Central Mindanao University

Musuan, Maramag, Bukidnon

Gabriel Synthesis
Levie Grace M. Traya
Department of Chemistry, Central Mindanao University, Musuan, Maramag, Bukidnon,
8710
A RTI C LE I N F O

ABSTRACT

Article history:
Date finished on May 2, 2015

The Gabriel synthesis is an organic reaction used to convert an alkyl halide to a primary am
using phthalimide with base and followed by hydrazine. The reaction begins with
deprotonation of the phthalimide which then attacks the alkyl halide in an SN2 fashion to g
an N-alkylphthalimide intermediate. The intermediate is then cleaved by hydrazine in a ser
of steps that end with the liberation of the final primary amine product and phthalhydrazide b
product. In this paper Gabriel synthesis was applied to the experiment on the synthesis
boron-containing primary amines where in this study, boron-containing primary amines w
synthesized for use as building blocks in the study of peptoids. In the first step, Gabr
synthesis conditions were modified to enable the construction of seven differ
aminomethylphenyl boronate esters in good to excellent yields. These compounds were furth
utilized to build peptoid analogs via an Ugi four-component reaction (Ugi-4CR) un
microwave irradiation. The prepared Ugi-4CR boronate esters were then successfu
converted to the corresponding boronic acids. Finally, the peptoid structures were successfu
modified by cross-coupling to aryl/heteroaryl chlorides via a palladium-mediated Suzu
coupling reaction to yield the corresponding derivatives in moderate to good yields.

Keywords:
Gabriel Synthesis
boron; multicomponent reactions
Ugi reaction
peptoid

1.

method is based on the fact that

the alkylation of

Introduction
2.
The Gabriel synthesis is a
chemical reaction that transforms
primary alkyl halides into primary
amines. Traditionally, the reaction
uses potassium phthalimide. The
reaction is named after the
German chemist Siegmund Gabriel.
The Gabriel reaction has been
generalized
to
include
the
alkylation of sulfon amides and
imides, followed by deprotection to
obtain amines. The utility of the

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3.
4.
5. ammonia is an unselective and
inefficient route to amines in the
laboratory(on an industriial scale,
the alkylation of ammonia is,
however, widely employed). The
conjugate
base
of
ammonia,
sodium amide (NaNH2), is more

basic than it is nucleophilic. In fact,

sodium
amide
is
used
to
deliberately
obtain
the
dehydrohalogenation product.
6.
7.
8. Mechanism
9. In
this
reaction,
potassium
phthalimide reacts with KOH. The
potassium
phthalimide
on
treatment with alkyl halides gives
N - alkyl phthalimide which on
gives pure primary amine [4].

16. Application: Synthesis of BoronContaining Primary Amines [1]

17. Data and results

Scheme 1. Stepwise mechanism of Gabriel

Synthesis

10. This
is
an
acid/base
reaction. The reaction starts with
the deprotonation of the imide N-H
group
proton
by
the
base,
hydroxide. This proton is more
acidic than a simple amine due to
the resonance stabilization by the
two adjacent C=O groups. This
generates a strong nucleophile.
The nucleophile then attacks the
electrophilic C of the alkyl halide
displacing the halide and creating
the new C-N bond. This product can
be compared to an N-alkyl amide.
The imide can be cleaved via a
mechanism analogous to that of
amides. Hydrolysis creates the
dicarboxylic acid and the required
amine. Presented below is the
stepwise reaction mechanism of
Gabriel synthesis.
11.
12.
13.
14.
15.

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Scheme 2. Overall mechanism of Gabriel Synthesis

18. Although there are many

synthetic methods that can be
used to prepare amines, strategies
for the specific synthesis of
primary amines are relatively
limited. The use of a reductive
amination reaction is one such
approach, whereby first an imine
intermediate is formed and then a
metal hydride reducing agent such
as sodium cyanoborohydride is
employed to reduce the imine
double bond. The use of a
protecting group is crucial when
using this method in order to
prevent over-alkylation, as an
unprotected starting material will
often result in the formation of
undesired secondary or tertiary
amine byproducts. However, this
need for the incorporation of a
protecting
group
presents
a
number
of
disadvantages,
including an increase in the total
number
of
synthetic
steps
(protection and deprotection steps)
and a decrease in atom economy.
An
alternative
strategy
for

producing primary amines is via

Gabriel synthesis. In this method,
the potassium salt of phthalimide is
reacted with a primary alkyl halide
to give the corresponding Nalkylphthalimide. This then reacts
with hydrazine to give the desired
primary amine. This synthetic
strategy avoids the formation of
secondary
or
tertiary
amine
byproducts without the need for a
protecting group. Although this is
one of the most commonly used
methods, the synthesis of boroncontaining primary amines via
Gabriel synthesis is relatively
unexplored. This is partly because
the reaction conditions are often
harsh, and there are concerns over
whether the boron functional group
can survive intact in such an
environment. In this report, we
demonstrate the synthesis of
boron-containing primary amines
via a modified Gabriel synthesis.
19. The synthesis proceeded
via the mixing of formylphenyl
boronic acid with pinacol and
magnesium sulfate in methanol to
give the corresponding boronate
ester. The progress was monitored
using 11B-NMR spectroscopy, and
when the reaction was seen to be
completed, the crude solution was
filtered. Sodium borohydride was
then added to the filtrate, and the
reaction was allowed to react at
room temperature for 5 hours to
afford the desired products 2ag in
good to excellent yields (Table 1).
20.
21. Although THF is often used
as the
involving

solvent in syntheses
phthalimide,
in
the

present study the desired product

could not be isolated using this as

3 | Page
* a In two steps; b 2a was also prepared
under similar synthetic conditions; c
preparation of 2f using different synthetic

either the solvent or co-solvent

(Table 2, entries 1 and 2). Instead
DMF was found to be the optimal
solvent for this reaction (Table 2,
entry 3). The use of 1.5 equiv. of
potassium phthalimide gave the
best yield (96%, entry 3), with a
reduced amount resulting in lower
yields (entries 4 and 5). In addition,
six further analogs 3ag were
successfully
synthesized
in
moderate
to
(entries 611).

excellent

yields

22.
23.
24.
25.
26.
27.
28.
29.
30.The next step involved the use of
the Ing-Manske procedure for the
synthesis
of
the
desired
aminomethylphenyl boronate ester from
the phthalimidophenyl boronate ester,
and optimization of the reaction
conditions. Initially, 3a was reacted with
six equivalents of hydrazine in ethanol
under reflux for 8 h, giving the desired
product 4a in poor yield (Table 3, entry
1). Increasing the reaction time in
addition to the amount of hydrazine

37.

* a 3a was also synthesized by the

similar synthetic
condition

used significantly improved the yield to

47% (Table 3, entry 2).
31.
32.Other solvent systems were also
investigated, and it was found that the
yield was improved from 47% to 73%
when methanol was used instead of
ethanol (entry 3). Additionally, the use
of THF improved the yield even further
from 73% to 87% (entry 4). By
employing these optimized conditions,
4bg were obtained in good to excellent
yield
(entries
510).
Interestingly,
phthalimidophenyl trifluoroborate failed
to
provide
the
desired
aminomethylphenyl
trifluoroborate
under the same reaction conditions, due
to stability issues of the boron moiety.
34. 33.
35.Three of the synthesized boroncontaining primary amines 4ac were
subsequently utilized as building blocks
for

the

microwave-assisted

Ugi-4CR

reaction, and the desired products 5ad

were successfully obtained in moderate
to good yields (Scheme 3).
36.

4 | Page

*a 4a was also synthesized by the similar synthetic

condition

38. After successful synthesis

of Ugi-4CR boronate esters 5ad,
transformation
into
the
corresponding boronic acids 6ac
was performed. The boronate
esters were first converted into
potassium
organotrifluoroborates
that then underwent hydrolysis to
give the desired boronic acids.
Although it was possible to isolate
each of the boronic acids, the
substrate bearing an electronwithdrawing group 5c gave a
particularly low yield over the two
steps Scheme 4.
39.
40.
41.

42.

43. The structural diversity of

the Ugi-4CR boronate esters was
further increased by using a
palladium-mediated
coupling
reaction,

Suzuki
where

aryl/heteroaryl
cross-coupled

were
boron-

chlorides
to
the

50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
63. REFERENCES
64.
1. Sheng-Hsuan

Ting-Ju

Lin, Qian-Yu Hu, Chia-Hua Tsai

and Po-Shen Pan. Synthesis of
Boron-Containing
Primary
Amines. 2013. Molecules 2013, 18,
12346-12367.
2. Z.-G. Le, Z.-C. Chen, Y. Hu, Q.G. Zheng, Synthesis. 2004.

containing analogs to give 8ab in

moderate to good yields (Scheme
5).

Chung,

44.

Organic
liquids:

Reactions in
N-Alkylation

Ionic
of

Phthalimide
and
Several
Nitrogen Heterocycles. 208212.
3. Organic

Chemistry

Portal.

(N.D.). Gabriel Synthesis.

4. Dr. Ian Hunt. (N.D.). Alkylation
45.
46.
47.
48.
49.

66.

5 | Page

of
Phthalimide
(Gabriel
synthesis of Primary Alkyl
Amines)
5. OChemPal.
Synthesis.
65.

2009.

Gabriel