alcohols, aldehydes, epoxides, indoles, nitroalkanes, and sulfides.
W. Zhao, R. P. Wurz, J. C. Peters, G. C. Fu, J. Am. Chem. Soc., 2017, 139, 12153-12156.

A fully fluorous Mitsunobu reaction employing a fluorous phosphine and a fluorous azodicarboxylate is described. Pure products can be isolated by rapid solid phase extraction (spe) over fluorous silica in excellent yields. The fluorous fraction containing the flourous phosphine oxide and the flourous hydrazide can be separated and the starting reagents can be regenerated using appropriate redox reactions.
S. Dandapani, D. P. Curran, Tetrahedron, 2002, 58, 3855-3864.

A highly chemoselective PPh₃-catalyzed three-component reaction of an imine, alkyl vinyl ketone, and phthalimide or succinimide gives various highly functional adducts with high diastereoselectivities via aza-Morita-Baylis-Hillman reactions of aryl-substituted imines and alkyl vinyl ketones followed by Michael additions of imides and then epimerization.
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.

A modular, practical, and general palladium-catalyzed, radical three-component coupling enables selective 1,4-difunctionalization of unactivated 1,3-dienes, such as butadiene, by employing different commercially available nitrogen-, oxygen-, sulfur-, or carbon-based nucleophiles and unactivated alkyl bromides.
H.-M. Huang, P. Bellotti, P. M. Pfüger, J. L. Schwarz, B. Heidrich, F. Glorius, J. Am. Chem. Soc., 2020, 142, 10173-10183.

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.

N-acyl- and N-alkoxycarbonylaminophthalimides are efficiently used as acid partners in Mitsunobu reaction. This reaction allows them to be alkylated by primary, secondary or benzyl groups. A final dephthaloylation step results in an efficient method for the preparation of 1,1-substituted hydrazines.
N. Brosse, M.-F. Pinto, B. Jamart-Grégoire, J. Org. Chem., 2000, 65, 4370-4374.

Conversion of Phthalimides to Other Functional Groups

A ruthenium catalyst enables an unprecedented transformation of a wide range of phthalimides into amides in high yields and short reaction time in a single-step. The mechanism involces a unique, homogeneous pathway via five-membered ring opening and CO₂ release with water as source of protons.
Y.-C. Yuan, R. Kamaraj, C. Brunaeu, T. Labasque, T. Roisnel, R. Gramage-Doria, Org. Lett., 2017, 19, 6404-6407.

The use of a simple undivided cell with carbon electrodes enables an efficient and practical electrochemical reduction of cyclic imides at room temperature to provide hydroxylactams and lactams in a controllable manner, tuned by electric current and reaction time. The reaction exhibits broad substrate scope and high functional group tolerance.
Y. Bai, L. Shi, L. Zheng, S. Ning, X. Che, Z. Zhang, J. Xiang, Org. Lett., 2021, 23, 2298-2302.

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.