An unprecedented approach to the Gabriel amine synthesis utilizing tosylhydrazones as alkylating agents

Article abstract of DOI:10.1039/c4ra05929h

A new and one-pot version of the Gabriel phthalimide amine synthesis utilizing carbonyl compounds as alkylating agents via their tosylhydrazone surrogates is disclosed. The alkylation involves copper catalysed carbene insertion into the N-H bond of phthalimide. Basically, the protocol also offers a powerful tool for deoxygenative hydroamination of carbonyl compounds.

Full text of DOI:10.1039/c4ra05929h

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An unprecedented approach to the Gabriel amine
synthesis utilizing tosylhydrazones as alkylating
agents†
Cite this: RSC Adv., 2014, 4, 34764
Received 18th June 2014
Accepted 29th July 2014
*
Arvind K. Yadav and Lal Dhar S. Yadav
DOI: 10.1039/c4ra05929h
www.rsc.org/advances
A new and one-pot version of the Gabriel phthalimide amine synthesis S–H,6u N–H,6k,t P–H6n,p and H–F,6l we hypothesised that phtha-
utilizing carbonyl compounds as alkylating agents via their tosylhy- limide could be alkylated by carbene insertion into its N–H
drazone surrogates is disclosed. The alkylation involves copper cata- bond. Interestingly, the reaction worked well to offer a valuable
lysed carbene insertion into the N–H bond of phthalimide. Basically, modication of the Gabriel synthesis. Notably, this is the rst
the protocol also offers a powerful tool for deoxygenative hydro- report on N-tosylhydrazone generated carbene insertion into
amination of carbonyl compounds.
the N–H bond of an imide. Furthermore, this method is a
superior alternative to the synthesis of primary amines by
reductive amination of carbonyl compounds7 because it
advantageously avoids the over-alkylation of primary amines
formed and does not use any other reducing agent making the
protocol cost-effective and operationally simple. This new way
of access to N-alkylphthalimides is very important owing to
their great synthetic potential and pharmaceutical applications
as anticonvulsant, anti-inammatory, analgesic, hypolipidimic
and immunodulatory.8 Fascinated by the above points and in
continuation of our recent research focused on strategic
synthetic transformations involving carbonyl functionality,9,6l
we conducted the detailed study presented herein.
To start with, acetophenone (1a) derived N-tosylhydrazone
(1a0) was chosen as a model alkylting agent for phthalimide in
reuxing solvents under basic condition, and optimized results
are compiled in Tables 1 and 2. The key reaction was performed
with phthalimide (1.0 mmol), 1a0 (1.0 mmol), K2CO3 (3 equiv.)
in dioxane at 110 ꢀC to explore transition metal-free access to N-
alkylphthalimides, but unfortunately, it did not produce 2a
(Table 1, entry 1). The isolated compound was a mixture of cis
Amines constitute a prominent class of compounds found in a
wide variety of natural products, pharmaceuticals, agrochemi-
cals and organic materials.1 Particularly, primary amines are
very important precursors of most prevalent biologically rele-
vant structural moieties.2 The Gabriel phthalimide amine
synthesis is a historically important, straightforward and robust
tool for chemists to target the synthesis of structurally diverse
primary amines uncontaminated by secondary or tertiary amine
by-products.3
The Gabriel amine synthesis involves two main steps: (i) the
preparation of N-substituted phthalimides, and (ii) hydrolysis
or hydrazinolysis of N-substituted phthalimides to afford
primary amines (Scheme 1(a)).4 Several improvements in the
Gabriel synthesis have been suggested so far, but most of them
involve conversion of phthalimide into primary amines starting
from alkyl or aryl halides.5a Additionally, tosylates, epoxides and
esters have also been used in place of alkyl halides.5b However,
all of these are based on the same mechanistic theme, i.e. the N-
alkylation of phthalimide involving displacement reactions.
Thus, we were intrigued to develop a new approach to access N-
alkylphthalimides followed by their hydrazinolysis to afford
primary amines in a one-pot operation (Scheme 1(b)).
Inspired by the utilization of N-tosylhydrazones as efficient
carbonyl surrogates in synthetically useful transformations via
carbene insertion into various bonds, viz. C–H,6a,q,s,z O–H,6v
Green Synthesis Lab, Department of Chemistry, University of Allahabad,
Allahabad-211002, India. E-mail: ldsyadav@hotmail.com; Fax: +91 5322460533;
Tel: +91 5322500652
† Electronic supplementary information (ESI) available: For experimental details
and characterisation of all compounds. See DOI: 10.1039/c4ra05929h
Scheme 1 (a) The Gabriel amine synthesis, and (b) its modification.
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Table 1 Optimisation of reaction conditionsa
affected on increasing the catalyst loading from 10 mol% to 15
mol% (Table 1, entry 3 versus 6). On decreasing the reaction
temperature from 110 ꢀC to 80 ꢀC the yield was considerably
decreased (Table 1, entry 4). It is noteworthy that the desired
product 2a could not be obtained, when potassium phthalimide
was used instead of phthalimide (Table 1, entry 2).
Next, we examined the inuence of bases and solvents on the
reaction and Cs2CO3 was found to be the most effective among
the screened bases K2CO3, Na2CO3, KOH and BuOK (Table 2,
entry 2 versus 1, 3–5) and dioxane as the best medium among
the tested solvents viz. toluene, CH3CN and THF (Table 2, entry
2 versus 6–9).
The usual hydrazinolysis of N-(1-phenylethyl)phthalimide 2a
with hydrazine hydrate afforded the corresponding primary
amine 3a in 94% yield. Prompted by the easy preparation of N-
tosylhydrazones by the reaction of N-tosylhydrazides with
carbonyl compounds and mild hydrazinolysis of N-alkylph-
thalimides to alkyl amines using H2NNH2$H2O,10 we executed
the Gabriel synthesis starting directly from carbonyl
compounds in a sequential one-pot procedure as depicted in
Scheme 2. To our pleasant surprise, it worked well and afforded
the desired primary amine 3a in 92% yield (Scheme 2) without
the isolation of tosylhydrazone 1a0 and N-(1-phenylethyl)-
phthalimide 2a.
Entry
Catalyst (mol%)
Temp. (ꢀC)
Time (h)
Yieldb (%)
t
1
2
3
4
5
6
7
8
9
—
110
110
110
80
110
110
110
110
110
110
2
2
2
4
2
2
3
3
4
4
Trace
Tracec
96
76
72
96
82
77
67
CuI (10)
CuI (10)
CuI (10)
CuI (5)
CuI (15)
CuBr (10)
CuCl (10)
Cu2O (10)
Cu(OAc)2 (10)
10
59
a
Reaction conditions: phthalimide (1.0 mmol), 1a0 (1.0 mmol), catalyst
(5–15 mol%), Cs2CO3 (3 equiv.), dioxane (4 mL) under N2 for each entry
b
(for Experimental procedure: see, ESI). Isolated yield of product 2a.
c
Reaction was carried out with potassium phthalimide.
Table 2 Optimisation of base and solventa
The generality of this one-pot protocol was demonstrated
across a wide range of aldehydes and ketones, including
aromatic, hetrocyclic and aliphatic, which were converted into
the corresponding primary amines in good to excellent yields
(70–94%) and high purity (Table 3). A variety of substituents
such as Me, MeO, Me2N, F, Cl, Br and NO2 were tolerated. In
general, the substrate bearing an electron-withdrawing group
required longer reaction time and afforded lower yields of
primary amines as compared to those bearing an electron-
donating group (Table 3). Also, the reaction worked well on a
gram-scale (Table 3, foot note e).
On the basis of the experimental results and the literature
reports,6 a plausible mechanism for the N-alkylation of phtha-
limide using N-tosylhydrazones 10 is depicted in Scheme 3.
Thermolysis of N-tosylhydrazones 10 under basic conditions
generates carbene, which in situ forms a carbene copper
complex A. Finally, insertion of the carbene in to the N–H bond
of phthalimide affords the desired N-alkyl phthalimide 2
through transition state B.
Entry Base (equiv.) Solvent
Temp. (ꢀC) Time (h) Yieldb (%)
1
2
3
4
5
6
7
8
9
10
K2CO3 (3)
Cs2CO3 (3)
Na2CO3 (3)
KOH (3)
Dioxane 110
Dioxane 110
Dioxane 110
Dioxane 110
Dioxane 110
Toluene Reux
CH3CN
THF
Dioxane 110
Dioxane 110
2
2
2
2
3
3
4
4
2
2
86
96
72
68
79
76
57
67
74
96
tBuOK (3)
Cs2CO3 (3)
Cs2CO3 (3)
Cs2CO3 (3)
Cs2CO3 (2)
Cs2CO3 (4)
Reux
Reux
a
Reaction conditions: phthalimide (1.0 mmol), 1a0 (1.0 mmol), CuI (10
mol%), base (2–4 equiv.), solvent (4 mL) under N2 for each entry (for
Experimental procedure: see, ESI). b Isolated yield of product 2a.
In conclusion, we have demonstrated a signicant modi-
cation of the Gabriel amine synthesis. The protocol involves
copper catalysed reductive coupling of tosylhydrazones with
phthalimide followed by hydrazinolysis to afford primary
amines in a one-pot operation. Furthermore, the reaction could
be carried out in one-pot fashion starting directly from carbonyl
compounds without the isolation of their tosylhydrazones.
and trans-2,3-diphenyl-2-butenes in 67% yield, which might be
formed by dimerisation of the carbene (PhMeC) generated in
situ. Then, we turned our attention to copper catalysed cross
coupling reaction of N-tosylhydrazone 1a0 with phthalimide.
Thus, a catalytic amount of CuI (10 mol%) was used. To our
delight, this worked well and afforded the desired product 2a in
96% yields (Table 1, entry 3). Then, the optimisation of catalyst
and catalytic loading was performed, which demonstrated that
CuI was the most effective catalyst in comparison to CuCl, CuBr,
Cu2O and Cu(OAc)2 (Table 1, entry 3 versus 7–10). The effective
catalytic amount without affecting yield and time was 10 mol%,
because on decrease in amount from 10 mol% to 5 mol%
decreased the yield (Table 1, entry 3 versus 5). The yield was not
Scheme 2 One-pot deoxygenative hydroamination of acetophenone.
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Table 3 Substrate scope in the one-pot Gabriel synthesisa
Notes and references
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a
For the Experimental procedure: see, ESI. b Isolated yield of product 3.
All the products are commercially available were well characterized by
c
authentic sample (see, ESI). d Total time required for the conversion of 1
into 3. Reaction also works well on a gram scale with 1a (1.20 g, 10
e
mmol), TsNHNH2 (1.86 g, 10 mmol), phthalimide (1.47 g, 10 mmol),
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Scheme 3 Plausible mechanistic pathway for insertion of carbene into
the N–H bond of phthalimide.
Basically, this method also offers a superior alternative to the
reductive amination of carbonyl compounds because it avoids
the over-alkylation of primary amines formed and does not
require any additional reducing agent.
˘
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