Suggested improved method for the Ing-Manske and related reactions for the second step of gabriel synthesis of primary amines

Article abstract of DOI:10.1081/SCC-200043164

This work demonstrates an improvement in the Ing-Manske and related procedures by the increase of pH of the reaction mixture after the complete disappearance of N-substituted phthalimide. Hydrazinolysis of N-phenylphthalimide (1a) gave 80% of the desired primary amines after 5.3 h in the absence of added NaOH. The reaction time was reduced to 1.6 h and 1.2 h when 1 eq. and 5eq. of NaOH were added to the reaction mixture after the complete disappearance of 1a. Hydroxyaminolysis of N-(4-ethylphenyl)phthalimide (1b) gave 80% of the desired primary amines after 7.5 h of reaction time (at added [NaOH] = 0). When 10 eq. and 20 eq. of NaOH were added to the reaction mixture after the disappearance of Ib, the reaction time was reduced to 4 h and 2 h, respectively. Methylaminolysis of N-(2-ethylphenyl)phthalimide (1c) gave 80% of the desired primary amines after 1.7 h (at added [NaOH] = 0). The reaction time was reduced to 1 h and 0.7 h when 1 eq. and 25 eq. of NaOH were added to the reaction mixture after the complete disappearance of 1c.

Full text of DOI:10.1081/SCC-200043164

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Suggested Improved Method
for the Ing‐Manske and
Related Reactions for the
Second Step of Gabriel
Synthesis of Primary Amines
Azhar Ariffin a , Mohammad Niyaz Khan a , Lai
Chwee Lan a , Fan Yen May a & Chien Siew Yun a
a Department of Chemistry, Faculty of Science,
University of Malaya, 50603, Kuala Lumpur,
Malaysia
Version of record first published: 10 Jan 2011.
To cite this article: Azhar Ariffin, Mohammad Niyaz Khan, Lai Chwee Lan, Fan
Yen May & Chien Siew Yun (2004): Suggested Improved Method for the Ing‐Manske
and Related Reactions for the Second Step of Gabriel Synthesis of Primary Amines,
Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 34:24, 4439-4445
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SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 24, pp. 4439–4445, 2004
Suggested Improved Method for the
Ing-Manske and Related Reactions for the
Second Step of Gabriel Synthesis of
Primary Amines
*
Azhar Ariffin, Mohammad Niyaz Khan, Lai Chwee Lan,
Fan Yen May, and Chien Siew Yun
Department of Chemistry, Faculty of Science, University of Malaya,
Kuala Lumpur, Malaysia
ABSTRACT
This work demonstrates an improvement in the Ing-Manske and related
procedures by the increase of pH of the reaction mixture after the com-
plete disappearance of N-substituted phthalimide. Hydrazinolysis of
N-phenylphthalimide (1a) gave 80% of the desired primary amines
after 5.3 h in the absence of added NaOH. The reaction time was
reduced to 1.6 h and 1.2 h when 1 eq. and 5 eq. of NaOH were added to
the reaction mixture after the complete disappearance of 1a. Hydroxyami-
nolysis of N-(4-ethylphenyl)phthalimide (1b) gave 80% of the desired
*
Correspondence: Azhar Ariffin, Department of Chemistry, Faculty of Science,
University of Malaya, 50603 Kuala Lumpur, Malaysia; Fax: 603-79674193; E-mail:
azhar70@um.edu.my.
4439
DOI: 10.1081/SCC-200043164
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

4440
Ariffin et al.
primary amines after 7.5 h of reaction time (at added [NaOH] ¼ 0). When
10 eq. and 20 eq. of NaOH were added to the reaction mixture after
the disappearance of 1b, the reaction time was reduced to 4 h and 2 h,
respectively. Methylaminolysis of N-(2-ethylphenyl)phthalimide (1c)
gave 80% of the desired primary amines after 1.7 h (at added
[NaOH] ¼ 0). The reaction time was reduced to 1 h and 0.7 h when
1 eq. and 25 eq. of NaOH were added to the reaction mixture after the
complete disappearance of 1c.
Key Words: Gabriel synthesis; Ing-Manske procedure; N-substituted
phthalimides; Aminolysis.
INTRODUCTION
Gabriel synthesis for the synthesis of primary amines involves two major
steps: (1) the synthesis of N-substituted phthalimides from halides and (2) the
synthesis of primary amines from N-substituted phthalimides.[1] The deprotec-
tion of primary amines from phthalimide building block involves either hydroly-
sis, whether acid- or base-catalyzed or hydrazinolysis (the Ing-Manske
procedure).[2] Osby, Martin, and Ganem[3] have reported the conversion of
phthalimides to primary amines in a two-stage operation using NaBH4/2-propa-
nol and then acetic acid. Several alternatives to Gabriel synthesis have been
recently reported.[2] An improved Ing-Manske procedure, which requires
shorter reaction time and milder reaction condition compared with the conven-
tional method, was observed.[4] Based upon the kinetic data on the cleavage of
phthalimide in the presence of hydrazine buffer, it was suggested that the
increase of pH of the reaction mixture after the complete disappearance of
N-substituted phthalimide, 1, should improve the Ing-Manske procedure.[5]
The present work was initiated with an aim to provide supports for this proposal
based upon synthetic data obtained in mixed CH3CN-H2O solvent. The details of
the procedure and results are described in this paper.
RESULTS AND DISCUSSION
Hydrazine, hydroxylamine, and methylamine were used as the reagents in
the Ing-Manske and related procedures to synthesize primary amines from 1.
The products and percentage yields were determined by GC with the addition
of an internal standard. The results for different phthalimides with different
reagents are shown in the Figs. 1, 2, and 3.
Figures 1, 2, and 3 clearly show that by increasing the pH of the reaction
mixture after the complete disappearance of 1 decreases the reaction time for

Improved Ing-Manske Procedure for Synthesis of Amines
4441
Figure 1. Plot of percentage yield against time (h) for hydrazinolysis of 1a without
and with addition of NaOH.
Figure 2. Plot of percentage yield against time for hydroxyaminolysis of 1b without
and with the addition of NaOH.

4442
Ariffin et al.
Figure 3. Plot of percentage yield against time (h) for methylaminolysis of 1c with-
out and with addition of NaOH.
80% recovery of the desired primary amines. Methylaminolysis of 1c gave 80% of
2-ethylaniline in about 1.7 h. Addition of 1 eq. NaOH after complete disappear-
ance of 1c decreased the reaction time to 1h, and to 0.7h if 25eq. of NaOH
was added. For hydrazinolysis of 1a, 80% of the aniline was isolated after
5.3 h. Addition of 1 eq. NaOH decreased the reaction time to 1.6 h and to 1.2 h
if 5 eq. of NaOH was added. For hydroxylaminolysis of 1b, 80% of the 4-ethylani-
line was isolated after a reaction time of 7.5 h. Addition of 10 eq. NaOH after com-
plete disappearance of 1b decreased the reaction time to 4 h and further reduction
of the reaction time (2 h) was obtained when 20 eq. of NaOH was added.
In terms of known facts[6] on the cleavage of phthalimide and 1 in aqueous
buffer solutions of primary amines, the overall reaction scheme for the cleavage
of 1 in the presence of primary amines (R0NH2) may be shown in Sch. 1. The
cyclization of 2 to 3 is expected to involve specific base (HO2) catalysis.[6]
The rates of conversion of 3 to 2, 2 to 1, and 1 to 4 can be greatly reduced if
[R0NH2]/[1] ꢀ 10. The rate of formation of RNH2 from 4 (i.e., second step of
usual Gabriel synthesis) under mild alkaline medium is extremely slow (the
half-life period, t1/2 ꢁ 264 h at 0.1 M NaOH, 1024 M 4 and 608C).[5] It is

Improved Ing-Manske Procedure for Synthesis of Amines
4443
Scheme 1.
obvious from Sch. 1, that in order to increase the rate of formation of RNH2 from
2, the pH of the reaction mixture should be increased only when 1 has comple-
tely disappeared. If NaOH is added to the reaction mixture at the start of reac-
tion, then added NaOH would increase the rate of formation of 4 and
consequently the yield of RNH2 would be decreased.
These results also indicated that methylamine is a better reagent for
aminolysis compared to hydrazine and hydroxylamine. This may be due to the
fact that methylamine is a stronger base (pKa ¼ 10.85)[7] compared to the other
two amines (NH2NH2, pKa 8.15 and NH2OH, pKa 5.97).[7] These results demon-
strate a faster, convenient, and mild reaction condition to deprotect the primary
amines and serve as an improved method for the second step in Gabriel synthesis.
EXPERIMENTAL
Materials
All the chemicals used were of reagent grade and were obtained from
Merck, Aldrich, and Fluka. Glass-distilled water was used throughout, and

4444
Ariffin et al.
the stock solutions of aniline and internal standard were prepared in aceto-
nitrile. The N-substituted phthalimide 1 was prepared according to the litera-
ture procedure.[8]
(a) Preparation of standard curve for aniline: Stock solutions of aniline
(0.8 M) and internal standard N,N-dimethylaniline (1.13 M) were prepared
in acetonitrile. A series of solution with different numbers of moles of
aniline and fixed amounts of N,N-dimethylaniline were prepared as follows:
Aniline (0.13 mL of 0.8 M) and N,N-dimethylaniline (0.10 mL of 1.13 M)
were pipetted into a 25-mL separating funnel. Water (10 mL) was added
and the solution was extracted with ethylacetate (5 ꢂ 10 mL). The organic
layer was separated and dried with Na2SO4 anhydrous and evaporated under
reduced pressure. The resulting residue was transfered quantitatively into a
sample vial using ether and blow-dried with nitrogen gas. Acetonitrile
(1.00 mL) was pipetted into the sample vial for GC analysis. A series of sol-
ution containing 0.0001 mole to 0.0005 mole of aniline and 0.00011 mole of
N,N-dimethylaniline was prepared. From the GC results a plot of ratio of peak
area vs. number of moles of aniline was obtained.
(b) Hydrazinolysis of N-phenylphthalimide: In a typical hydrazinolysis
reaction: 1a (1.03 g, 4.61 mmole) was dissolved in acetonitrile (50.0 mL) in
a 250-mL, two-neck round-bottom flask. Water (47.77 mL) and hydrazine
hydrate (2.23 mL, 46.05 mmole) were added to the reaction mixture. The reac-
tion mixture was stirred vigorously at room temperature, then 10 mL of
the reaction mixture was pipetted out after a designated time interval. The
solvent was evaporated under reduced pressure. N,N-dimethylaniline
(0.10 mL of 1.13 M) and 10.00 mL H2O were added to the evaporated reaction
mixture. The purification and GC analysis are the same as in method (a). From
the GC results, the amount of aniline obtained was determined from the stan-
dard curve prepared in (a).
(c) Hydrazinolysis of N-phenylphthalimide with added NaOH: In a typical
hydrazinolysis reaction, the known amount of NaOH was added after thin-
layer chromatography (TLC) indicated complete disappearance of 1a, the
reaction mixture was stirred at room temperature, and then 10 mL of the reac-
tion mixture was pipetted out after a designated time interval. The purification
and GC analysis of samples are the same as in (a). Similar procedures (as in a,
b, and c) were used in the hydroxyaminolysis and methylaminolysis of 1b and
1c, respectively.
ACKNOWLEDGMENTS
We wish to thank the University of Malaya for financial support (Vote
F0718/2002B) and IRPA (Grant No. 09-02-03-0147).

Improved Ing-Manske Procedure for Synthesis of Amines
REFERENCES
4445
1. Gibson, M.S.; Bradshaw, R.W. Gabriel synthesis of primary amines.
Angew. Chem., Int. Ed. Engl. 1968, 7, 919–930.
2. (a) March, A. Advanced Organic Chemistry: Reactions, Mechanisms and
Structures, 4th Ed.; John Wiley & Sons: New York, 1992; 426 and refer-
ences cited therein; (b) Georges, T.; Bonnet, A. An enantioselective
synthesis of a 4-fluoromethylazetidinone. Tetrahedron Lett. 1984, 25,
1561–1562.
3. Osby, J.O.; Martin, M.G.; Ganem, B. An exceptionally mild deprotection
of phthalimides. Tetrahedron Lett. 1984, 25, 2093–2096.
4. (a) Wu, W.; Zhang, Y. Enantioselective synthesis of a-amino acids in
chiral reverse micelles. Tetrahedron: Asymmetry 1998, 9, 1441–1444;
(b) Brosse, N.; Pinto, M.-F.; Brodiguel, J.; Jamet-Gregoire, B. A new syn-
thetic route to protected a-hydrazinoesters in high optical purity using the
Mitsunobu protocol. J. Org. Chem. 2001, 66, 2869–2873; (c) Alex, M.A.;
Michael, H.G. Phthalimide resin reagent for efficient Mitsunobu amino-
dehydroxylation. Tetrahedron Lett. 1998, 39, 4947–4950.
5. Khan, M.N. Suggested improvement in the Ing-Manske procedure and
Gabriel synthesis of primary mines: Kinetic study on alkaline hydrolysis
of N-phthaloylglycine and acid hydrolysis of N-(o-carboxybenzoyl)gly-
cine under H2O-MeCN solvents. J. Org. Chem. 1996, 61, 8063–8068.
6. (a) Shafer, J.A.; Marawetz, H. Participation of the neighboring amide
group in the decomposition of esters and amides of substituted phthalamic
acids. J. Org. Chem. 1963, 28, 1899–1901; (b) Khan, M.N. The kinetics
and mechanism of a highly effective intra-molecular nucleophilic reac-
tion. The cyclization of ethyl N-[o-(N-hydroxycarbamoyl)benzoyl]carba-
mate to N-hydroxy-phthalimide. J. Chem. Soc. Perkin Trans. 2 1988,
213–219; (c) Khan, M.N. Kinetic evidence for the occurrence of a step-
wise mechanism in hydrazinolysis of phthalimide. J. Org. Chem. 1995,
60, 4536–4541.
7. Khan, M.N. Intramolecular general base catalysis and the rate-determining
step in the nucleophilic cleavage of ionized phenyl salicylate with
primary and secondary amines. J. Chem. Soc. Perkin Trans. 2 1989,
199–207 and references cited therein.
8. Sim, Y.L.; Ariffin, A.; Khan, M.N. Effects of mixed aqueous-organic sol-
vents on the rate of intramolecular carboxylic group-catalyzed cleavage
of N-(40-methoxyphenyl)phthalamic acid. Int. J. Chem. Kinet. 2004, 36,
316–325.
Received in India August 6, 2004