Palladium-catalyzed multicomponent synthesis of 2-imidazolines from imines and acid chlorides

Article abstract of DOI:10.3390/molecules171213759

We describe the palladium-catalyzed multicomponent synthesis of 2-imidazolines. This reaction proceeds via the coupling of imines, acid chlorides and carbon monoxide to form imidazolinium carboxylates, followed by a decarboxylation. Decarboxylation in CHCl3 is found to result in a mixture of imidazolinium and imidazolium salts. However, the addition of benzoic acid suppresses aromatization, and generates the trans-disubstituted imidazolines in good yield. Combining this reaction with subsequent nitrogen deprotection provides an overall synthesis of imidazolines from multiple available building blocks.

Full text of DOI:10.3390/molecules171213759

Molecules 2012, 17, 13759-13768; doi:10.3390/molecules171213759
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Communication
Palladium-Catalyzed Multicomponent Synthesis of
-Imidazolines from Imines and Acid Chlorides
2
Boran Xu, Kraig Worrall and Bruce A. Arndtsen *
Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montreal, QC H3A 2K6,
Canada; E-Mails: boran.xu@mail.mcgill.ca (B.X.); kraig.worrall@gmail.com (K.W.)
*
Author to whom correspondence should be addressed; E-Mail: bruce.arndtsen@mcgill.ca;
Tel.: +1-514-398-6903; Fax: +1-514-398-3797.
Received: 25 October 2012; in revised form: 13 November 2012 / Accepted: 14 November 2012 /
Published: 22 November 2012
Abstract: We describe the palladium-catalyzed multicomponent synthesis of 2-imidazolines.
This reaction proceeds via the coupling of imines, acid chlorides and carbon monoxide to
form imidazolinium carboxylates, followed by a decarboxylation. Decarboxylation in
3
CHCl is found to result in a mixture of imidazolinium and imidazolium salts. However,
the addition of benzoic acid suppresses aromatization, and generates the trans-disubstituted
imidazolines in good yield. Combining this reaction with subsequent nitrogen deprotection
provides an overall synthesis of imidazolines from multiple available building blocks.
Keywords: 2-imidazoline; palladium; catalysis; multicomponent synthesis
1
. Introduction
-Imidazolines, the 4,5-reduced counterpart of imidazoles, are an important class of small
2
molecules. The skeletal core of imidazolines can be found in many biological active compounds, including
anti-cancer agents [1,2], antidepressants [3,4], analgesics [5,6], and anti-inflammatory agents [7,8]. In
addition, imidazolines are useful in coordination chemistry, serving as N-donor ligands in various
transition metals complexes [9–11] or as precursors to N-heterocyclic carbenes [12,13].
The traditional method to synthesize imidazolines involves the coupling of a 1,2-diamine with an
appropriate condensation partner, such as aldehydes, esters, amides or imidates [14–18]. More
recently, other synthetic routes to imidazolines have been reported, including the ring opening of
aziridines [19,20], the reaction of imines with isocyanates [21–23], and the cycloaddition of imines to

Molecules 2012, 17
13760
azomethine ylides [24]. While these methods are each effective, they often require the use of synthetic
precursors which can themselves require a multistep synthesis. This can make it challenging to both
generate polysubstituted imidazolines, and to diversify their structure to modify properties.
We have previously reported a palladium-catalyzed multicomponent synthesis of imidazolinium
carboxylates from imines, acid chlorides and CO (Scheme 1) [25–27]. Transition-metal catalyzed
multicomponent reactions have emerged as a powerful tool in synthesis as they can allow the
controlled assembly of multiple simple units directly into complex products [28–33]. The generation of
1
proceeds via imine cycloaddition to an in situ generated münchnone (Scheme 1). This reactivity is
similar to alkene cycloaddition to münchnones, which, upon themolysis, can undergo decarboxylation
to yield pyrrolines [34,35]. As such, we became interested in the analogous reaction of 1. The latter
could provide a modular assembly of imidazolines. Tepe and co-workers have recently reported that
similar 2-imidazoline carboxylates can undergo thermal decarboxylation under certain conditions [36].
This observation prompted us to investigate decarboxylation as a platform to access substituted
imidazolines from 1.
Scheme 1. Palladium catalyzed synthesis of imidazolinium carboxylates.
2
. Results and Discussion
In order to test the viability of this chemistry in imidazoline synthesis, imidazolinium carboxylate
1
4
2
3
5
1
a (R , R = benzyl, R , R , R = phenyl) was prepared via the palladium catalyzed multicomponent
(2-biphenyl)]. The heating of 1a in CDCl at 65 °C
synthesis shown in Scheme 1 [JOHNPHOS = P(t-Bu)
2
3
for 6 h leads to the complete conversion of starting compound and the formation of three products,
identified as the trans- and cis-isomers of the imidazolinium 2a, as well as the aromatized imidazolium
3
a in yields of 59:16:13, respectively (Scheme 2) [37]. The thermal decarboxylation of 1a presumably
proceeds via the initial loss of CO to generate the ylide 1a', which could either be protonated by the
2
solvent (compound 2a) or undergo oxidation to form 3a. To favor the generation of 2a, we examined
the influence of acids on the reaction. As shown in Table 1, performing the decarboxylation with one
equivalent of benzoic acid leads to the exclusive formation of the imidazoline in 78% yield (entry 1).
Other organic carboxylic acids are also effective, and result in similar yields and selectivities (entries 2–3).

Molecules 2012, 17
13761
Scheme 2. Thermal decarboxylation of imidazolinium carboxylates.
Ph
Ph
Ph
Ph
CHCl3
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
N
N
N
N
N
N
N
N
o
6
5 C
Ph
CO2
6
h
Ph
Ph
trans-2a
9%
Ph
Ph
Ph
Ph
Ph
1
a
cis-2a
16%
3a
13%
5
Ph
Bn
Bn
N
N
Ph
Ph
1
a'
Table 1. Influence of acids on the generation of imidazolinium salts.
o
Ph
Ph
Ph
6
5 C
6
h
Bn
Bn
Bn
Bn
Bn
Bn
N
N
N
N
N
N
+
Acid
+
Ph
CO2
CHCl3
Ph
Ph
Ph
Ph
Ph
cis-2a
trans-2a
1a
Entry
Acid
Yield 2a
trans : cis 2a
1
78%
3.2:1
O
2
3
78%
87%
2.7:1
2.7:1
H C
3
OH
a
4
5
HCl
-
-
-
a
-
a
6
7
-
-
24%
86%
1.5:1
8
9
20:1
-
b
H O (20 equiv.)
2
-
Reaction conditions: 1a (0.1 mmol) and acid (0.1 mmol) in 5 mL CHCl
3
a
heated at 65 °C for 6 h. Yields
1
determined by H-NMR relative to a benzyl benzoate internal standard. Recovery of protonated starting
b
material. Decomposition of starting material.
In all cases, no significant amount of aromatized product 3a is observed, indicating a rapid
protonation of the ylide intermediate. The use of stronger acids did not lead to decarboxylation

Molecules 2012, 17
13762
(
entries 4–6). In addition, the use of a large excess of benzoic acid inhibited the reaction (entry 7). This
suggests that the decarboxylation occurs from zwitterionic 1a.
The above reactions all generate imidazolium salt 2a as a mixture of stereoisomers. However,
during our studies on this decarboxylation, we were surprised to find that the use of wet chloroform
solvent significantly favored the generation of trans-2a over the cis-isomer. This can be performed in a
more controlled fashion, where the addition of an excess of water (20 equiv.) with benzoic acid leads
to the formation of trans-2a in 86% yield, and almost completely suppresses the cis-product (entry 8).
The mechanism by which water influences the protonation is not known, although a control
experiment using water without acid leads to decomposition of the starting material (entry 9),
suggesting water in concert with benzoic acid results in a proton source that favors proton transfer on
the same face as the pendant aromatic unit.
This sequence of palladium catalyzed multicomponent coupling and decarboxylation provides a
method to selectively generate trans-substituted imidazolinium salts. As imines are readily available
from aldehydes and amines, it is straightforward to synthesize asymmetrically substituted
imidazolines. This can include the incorporation of orthogonal nitrogen protecting groups. For
example, imidazolinium carboxylate 1b bearing both N-allyl and N-para-methoxybenzyl (PMB)
protecting groups can be generated through palladium catalysis (Scheme 3). Subsequent
decarboxylation followed by deallylation yields imidazoline 4b. Alternatively, the para-methoxybenzyl
group can be cleaved from imidazolinium cation 2b, affording imidazoline 5b.
Scheme 3. Nitrogen deprotection of imidazolines.
1
0% Pd(PPh3)4
Ph
PhSiH3
PMB
DCM, rt, 16 h
N
N
Ph
Ph
4
7
b
Ph
Ph
5%
PhCO H
H O
2
2
PMB
PMB
trans:cis = 13:1
N
N
N
N
Ph
CO2
CHCl
3
Ph
Ph
Ph
1. BBr3
o
6
5 C
Ph
2b
o
1b
DCM 0 C
6
h
2
h
N
N
2
. 1M NaOH
Ph
Ph
15 min, rt
5b
40%
trans:cis = 20:1
As an illustration of the versatility of this approach, a number of orthogonally substituted
imidazolines have been generated via the palladium catalyzed synthesis of 1 and selective
decarboxylation (Scheme 4). The substituents of the imidazoline core can be varied by choosing the
appropriate imine(s) and acid chloride, while functional groups such as esters, aryl ethers, alkenes and
aryl-halides are all tolerated. This modularity can allow for the rapid synthesis of imidazolines with
independent control of four separate substituents.

Molecules 2012, 17
13763
Scheme 4. Modular synthesis of imidazolines.
3. Experimental
3.1. General Considerations
All solvents used were dried by passage through a column of alumina prior to use. All common
reagents were purchased from Aldrich (Oakville, Canada) and used as received unless otherwise noted.
Pd(PPh was purchased from Strem (Boston, MA, USA) and stored in a nitrogen glovebox. Imines
were synthesized by the condensation of the appropriate aldehyde and amine in the presence of MgSO
3 4
)
4
and purified by distillation under vaccum, according literature methods [38]. Amide-chelated palladium
catalysts were synthesized according to a literature protocol [39]. N,N-diisopropylethylamine was
2
distilled over CaH prior to use. Carbon monoxide was purchased at 99.99% purity MEGS (Montreal,
Canada) and used as received. NMR characterization was performed at 300 MHz, 400 MHz and
1
13
5
1
00 MHz for H-NMR and 75 MHz and 126 MHz for C-NMR on Varian spectrometers. Resonances at
1
3
45.5 and 53.2 ppm in the C-NMR spectra are artifacts generated during data collection and do not
represent real product signals. Chemical shifts are reported in parts per million relative to the residual
solvent signal. Mass spectra were recorded on a Agilent LC-MSD TOF high-resolution electrospray
ionization quadrupole spectrometer.
3
.2. Synthesis of trans-1,3-Dibenzyl-2,4,5-triphenyl-4,5-dihydro-3H-imidazol-1-ium (trans-2a) and
cis-1,3-Dibenzyl-2,4,5-triphenyl-4,5-dihydro-3H-imidazol-1-ium (cis-2a)
Imidazolinium carboxylate 1a (52.2 mg, 0.100 mmol) and benzoic acid (12.2 mg, 0.100 mmol)
were dissolved in CHCl (5 mL). Benzyl benzoate (10 μL) was added as an internal standard and an
3
1
aliquot of this mixture was taken for H-NMR analysis. Water (36 μL, 2 mmol) was added by
micropipette and the vial was capped and heated at 65 °C for 6 h. The solvent was then removed and

Molecules 2012, 17
13764
1
the yield of the products was determined by H-NMR analysis in CDCl . The identity of cis- and
3
trans-2a was determined by the palladium-catalyzed cleavage of the benzyl protecting groups
(5 mol% Pd(OH)
2
, AcOH, 65 °C, 48 h), and comparing the resulting imidazoline to previously
reported compounds [16,40].
3
.3. Synthesis of 1,3-Dibenzyl-2,4,5-triphenyl-3H-imidazol-1-ium (3a)
In a septum sealed NMR tube, 1-benzyl-2,4,5-triphenyl-1H-imidazole [41] (19.5 mg, 0.05 mmol)
was dissolved in CDCl (1.5 mL). Benzyl bromide (9.0 μL, 0.075 mmol) was added by microsyringe.
3
The tube was heated at 75 °C for 3 days. The solvent was removed in vacuo and the resulting residue
2 2
was redissolved in CH Cl (500 μL). Diethyl ether (10 mL) was slowly layered on top of this solution,
resulting in the precipitation of a white solid. This solid was further triturated with diethyl ether to
1
afford 3a as a white solid. (12.2 mg, 43%) H-NMR (500 MHz, CDCl
3
): δ 8.00–7.99 (m, 1H),
7
6
1
4
.56–7.53 (m, 3H), 7.46 (t, J = 7.7 Hz, 1H), 7.32–7.29 (m, 1H), 7.27–7.23 (m, 2H), 7.20–7.14 (m, 3H),
1
3
.76–6.75 (m, 2H), 5.25 (s, 2H). C-NMR (126 MHz, CDCl ): δ 145.1, 134.1, 132.8, 132.3, 131.5,
3
+
31.4, 130.0, 129.4, 128.8, 128.7, 128.2, 127.1, 125.4, 122.1, 50.7 HRMS (ESI): C35
77.23359 observed; 477.23253
H
29
N
2
(M) calcd;
3
.4. Synthesis of 1-(4-Methoxy-benzyl)-2,4,5-triphenyl-4,5-dihydro-1H-imidazole (4b)
Compound 1b was prepared according to a literature procedure [25]. In a glovebox under nitrogen
atmosphere, (4-CH )HC=NCH (4-C OCH ) (67.8 mg, 0.300 mmol) and benzoyl chloride
54.8 mg, 0.390 mmol) were dissolved in CH
3
C
6
H
4
2
6
H
4
3
(
3
CN (5 mL). The mixture was then transferred to a 50 mL
2
thick walled Schlenk tube and allowed to stir for 15 min. [Pd(Cl)[ -CH(4-CH
3
C
6
H
4
)-NCH
2
(4-
6 4 2 2
C H OMe)COPh]] (14.2 mg, 0.015 mmol), P(t-Bu) (2-biphenyl) (13.4 mg, 0.045 mmol) and
N,N-diisopropylethylamine (50.3 mg, 0.390 mmol) were combined in THF (5 mL) and added to the
mixture. The solution was stirred for 5 min before the Schlenk tube was briefly evacuated, brought
outside of the glovebox, charged with 4 atm of CO, and heated at 45 °C for 16 h. The CO atmosphere
was replaced with nitrogen, the tube was brought into the glovebox, and PhHC=N(CH
87.0 mg, 0.600 mmol) and PhSO H (40.0 mg, 0.25 mmol) in THF (2 mL) were added. The mixture
was stirred for 16 h. The reaction mixture was diluted with CH Cl (25 mL), then sequentially washed
2 2
CH=CH )
(
3
2
2
with brine, 0.1 M HCl and sat. NaHCO
3
2 2
, extracting with additional CH Cl in each wash. The
combined organic layers were dried with Na
2
SO , filtered and concentrated to 1 mL of solvent. Diethyl
4
ether (20 mL) was slowly layered on the solution resulting in precipitation of the product, which was
subsequently triturated with additional diethyl ether, providing 1b as a yellow solid which was
immediately used the subsequent decarboxylation reaction.
To a sample of 1b (50.2 mg, 0.100 mmol), was added benzoic acid (12.2 mg, 0.100 mmol) in
CHCl
3
(5 mL). Water (36 μL, 2 mmol) was added by micropipette and the vial was capped and heated at
Cl (20 mL),
. The combined organic layers were dried
65 °C for 6 h. The mixture was allowed to cool to room temperature, diluted with CH
2
2
then washed with brine, extracting with additional CH
2
Cl
2
−
with Na SO , filtered and concentrated to give imidazolinium 2b as a yellow solid. This compound
2
4
was transferred without further purification to a dry Schlenk flask and placed under N
2 3 4
. Pd(PPh )
(
11.5 mg, 0.010 mmol) was added as a solution in dry CH Cl (2 mL) followed by PhSiH
2
2
3
(25.0 μL,

Molecules 2012, 17
13765
0
.2 mmol) in CH Cl (2 mL). The reaction mixture was allowed to stir at room temperature for 16 h.
2 2
The solution was then diluted with additional with CH
2
Cl
2
(20 mL) and washed with brine, extracting
−
with additional CH Cl
2
2
. The organic layers were dried with Na
2
SO , filtered and concentrated to give
4
a brown solid which was purified by flash column chromatography (5% MeOH in CH Cl ) to yield
2
2
1
imidazoline 4b as a brown solid (31.9 mg, 76% dr: 13:1) H-NMR (300 MHz, CDCl
.3 Hz, 2H), 7.57–7.51 (m, 4H), 7.43–7.20 (m, 10H), 7.12–7.07 (m, 2H), 6.92–6.83 (m, 2H), 6.75 (d,
J = 8.6 Hz, 2H), 5.03–5.00 (m, 1H), 4.70 (d, J = 15.3 Hz, 1H), 4.38–4.35 (m, 1H), 3.87 (d, J = 15.3 Hz,
3
): δ 7.84 (dt, J = 6.7,
3
1
3
1
1
H), 3.76 (d, J = 7.0 Hz, 3H). C-NMR (75 MHz; CDCl ): δ 166.0, 159.0, 143.3, 141.3, 130.5, 129.3,
3
28.9, 128.8
3
, 128.7
7
, 128.6
9
, 128.5, 127.9
7
, 127.9
0
, 127.8
8
, 127.2, 126.7, 113.9, 77.2, 72.3, 55.3, 49.0
+
HRMS (ESI): C H N O (M+H) calcd; 419.21179 observed; 419.21203.
2
9
26
2
1
1
-Benzyl-2,4,5-triphenyl-4,5-dihydro-1H-imidazole (4c). Yield: 39% dr: 9:1); H-NMR (400 MHz,
CDCl ): δ 7.86–7.81 (m, 2H), 7.51–7.48 (m, 3H), 7.41–7.19 (m, 12H), 7.13–7.11 (m, 2H), 6.97–6.94
3
(
m, 2H), 5.00 (d, J = 8.6 Hz, 1H), 4.73 (d, J = 15.6 Hz, 1H), 4.35 (d, J = 8.6 Hz, 1H), 3.93 (d, J = 15.6 Hz,
1
3
1
H). C-NMR (75 MHz, CDCl
3
): δ 166.0, 143.8, 141.8, 136.4, 131.2, 130.2, 128.9, 128.7
2
, 128.6
8
,
1
28.5, 128.4, 128.0, 127.8, 127.5, 127.2, 127.0, 126.8, 77.2, 72.5, 49.6 HRMS (ESI): C H N
2
8
24
2
+
(
M+H) calcd; 389.20123 observed; 389.20148.
4
6
7
1
-(1-Ethyl-2-phenyl-5-p-tolyl-4,5-dihydro-1H-imidazol-4-yl)-benzoic acid methyl ester (4d). Yield:
1
3
0% dr: 20:1; H-NMR (500 MHz, CDCl ) δ 8.04–8.03 (m, 2H), 7.91–7.89 (m, 1H), 7.79–7.76 (m, 2H),
.53–7.47 (m, 3H), 7.42–7.38 (m, 3H), 7.32–7.22 (m, 5H), 5.15 (d, J = 8.9 Hz, 1H), 4.46 (d, J = 9.0 Hz,
13
3
H), 3.35–3.28 (m, 1H), 3.11–3.03 (m, 1H), 2.39 (s, 3H), 0.90–0.84 (m, 4H). C-NMR (CDCl , 126 MHz):
δ 167.2, 167.0, 148.5, 138.2, 138.1, 130.6, 130.0, 129.8, 129.2, 128.6, 128.4, 127.8, 127.1, 126.6, 75.9,
+
7
3.9, 52.1, 41.1, 21.2, 13.1 HRMS (ESI): C26
H N O
26 2 2
(M+H) calcd; 399.20670 observed; 399.20664.
1
6
7
-Benzyl-4-(4-bromo-phenyl)-2-(4-methoxy-phenyl)-5-p-tolyl-4,5-dihydro-1H-imidazole (4e). Yield
1
3% dr: 20:1; H-NMR (500 MHz, CDCl
3
): δ 7.77–7.74 (m, 2H), 7.37–7.34 (m, 2H), 7.24–7.16 (m,
H), 7.02–6.99 (m, 2H), 6.96–6.92 (m, 4H), 4.91 (d, J = 8.6 Hz, 1H), 4.75 (d, J = 15.6 Hz, 1H), 4.21
13
(
d, J = 8.7 Hz, 1H), 3.88 (d, J = 15.6 Hz, 1H), 3.87(s, 3H), 2.39 (s, 3H). C-NMR (75 MHz, CDCl
3
): δ
1
1
66.0, 161.3, 142.8, 138.1, 137.9, 136.2, 131.5, 130.3, 129.7, 128.6, 128.4, 128.0, 127.7, 127.1, 122.6,
+
2
21.0, 114.1, 76.3, 72.2, 55.4, 49.5, 21.2 HRMS (ESI): C30H27BrNO (M+H) calcd; 511.13795
observed; 511.13808.
3
.5. Synthesis of 1-Allyl-2,4,5-triphenyl-4,5-dihydro-1H-imidazole (5b)
Compound 2b (95.6 mg, 0.19 mmol) was prepared as described above, and transferred without
further purification to a dry Schlenk flask and placed under N . The solid was dissolved in dry CH Cl
5 mL) and cooled to 0 °C. BBr (1.0 M in CH Cl , 2 mL, 2 mmol, 10 equiv.) was added slowly and
2
2
2
(
3
2
2
the mixture was allowed to warm to room temperature. The solution was stirred at room temperature for
h. Sodium hydroxide (10 mL 1.0M solution) was rapidly added to the solution, which was then
2
diluted with CH
2
Cl
2
(20 mL), and washed with brine, extracting with additional CH
2
Cl
2
. The organic
−
layers were dried with Na SO , filtered, and concentrated to give a yellow oil which was purified by
2
4
2 2
flash column chromatography (5% MeOH in CH Cl ) to give a imidazoline 5b as a yellow oil

Molecules 2012, 17
13766
1
(
27.8 mg, 40%, dr: 20:1) H-NMR (400 MHz, CDCl ): δ 7.78–7.74 (m, 2H), 7.51–7.44 (m, 3H),
3
7
3
1
4
.43–7.32 (m, 6H), 7.30–7.26 (m, 3H), 5.55 (m, 1H), 5.06–4.92 (m, 3H), 4.51 (d, J = 8.9 Hz, 1H),
13
.96–3.91 (m, 1H), 3.47 (dd, J = 16.1, 7.3 Hz, 1H). C-NMR (126 MHz; CDCl
3
): δ 166.4, 144.0,
42.0, 133.0, 131.2, 130.1, 128.9, 128.5 , 128.4 , 128.4 , 127.8, 127.2, 127.1, 126.8, 118.2, 77.8, 74.0,
2
7
5
+
22 2
9.1 HRMS (ESI): C24H N (M+H) calcd; 339.18558 observed; 339.18605.
4
. Conclusions
In conclusion, the coupling of the palladium catalyzed multicomponent synthesis of imidazolium
carboxylates with stereoselective decarboxylation provides a new and modular synthesis of
imidazolines. Efforts towards elucidating the mechanism of the decarboxylation reaction, and directing
this towards other classes of heterocyclic products, are currently underway.
Supplementary Materials
Supplementary materials can be accessed at: http://www.mdpi.com/1420-3049/17/12/13759/s1.
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