Synthesis of 1,2 diamines under environmentally benign conditions: application for the preparation of imidazolidiniums

Article abstract of DOI:10.1016/j.tetlet.2009.12.072

An environmentally friendly and economically attractive access to unsymmetrical and symmetrical 1,2-diamines has been developed. Chemoselective N-monoalkylation in water and alcoholic solvents was demonstrated. This method represents a simple and scalable preparation (2-3 steps) of symmetrical and unsymmetrical imidazolidinium salts, precursors of N-Heterocyclic Carbenes.

Full text of DOI:10.1016/j.tetlet.2009.12.072

Tetrahedron Letters 51 (2010) 1265–1268
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of 1,2 diamines under environmentally benign conditions:
application for the preparation of imidazolidiniums
Stéphane P. Roche a,b, , Marie-Laure Teyssot b, Arnaud Gautier b,c,
*
a Department of Chemistry, Boston University, 590 Commonwealth Avenue, Boston, Massachusetts 02215, USA
b Clermont Université, Université Blaise Pascal, Laboratoire SEESIB, BP 10448, F-63000 Clermont-Ferrand, France
c CNRS, UMR 6504, SEESIB, 24 Avenue des Landais, F-63177 Aubière CEDEX, France
a r t i c l e i n f o
a b s t r a c t
Article history:
An environmentally friendly and economically attractive access to unsymmetrical and symmetrical 1,2-
diamines has been developed. Chemoselective N-monoalkylation in water and alcoholic solvents was
demonstrated. This method represents a simple and scalable preparation (2–3 steps) of symmetrical
and unsymmetrical imidazolidinium salts, precursors of N-Heterocyclic Carbenes.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 23 November 2009
Revised 9 December 2009
Accepted 11 December 2009
Available online 21 December 2009
Keywords:
1,2-Diamines
Imidazolidinium
The replacement of classical organic solvents by environmen-
tally friendly reaction media is of contemporary attention. Water
and alcohols are ideally suited for industrial purpose due to their
nontoxic character. Indeed, water has special characteristics which
are not encountered with other solvents such as high thermal
capacity, hydrophobic association, high polarity, and hydrogen-
bonding ability.1 Due to these properties, reactions in and ‘on’
water often show higher reaction rates, better selectivity and
yields than those performed in classical organic solvents.2
Within the course of a research program in the field of metal-N-
Heterocyclic Carbenes (NHCs) devoted to biological applications
and click reaction catalysis,3 a fast synthesis of various imidazolid-
inium cations was needed. NHCs, that constitute an important
class of ligand for multiple catalyzed chemical transformations,4
are generally obtained from their imidazolidinium precursors 1a–
b. The symmetrical imidazolidiniums 1a are classically obtained
in three steps: azadiene 3 formation from glyoxal 5 condensation
with a primary amine 6 followed by reduction yielding 1,2-dia-
mine 2a and cyclization (Scheme 1).5 The unsymmetrical imidazo-
lidinium 1b results from a sequential addition of two different
amines (6 and 13) to methyl oxalyl chloride6 10 or chloroacetyl
chloride7 14 followed by reduction to access to the unsymmetrical
1,2-diamine 2b (Scheme 1).8 In all cases, an oxidation level adjust-
ment along the synthesis is needed. Unfortunately this step proved
to be often problematic. We postulated that both symmetrical and
unsymmetrical 1,2 secondary diamines 2a–b could be accessed di-
rectly, avoiding any reduction step, from substitution on 1,2-diha-
logenoethane 7 or halogenoethylammonium 15 by substitution
reactions in one or two steps, respectively. We were then facing
the challenging preparation of symmetrical and unsymmetrical
1,2-diamines 2a–b in one or two steps, respectively.
Previous literature report
Ar NH2
6
ArN NAr
ArHN NHAr
N N
Ar
Ar
+
O
3
2a
1a
This work
X
O
5
X
7
ArNH2
ArHN NHAr
ArN NAr
+
6
1a
2a
X
X
Previous literature report
ArNH2
+
6
O
O
O
O
Cl
OMe
ArHN NHR
ArHN OMe
8
9
O
O
10
ArN NR
ArHN NHR
or
O
O
ArNH2
6
2b
1b
X
ArHN Cl
+
ArHN NHR
Cl
Cl
12
14
11
RNH
+
13
2
O
This work
ArN NR
ArNH2
NH3
6
+
ArHN NH2
2 HX
ArHN NHR
X
1b
2b
X
* Corresponding author. Tel.: +33 473 407 646; fax: +33 473 407 717.
E-mail address: Arnaud.Gautier@univ-bpclermont.fr (A. Gautier).
Present address: Department of Chemistry, Boston University, 590 Common-
wealth Avenue, Boston, Massachusetts 02215, USA.
15
X
16
Scheme 1. Symmetrical and unsymmetrical imidazolidiniums retrosynthesis.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.12.072

1266
S. P. Roche et al. / Tetrahedron Letters 51 (2010) 1265–1268
water, we were pleased to observe a selective N-monoalkylation
of mesitylamine 17a to provide the desired alkylated aniline 15a
in 60% yield.
R NH3
13 (pKa ~ 3)
X
H2
N
X( )
NH
3 X
2X
n
R
NH3
After numerous experiments, we noticed that 2 equiv of mesi-
tylamine 17a in more concentrated media (H2O, 6 M) for a shorter
reaction time (18 h) were the optimal conditions to obtain the de-
sired N-monoalkylated product 15a in 77% yield (Scheme 3, meth-
od B). Encouraged by these preliminary results, we decided to
extend this efficient and simple method to a larger set of aryl-
amines 17a–f (Table 1). Our protocol consists in using ‘on water’
conditions; a layer of aniline 17a–f (2.0 equiv) is stirred vigorously
for 18 h at 95 °C, in the presence of a 6M solution of 11a–c
(1.0 equiv) in water. Simple extraction of the resulting solution al-
lowed the recovery of unreacted anilines 17a–f, whereas the de-
sired products 15a–j remained in the aqueous phase and could
either be directly precipitated at 0 °C or concentrated to dryness
and further crystallized from alcohol. The reaction proceeded well
with mesitylamine 17a regardless of the nature of the alkylating
agent 16a–b (Br or Cl) and the chain length 16c (Table 1, entries
1–3). Aniline 17b as well as p-isopropylaniline 17c were also
prompt to produce the corresponding N-monoalkylated products
15d, 15e, and 15f in good yields with the various alkylating agents
(Table 1, entries 4–6). The substitution in para position by chloro
and acetamido groups did not affect the alkylation process, and
products 15g–i were obtained respectively in 51%, 58%, and 91%
yield, respectively, (Table 1, entries 7–9). On the other hand, 2,6-
diisopropylaniline 17f, due to the high steric hindrance surround-
ing the nucleophilic center and/or for hydrophobic reasons was
unreactive toward the different alkylating agents tested in water
(Table 1, entry 10).
X
16 (pKa ~ 11)
15
NH3
(1st pKa ~ 4, 2nd pKa ~ 11)
6 (pKa ~ 5)
H2
H2O
X( )
16
NH
3 X
N
2X
R NH2
+
n
R
NH3
15
?
13
Scheme 2. Influence of pKas on the N-monoalkylation of primary amines in water.
Generally, polyamines and 1,2-diamines,9 which are of great
importance in the chemical industry as basic and key intermedi-
ates, are obtained using harsh conditions or multistep sequences.
Secondary or tertiary amines could be prepared by reductive ami-
nation,10 amide reduction,11 oxidative coupling,12 hydroamina-
tion,10h–j,13 or N-alkylation.14 The last solution seemed to us the
most attractive, considering the desired oxidation state, and there-
fore a shorter number of steps to prepare the final imidazolidini-
ums 1a and 1b. We are presenting in this letter, our efforts for
the N-monoalkylation of amines in water and their further trans-
formation into imidazolidiniums (Scheme 1).
An important drawback for the N-alkylation of amines is the
formation of several polyalkylated/halogenated by-products, aris-
ing from multiple alkylation reactions, when alkyl halides are used.
Recently, some strategies have emerged to solve this long standing
problem of N-polyalkylation of primary and secondary amines
using either basic conditions (pH controlled),15 anhydrous cesium
hydroxide,16 or phase transfer catalysts.17 Along these elegant re-
ports and to the best of our knowledge, the direct N-monoalkyla-
tion of primary amines in water without any additive, taking
advantage of pKa difference between the primary amine (starting
material: alkyl- or aryl-amine) and the secondary amine (product)
has not yet been reported (Scheme 2).
The question was simple: could we N-monoalkylate the pri-
mary amine 13 and release the secondary ammonium salt 15 to
avoid N-polyalkylation? Our plan consisted in comparing the reac-
tivity of 6 (pKa ꢀ 5) and other primary alkylamines 13 (pKa ꢀ 3)
with bromoethylammonium 16a (pKa ꢀ 11) under basic and neu-
tral aqueous conditions (Scheme 3).18 As expected, the reaction
in the presence of base led to the formation of multiple unidenti-
fied side products, whereas the reaction in water produced the de-
sired N-monoalkylated mesitylamine 15a in 60% yield (Scheme 3).
We suspected that the bromoethylamine generated under basic
conditions could form the corresponding aziridine and multiple
side products. As the inspection of pKa values of N-monoalkylated
ammonium 16 (pKa ꢀ 11) and aniline 6 (pKa ꢀ 5) has revealed that
the proton exchange equilibrium is largely displaced toward the
former, we assume that the hydrobromide salt could act as the pro-
tecting group for 16 and diamine 15 and would avoid the forma-
tion of side products. Consequently, using base free conditions in
Kotschy and co-workers described the formation of N,N0-diary-
lated 1,2-diamines using Buchwald–Hartwig coupling or selective
reductive amination (at the primary amine site) to introduce an
arylmethyl moiety.7b Interested in the possible formation of fluo-
rescent NHCs, we proposed the introduction of a pyrenyl moiety
on an imidazolidinium precursor using a reductive amination reac-
tion (Scheme 4).3d The N-monoarylated 1,2-diamine dihydrobro-
mide salt 15a was thus condensed with 1-pyrenecarboxaldehyde
18 generating an imine intermediate, which was reduced in situ
with sodium cyanoborohydride to yield the unsymmetrical disub-
stituted 1,2-diamine. Further treatment with hydrochloric acid
afforded the 1,2-diamine dihydrochloride salt 19. Subsequent
cyclization using the orthoester condensation procedure provided
the desired unsymmetrical imidazolidinium 20, in three steps
and a 76% overall yield (Scheme 4).
After demonstrating the applicability and efficiency of our N-
monoalkylation in water, we examined the use of methanol, a sol-
vent that allows a better solubilization of all reactants and a de-
creased reaction temperature, for the preparation of symmetrical
N,N0-disubstituted 1,2-diamines 21 (Scheme 5).20 We were pleased
to observe that alkylation of mesitylamine 17a with 1,2-dibromo-
ethane 7 yielded the desired N,N0-diarylated 1,2-diamine dihyd-
robromide salt 21a in 56% yield (unoptimized). As expected the
N-alkylation of the hydrophobic adamantylamine proved to be
more difficult and the corresponding 1,2-diamine dihydrobromide
salt 21b was isolated in a modest 38% yield. Both 1-naphthylamine
and cyclohexylamine, less crowded substrates, furnished the de-
sired 1,2-diamines 21c and 21d in 57% and 65% yield, respectively,
as pure hydrobromide salts after a simple filtration.
H2O
Multiple
NaHCO3 Unidentified products
Br
NH2
NH3
2 Br
H2
N
Br
H2O
NH3
The formic acid catalyzed cyclisation reaction with trimethylor-
thoformate completed the synthesis of the symmetrical imidazo-
lidiniums 22a–c in excellent yields (Scheme 6).22 This new N-
monoalkylation protocol of alkyl and aryl amines resulted in a
two-step access to the common SIMes,HX imidazolidinium (1,3-
bis-(2,4,6-trimethylphenyl-1-yl)-imidazolidinium) 22a, and to the
less-examined SIAd,HX (1,3-bis-(adamantyl)imidazolidinium))
16a
17a
95°C, 30h
method A or B
15a 60-77%
Scheme 3. First result of N-monoalkylation in water. Method A: mesitylamine 17a
(1.0 equiv), bromoethylammonium 16a (1.0 equiv), H2O (1 M), 95 °C, 30 h (60%
yield); Method B: mesitylamine 17a (2.0 equiv), bromoethylammonium 16a
(1.0 equiv), H2O (6 M), 95 °C, 18 h (77% yield).

S. P. Roche et al. / Tetrahedron Letters 51 (2010) 1265–1268
1267
Table 1
Scope of the N-monoalkylation of arylamines in water19
H2
( )
NH3
n
X
H2O
( )
Ar NH2
17a-f
N
2X
NH3
Ar
X
95°C, 18h
n
16a: X=Br, n=1
16b: X=Cl, n=1
16c: X=Br, n=2
15a-j
Entry
1
Alkylating agent
Arylamine (Ar=)
Product
Yield (%)
H2
N
2 Br
2 Cl
16a
17a (C9H11
17a (C9H11
17a (C9H11
)
)
)
NH3
15a
71
70
72
H2
N
2
3
16b
16c
NH3
15b
H2
N
2 Br
NH3
15c
H2
N
2 Br
NH3
15d
H2
4
5
16a
16a
17b (C6H)
72
58
N
2 Br
NH3
15e
17c (C9H11
17c (C9H11
)
)
H2
N
NH3
2 Br
6
16c
40
15f
H2
N
NH3 2 Br
15g
7
8
9
16a
16c
16a
17d (C6H4Cl)
17d (C6H4Cl)
17e (C8H8NO)
51
58
91
Cl
Cl
H2
N
NH3
2 Br
15h
H2
N
NH3
2 Br
AcHN
H2
15i
N
2 Br
NH3
10
16a
17f (C12H17
)
0
15j
R1-NH2 (2 eq.)
CH3OH (12M)
H
N
H2
N
R1
2 HBr
Br
N
H
R1
O
Br
H2
N
i) MeOH,
N
7
21a-d
H2
then NaBH3CN
NH3
2 Br
+
ii) HCl
98%
2 Cl
H
N
15a
H
N
19
HC(OMe)3, H+
18
N
N
H
H
2 HBr
2 HBr
N
N
21a, 56%
21b, 38%
78%
Cl
20
H
N
H
N
N
H
Scheme 4. Preparation of unsymmetrical imidazolidinium 20.
N
H
2 HBr
2 HBr
21c, 57%
21d, 65%
22b and SINap,HX (1,3-bis(naphthalen-1-yl)-imidazolidinium)
22c.23 Notably, the preparation of SINap,HBr 22c by the known
azadiene method proved to be difficult and was achieved in the lit-
erature by a double Hartwig–Buchwald reaction. In our hands, the
reaction of 1-naphthylamine with glyoxal resulted systematically
in the formation of an untreatable black precipitate.
Scheme 5. Preparation of symmetrical N-monoalkylated or arylated 1,2-diamines
21a–d.21
1,2-diamines and unveiled primary amines reactivity for N-mono-
alkylation in water and methanol. This environmentally friendly
protocol, which represents the most simple and scalable prepara-
In conclusion, in this preliminary communication, we have
presented a valuable access to unsymmetrical and symmetrical

1268
S. P. Roche et al. / Tetrahedron Letters 51 (2010) 1265–1268
6. (a) Waltman, A. W.; Grubbs, R. H. Organometallics 2004, 23, 3105; (b) Hadei, N.;
2 HBr
R
H
H
HC(OMe)3
Kantchev, E. A. B.; O’Brien, C. J.; Organ, M. G. J. Org. Chem. 2005, 70, 8503; (c)
Meinhard, D.; Rieger, B. Chem. Asian J. 2007, 2, 386.
Br
N
N
R
N
R
R
N
HCO2H cat.
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21a-c
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N
N
N
N
Br
Br
22b, 96%
22a, 95%
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Tetrahedron 2008, 64, 1943.
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1996, 61, 6720. and references cited therein.; For a review see: (b) Müller, T. E.;
Hultzsch, K. C.; Yus, M.; Foubelo, F.; Tada, M. Chem. Rev. 2008, 108, 3795.
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R. N.; Durst, T. J. Org. Chem. 1998, 63, 3117; (c) Koh, K.; Ben, R. N.; Durst, T.
Tetrahedron Lett. 1993, 34, 4473; (d) Valot, F.; Fache, F.; Jacquot, R.; Spagnol, M.;
Lemaire, M. Tetrahedron Lett. 1999, 40, 3689; (e) Suga, K.; Watanabe, S.; Fujita,
T.; Pan, T. P. Bull. Chem. Soc. Jpn. 1969, 42, 3606.
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Jung, K. W. J. Org. Chem. 2002, 67, 674.
N
N
Br
22c, 93%
Scheme 6. Two-step synthesis of symmetrical imidazolidiniums 22a–c.
tion of these compounds in the literature, led to an efficient prep-
aration of several symmetrical and unsymmetrical imidazolidini-
um salts in two or three steps. However, for unsymmetric
compounds, our protocol is limited to derivatives bearing one aro-
matic substituent. We are currently studying the synthetic paths to
get around such limitations; results will be published in due
course.
Supplementary data
Supplementary data (procedures, copies of 1H and 13C spectra)
associated with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2009.12.072.
References and notes
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19. Typical experimental procedure for N-monoalkylation of amines in water: 2,4,6-
trimethylaniline (8.45 mL, 60 mmol) and 1,2-dibromoethane (6.15 g, 30 mmol)
were sequentially added at room temperature to water (15 mL). The two-
layered solution was vigorously stirred at 95 °C overnight. The solution was
cooled to room temperature and 15 mL of water was added. Extraction with
3 ꢁ 15 mL of EtOAc and evaporation of the aqueous phase furnished a brown
solid which was recrystallized from MeOH/EtOAc to yield 7.1 g (21 mmol, 70%)
of 15a as a white solide.
20. Ethanol and isopropanol were also tested but with poor success.
21. Procedure for the preparation of (N,N0-dicyclohexyl) 1,2-ethanediamine
dihydrobromide 21d in alcoholic solvent: Cyclohexylamine (20.0 g, 202 mmol,
3.0 equiv) and 1,2-dibromoethane (12.6 g, 67.0 mmol, 1.0 equiv) were
sequentially added at room temperature to methanol (50 mL). The solution
was vigorously stirred under reflux overnight. The solution was evaporated
under reduced pressure to furnish a brown solid which was triturated with
acetone (40 ml), filtrated, and washed with acetone to yield 16.7 g of
compound 21d as a white solid (65%).
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