A resource-efficient and highly flexible procedure for a three-component synthesis of 2-imidazolines

Article abstract of DOI:10.1021/jo070840x

(Chemical Equation Presented) A multicomponent reaction between α-acidic isonitriles, primary amines, and carbonyl compounds was studied using 14 different solvents. Depending on the isocyanide that was used, optimal yields for the three-component synthesis of 2H-2-imidazolines were observed in different solvents. The solvents could be used as purchased, and in situ preformation of the imine was not required. By selecting the appropriate solvent, it was possible to considerably expand the range of compatible isocyanides toward less α-acidic isocyanides. Further process simplification was achieved by performing the reaction at higher concentrations and avoiding purification by column chromatography, resulting in a fast, easy to perform, and resource-efficient protocol for this three-component reaction.

Full text of DOI:10.1021/jo070840x

A Resource-Efficient and Highly Flexible Procedure for a
Three-Component Synthesis of 2-Imidazolines
Niels Elders, Rob F. Schmitz, Frans J. J. de Kanter, Eelco Ruijter, Marinus B. Groen, and
Romano V. A. Orru*
Department of Organic and Inorganic Chemistry, Faculty of Sciences, Vrije UniVersiteit Amsterdam, De
Boelelaan 1083, 1081 HV Amsterdam, The Netherlands
orru@few.Vu.nl
ReceiVed April 25, 2007
A multicomponent reaction between R-acidic isonitriles, primary amines, and carbonyl compounds was
studied using 14 different solvents. Depending on the isocyanide that was used, optimal yields for the
three-component synthesis of 2H-2-imidazolines were observed in different solvents. The solvents could
be used as purchased, and in situ preformation of the imine was not required. By selecting the appropriate
solvent, it was possible to considerably expand the range of compatible isocyanides toward less R-acidic
isocyanides. Further process simplification was achieved by performing the reaction at higher concentrations
and avoiding purification by column chromatography, resulting in a fast, easy to perform, and resource-
efficient protocol for this three-component reaction.
Introduction
catalysis.5 2-Imidazolines show great structural similarities to
the widely used oxazolines6 and have attracted considerable
interest as auxiliaries in asymmetric synthesis.7 In general,
2-imidazolines are stronger bases than the corresponding
oxazolines, and tuning of the basicity, nucleophilicity, and donor
2-Imidazolines are an interesting class of heterocyclic scaf-
folds. They can be found in marine natural products with
potential antiviral and antitumor activities such as topsentin and
cylindrospermopsin derivatives.1,2 More important is the wide-
spread use of 2-imidazoline cores as synthetic intermediates for
the construction of ligands relevant for applications in catalysis
and medicinal chemistry.3 In coordination chemistry and orga-
nometallic catalysis, 2-imidazolines are increasingly used as
precursors for N-heterocyclic carbene (NHC) ligands.4 Further-
more, they have been employed as chiral ligands in asymmetric
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10.1021/jo070840x CCC: $37.00 © 2007 American Chemical Society
Published on Web 07/12/2007
J. Org. Chem. 2007, 72, 6135-6142
6135

Elders et al.
SCHEME 1. Discussed Synthetic Approaches toward 2-Imidazolines
SCHEME 2. Multicomponent Synthesis of 2H-2-Imidazolines
strength by changing the N1 substituent can be achieved over
a much wider range.8
synthesis of 2-imidazolines.22-25 For example, a well-known
approach involves the reaction of isocyanoacetates or R-lithiated
2-Imidazolines are also of considerable importance because
of their wide variety of biological activities. For example, several
2-imidazolines have a high affinity for imidazoline binding sites
(IBS),9 which are involved in regulation of blood pressure,
insulin secretion control, hypertension, and numerous human
brain disorders such as depression, neurodegeneration, and
opioid tolerance/dependence.10 In addition, 2-imidazolines have
been studied for modulation of the estrogen receptor11 and the
R2-adrenoceptor.12 Furthermore, 2-imidazolines have been
studied as, among others, antihyperglycemic,13 anti-inflamma-
tory,14 antihypertensive,12,15 antihypercholesterolemic,16 and
antidepressant17 agents. 2-Imidazolines are also used as con-
venient building blocks for the synthesis of azapenams, (bis)-
dioxocyclams, and diazepinones.18 Suitably functionalized
2-imidazolines are easily converted to 2,3-diamino acids, which
are incorporated in a wide range of antibiotics and other
biologically active compounds.19 Moreover, a series of highly
substituted cis-imidazoline analogues called nutlins (Nutley
inhibitors) have been successfully screened as inhibitors of
MDM2, a protein that negatively modulates the transcriptional
activity and stability of the p53 tumor suppressor protein.20
Consequently, 2-imidazolines are an attractive synthetic target
for several areas of chemical and pharmaceutical research.
A traditional synthetic approach toward 2-imidazolines is the
ring closure of 1,2-diamines,21 which is rather limited in scope.
In addition to this, a range of methods are available for the
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6136 J. Org. Chem., Vol. 72, No. 16, 2007

Three-Component Synthesis of 2-Imidazolines
SCHEME 3
isocyanides with imines (Scheme 1, Method I).22a In a related
procedure, tosylmethyl isocyanide (TosMIC) can be employed
(Method II). Some catalytic diastereo- and enantioselective
routes toward 2-imidazolines using chiral ferrocene-based
catalysts have also been reported, although this only proved
successful when N-tosylimines were employed (Method III).22b-f
A powerful alternative strategy for the rapid introduction of
molecular diversity involves multicomponent reactions (MCRs).26
A recently reported multicomponent synthesis of 2-imidazolines
involves the TMSCl-mediated 1,3-dipolar cycloaddition of
oxazolones to in situ generated imines, which affords C2-
substituted 2-imidazolines diastereoselectively (Scheme 1, Method
IV).25 The diastereochemical outcome of the reaction is dictated
by the oxazolone substituents. Recently, we have also contrib-
uted in this area and reported a flexible MCR for the synthesis
of 2H-2-imidazolines suitable for combinatorial applications.27
In situ preformation of the imine by stirring an aldehyde and a
primary amine in DCM followed by the addition of an R-acidic
isonitrile afforded the corresponding 2-imidazolines in moderate
to good yields (Scheme 2). The mechanism for this MCR
probably involves a Mannich-type addition of deprotonated
isocyanide 4 to (protonated) imine 3 followed by ring closure
of intermediate A. However, a concerted cycloaddition of 3 and
deprotonated 4 to produce 5 cannot be excluded.28
Although the application of the simplest isocyanoacetate (4a,
R4 ) CO2Me, R5 ) H) did not give satisfying results, somewhat
more reactive isocyanides (4b and 4c) provide the corresponding
2-imidazolines smoothly using DCM as the solvent. In both the
amine and the aldehyde components, a wide variety of aliphatic,
aromatic, heteroaromatic, and olefinic substituents are allowed.
When 4b was applied, the diastereoselectivity of the reaction
was only moderate but always in favor of the isomers with the
large substituents cis to each other. The scope of the MCR was
considerably extended by the application of ketones as the
carbonyl input. However, in these cases the use of catalytic
amounts of AgOAc was found to be essential.28 Also, the use
of p-nitrobenzyl isocyanide (4d) in our MCR was only suc-
cessful in the presence of AgOAc. However, the use of allyl
isocyanide (4e) remained without success. Density functional
theory calculations showed that the proton affinity, the energy
of the HOMO of the R-anion, as well as the contribution of the
carbanion (pz) orbital in the HOMO are important features that
can rationalize the reactivity of the various isocyanides. This
led us to believe that the type of solvent used plays a crucial
role in the performance of this three-component condensation
reaction. Thus far, DCM was the solvent of choice to obtain
optimal yields of 2-imidazolines. However, with 4b as the
isocyanide input, MeOH, toluene, and DCM are all solvents in
which the MCR runs efficiently.27 Furthermore, preliminary
studies for isocyanide 4a, which otherwise reacts sluggishly,
indicate that the MCR can yield a 2-imidazoline using MeOH
as the solvent, albeit in moderate yield. These considerations
prompted us to study the influence of the solvent on the
performance of the three-component reaction (3-CR) for 2-imi-
dazolines. In particular, the relation between the solvent used
and the scope of compatible isocyanide inputs was investigated
in more detail. The results of this study are presented here.
(18) (a) Betschart, C.; Hegedus, L. S. J. Am. Chem. Soc. 1992, 114,
5010-5017. (b) Hsiao, Y.; Hegedus, L. S. J. Org. Chem. 1997, 62, 3586-
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Org. Chem. 1998, 63, 2045-2048.
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Liu, E. A. Science 2004, 303, 844-848.
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references therein. (b) Jones, R. C. F.; Howard, K. J.; Snaith, J. S.
Tetrahedron Lett. 1996, 37, 1707-1710. (c) Fujioka, H.; Murai, K.; Ohba,
Y.; Hiramatsu, A.; Kita, Y. Tetrahedron Lett. 2005, 46, 2197-2199. (d)
Gogoi, P.; Konwar, D. Tetrahedron Lett. 2006, 47, 79-82. (e) Ishihara,
M.; Togo, H. Synlett 2006, 2, 227-230. (f) Sayam, S. Synlett 2006, 2,
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(22) (a) Meyer, R.; Scho¨llkopf, U.; Bo¨hme, P. Liebigs Ann. Chem. 1977,
1183-1193. For later applications, see: (b) Hayashi, T.; Kishi, E.;
Soloshonok, V. A.; Uozumi, Y. Tetrahedron Lett. 1996, 37, 4969-4972.
(c) Lin, Y.-R.; Zhou, X.-T.; Dai, L.-X.; Sun, J. J. Org. Chem. 1997, 62,
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Xia, L.-J.; Tang, M.-H. J. Org. Chem. 1999, 64, 1331-1334. (f) Benito-
Garagorri, D.; Bocokic´, V.; Kirchner, K. Tetrahedron Lett. 2006, 47, 8641-
8644.
Results and Discussion
From our earlier studies, it was known that p-nitrobenzyl-
isocyanide (4d) and acetone (6) are relatively poor inputs for
the 3-CR. Using DCM as the solvent, we found that the
corresponding 2-imidazolines were only formed in the presence
of AgOAc.28 Consequently, we decided to use the reaction
between p-nitrobenzylisocyanide (4d), acetone (6), and benzy-
lamine (7) for the synthesis of imidazoline 5d to study the
influence of the type of solvent on the performance of the 3-CR
(Scheme 3). We studied the reaction in 14 different solvents
ranging from polar aprotic and polar protic to very apolar. All
experiments were performed at a concentration of 0.1 M of 4d
(23) van Leusen, A. M.; Wildeman, J.; Oldenziel, O. H. J. Org. Chem.
1977, 42, 1153-1159.
(24) (a) Dghaym, R. D.; Dhawan, R.; Arndtsen, B. A. Angew. Chem.,
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6, 1681-1683. (c) Concello´n, J. M.; Riego, E.; Sua´rez, J. R.; Garc´ıa-Granda,
S.; D´ıaz, M. R. Org. Lett. 2004, 6, 4499-4501. (d) Gandhi, S.; Bisai, A.;
Prasad, B. A. B.; Singh, V. K. J. Org. Chem. 2007, 72, 2133-2142.
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3533-3535. (b) Peddibhotla, S.; Tepe, J. J. Synthesis 2003, 9, 1433-1440.
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J. Org. Chem, Vol. 72, No. 16, 2007 6137

Elders et al.
FIGURE 1. Conversion of the MCR for imidazoline 5d using 4d, 6, and 7 in different solvents.
TABLE 1. Data Solvent Study without AgOAca
the 3-CR proceeds smoothly. In all solvents, a conversion
between 80 and 100% was observed (Figure 1, black bars).
However, under these conditions, no general trends for the
conversion of the isocyanide 4d in relation to the nature of the
investigated solvents could be observed. In the absence of the
AgOAc catalyst, however, the reaction was found to be strongly
solvent dependent (Figure 1, white bars). As reported previ-
ously,28 2-imidazoline 5d could not be detected in DCM. Also,
in chloroform and 1,2-dichloroethane 5d was not formed,
suggesting that chlorinated solvents should be avoided for this
combination of inputs. In all other solvents studied, product
formation was observed even without the use of AgOAc (Figure
1 and Table 1).
conversion (%) after
d
entry
solvent
µ/Db
ꢀc
ETN
0.25 h 2 h 5 h 21 h
1
2
3
4
5
6
7
8
9
10
11
12
13
14
DMF
DMSO
THF
EtOH
MeCN
MeOH
i-PrOH
EtOAc
DME
Et2O
toluene
(CH2Cl)2 1.80 10.42
CH2Cl2
CHCl3
3.82 38.25
3.96 47.24
1.75
1.69 25.3
3.92 36.64
1.70 33.0
1.56 20.18
0.386
0.444
1
2
1
0
0
2
0
0
0
0
0
0
0
0
17
24
5
5
5
5
3
3
2
1
0
0
0
42
43
17
16
15
15
11
10
8
2
0
0
0
94
61
55
53
48
46
50
38
35
12
6
7.52e 0.207
0.654
0.460
0.762
0.546
0.228
1.78
6.08
7.30f 0.231
1.15
4.27
2.38g 0.099
0.327
8.93g 0.309
1.04 10.0e
0.259
0.117
0.37
0
0
0
The data generally indicate a correlation between solvent
polarity and conversion. The conversions are definitely higher
in polar (aprotic) solvents such as DMSO and DMF compared
to those in apolar solvents such as toluene. The initial conversion
in DMSO seems somewhat higher as compared to that in DMF
(Table 1, entries 1 and 2). However, in DMSO formation of 5d
stops at 61%, whereas in DMF 5d was formed in 94% after 21
h (entry 1).31 Although in general the 3-CR performs better in
more polar solvents, no clear relation between electrostatic
parameters such as the dipole moment (µ/D) or the dielectric
constant (ꢀ) of the solvent and the conversion can be concluded.
For example, conversions were found to be higher in THF than
in MeOH, EtOH, or MeCN (entries 3-6). Because the
electrostatic approach neglects specific solute/solvent interac-
tions, it often fails in correlating observed solvent effects with
physical solvent parameters.30a Reichardt and Harbusch-Go¨rnert
introduced a multiparameter solvent polarity scale (ENT) to
define “solvent polarity” as the overall solvation capability (or
solvation power).30b However, also no clear correlation between
the normalized dimensionless ENT values and the conversion
1.60
0
0
a All reactions were performed in duplicate at 0.5 mmol scale (0.1 M).
Reported conversions are the mean values of duplicate experiments.
Reproducibility was usually within 3% variation. Conversions were
determined by HPLC: Pathfinder AS column, NH4OAc buffer (pH 7.32)/
acetonitrile (63:37), 30 °C, 1.0 mL/min. 4d (2.0 min, 274 nm), 5d (4.8
min, 267 nm), and 2,2′-dinitrobiphenyl (I.S., 10.9 min, 264 nm). b µ: electric
dipole moment in debye units.29 c ꢀ: dielectric constant (relative permit-
tivity);29 at 293 K unless stated otherwise. d ENT: dimensionless normalized
solvent polarity scale, using H2O (1.000) and TMS (0.000) as extreme polar
and nonpolar reference solvents (measured at 25 °C and 1 bar).30 e At 295
K. f At 296 K. g At 298 K.
to ensure that the isocyanide was completely dissolved. Fur-
thermore, all reactions were run in duplicate in the presence
and in the absence of AgOAc. The formation of 5d was followed
in time by HPLC using 2,2′-dinitrobiphenyl as internal standard.
In all cases, acetone (6) was added as the final component to
examine the performance of the MCR without preformation of
the imine. The data are summarized in Figure 1 and Table 1.
In the majority of the solvents used, 2-imidazoline 5d could
be detected after 21 h at room temperature, which demonstrates
that the MCR can be performed without in situ preformation
of the imine. Also, all solvents were used as purchased and did
not require drying before use, which shows that the experimental
procedure indeed is very robust. In the presence of AgOAc,
(29) Lide, D. R. CRC Handbook of Chemistry and Physics, 83rd ed.;
CRC Press: Boca Raton, FL, 2002.
(30) (a) Reichardt, C. Chem. ReV. 1994, 94, 2319-2358. (b) Reichardt,
C.; Harbusch-Go¨rnert, E. Liebigs Ann. Chem. 1983, 721-743.
(31) Thirty-five percent of unreacted 4d could be isolated from a separate
reaction at 2 mmol scale.
6138 J. Org. Chem., Vol. 72, No. 16, 2007

Three-Component Synthesis of 2-Imidazolines
TABLE 2. Solvent Study for the MCR Using Methyl
Isocyanoacetate (4a)a
SCHEME 4. r-Isocyano Esters Synthesis
conversion (%) after
entry
solvent
2 h
5 h
24 h
1
2
3
4
5
6
7
8
MeOH
EtOHb
i-PrOH
DCM
EtOAc
THF
87
81
59
24
33
23
30
62
98
98
83
48
45
35
33
64
98
98
83
92
82
86
52
74
MeCN
DMF
a Reactions were performed at 0.5 mmol scale (0.2 M). Acetone (6) was
added as the final substrate to prevent the preformation of imine.
Conversions were determined by 1H NMR. b Transesterification was
observed (5a/ethyl ester ) 45:55 after 5 h).
TABLE 3. Scope of Compatible r-Acidic Isocyanoacetatesa
could be observed. It should be realized that three different
reactions proceed in one pot for the investigated 3-CR: initial
imine formation, subsequent Mannich-type addition, followed
by cyclocondensation. The kinetics may differ for unrelated
solvents and may therefore be hard to establish precisely. This
probably also accounts for the fact that the 3-CR using 4b,
isobutyraldehyde, and isopropylamine as inputs performs simi-
larly well in MeOH, toluene, and DCM, as was reported by us
earlier.27
These observations led us to reinvestigate the performance
of the 3-CR using methyl isocyanoacetate (4a) as the isocyanide
input (Table 2). When this isocyanide was combined in one
pot with benzaldehyde and benzylamine (7), the corresponding
2-imidazoline was only formed in poor yields.27 To directly
compare the 3-CR using 4a, with the reaction affording 5d as
described above, 4a was combined with acetone (6) as the
carbonyl component and 7 using a similar protocol as for the
3-CR using 4b. In contrast to our earlier findings, conversion
of 4a to the 2-imidazoline 5a went smoothly at room temper-
ature using a range of different solvents (Table 2). Apparently,
the difference in reactivity arises from the carbonyl component
used. Presumably, the electrophilicity of the (protonated)
intermediate imine determines the efficiency of the subsequent
Mannich-type addition of the R-acidic isocyanide.
As noted above, the conversions after 24 h for the MCR using
4a were good to excellent. The results show that after 2 h the
reaction was almost complete in MeOH and EtOH (87 and 81%
conversion, respectively). However, in other solvents the 3-CR
proceeds more slowly. Thus, when 4a is used as the isocyanide
input, protic polar solvents give optimal conversions. After the
initial deprotonation of 4a by, for example, the imine, the
resulting anion may be more efficiently stabilized by hydrogen
bonding with the solvent, resulting in a higher concentration of
the reactive species.
Scope of Compatible Isocyanides. The results described
above show that the MCR using methyl isocyanoacetate (4a)
in MeOH is complete within 5 h even without the use of a
catalyst. Therefore, we decided to explore the scope of compat-
ible isocyanides in this reaction in further detail. Thus, six
additional R-isocyano esters (4f-k) with different R-substituents
conversionb
(isolated yield)c
(%)
entry
isonitrile
R1
R2
time
5 h
22 h
22 h
48 h
8 h
48 h
48 h
48 h
1
2
4a
4f
H
H
Me
Me
Me
Et
Me
t-Bu
Me
Me
Me
Me
Me
Me
Me
Me
Me
98 (89)
100 (98)
96 (80)
93 (90)
91 (89)
90 (73)
100 (quantitative)
82 (77)
84 (57)
66
3
4g
4g
4g
4h
4i
4d
5d,e
6
7
Bn
8
4j
i-Bu
i-Pr
i-Pr
i-Pr
9f
4k
4k
4k
4 weeks
4 weeks
2 weeks
10d-f
11d,e,g
100 (quantitative)
a Unless stated otherwise, reactions were performed at 1.0 mmol scale
(0.2 M). Acetone (6) was added as the final substrate to prevent preformation
of imine. b Conversions were determined by 1H NMR. c Isolated yield was
determined from a separate reaction at 2.0 mmol scale. d Substrates were
mixed at a 1:1:1 ratio, workup by extraction only. e Reaction performed at
2.0 M, 2.0 mmol scale. f In the presence of 2 mol % AgOAc. g In the
presence of 10 mol % AgOAc.
were used as input for the MCR together with acetone (6) and
benzylamine (7) in MeOH as the solvent (Table 3). Generally,
the R-isocyano esters were prepared via slight modifications of
standard protocols,27,32 in three steps from their corresponding
R-amino acids, without the use of chromatographic purification
(Scheme 4).
All isocyanides afforded the desired 2-imidazolines 5a,f-k
in good to excellent isolated yields (Table 3). For example,
application of 4f with a sterically demanding substituent R2 gave
the corresponding 2-imidazoline 5f in 98% isolated yield (entry
2). However, it should be noted that to reach completion the
reaction took 22 h at room temperature. In addition, the use of
isocyanide 4g, with a methyl group at the R-carbon, resulted in
a similarly efficient but somewhat slow reaction (entry 3). The
conversion was high (96%), but the product 5g was only isolated
(32) Obrecht, R.; Herrmann, R.; Ugi, I. Synthesis 1985, 400-402.
J. Org. Chem, Vol. 72, No. 16, 2007 6139

Elders et al.
in 80% yield. According to the 1H NMR spectrum of the crude
reaction mixture, this MCR proceeds without the formation of
any side products. Therefore, the observed loss of material most
likely occurs during the purification by column chromatography.
However, column chromatography can be avoided by mixing
the isocyanide 4g, acetone (6), and benzylamine (7) in equimolar
amounts. After the reaction, simple extraction and evaporation
of solvents then affords the corresponding 2-imidazoline 5g in
good isolated yield (entry 4). The slower conversion (93% after
48 h) arising from the lower concentration of the intermediate
imine was compensated by performing the reaction at 2.0 M
concentration. At this concentration, a similar conversion (91%,
entry 5) was already observed after 8 h at room temperature,
thus resulting in a faster, easier, and more resource-efficient
protocol for the 3-CR.
The results presented in Table 3 also show that reaction rates
decrease as the steric bulk of the R-substituents R1 increases.
When isocyanides 4h-j were used as starting materials in this
reaction, generally 48 h are required to achieve good to excellent
conversion (entries 6-8). The conversions toward the corre-
sponding imidazolines 5h-j decrease in the order of R1 )
benzyl > ethyl > i-butyl. This suggests that, in addition to steric
effects, also electronic effects of the R1 substituent influence
the progress of our 3-CR. The reaction with isocyanide 4k (with
R1 ) isopropyl) seems to approach the limits for this MCR.
After stirring 4k, acetone (6), and benzylamine (7) for two weeks
in MeOH at room temperature, we could detect only unreacted
isocyanide 4k and the corresponding imine. Heating the reaction
mixture at reflux temperature for 2 weeks also did not result in
the formation of detectable amounts of 2-imidazoline 5k.
However, when AgOAc was added as catalyst, 2-imidazoline
5k was found in a very acceptable 84% conversion, although a
long reaction time (4 weeks) was required to achieve this
conversion. Increasing the concentrations of the inputs did not
result in a significant improvement (entry 10), but using
increased amounts of AgOAc (10 mol %) afforded 2-imidazoline
5k quantitatively after 2 weeks (entry 11).
and 2,2′-dinitrobiphenyl (0.17 M) in DCM) or stock solution 2 (4d
(0.50 M), 2,2′-dinitrobiphenyl (0.17 M) and AgOAc (0.010 M) in
DCM) was transferred to a 10-mL reaction vial and evaporated to
dryness under reduced pressure. Five milliliters of the appropriate
solvent, 100 mg of Na2SO4, 65 µL of benzylamine (7) (0.60 mmol,
1.2 equiv), and 75 µL of acetone (6) (1.0 mmol, 2.0 equiv) were
added, and the reaction mixture was stirred for 21 h. Aliquots (40
µL) were taken 0.25, 1, 2, 5, and 21 h after the addition of acetone,
quenched in a 0.1 M (aq) HCl/MeCN mixture (30:70), and analyzed
by HPLC (Shimadzu Pathfinder AS column (150 × 4.6 mm), NH4-
OAc buffer (pH 7.32)/acetonitrile (63:37), 30 °C, 1.0 mL/min. 4d
(2.0 min, 274 nm), 5d (4.8 min, 267 nm), and 2,2′-dinitrobiphenyl
(I.S., 10.9 min, 264 nm)).
General Procedure 2: Reaction of 4a, 6, and 7 in Different
Solvents. A 10-mL reaction vial was charged with isocyanide 4a
(0.50 mmol), the appropriate solvent (2.5 mL), Na2SO4 (50 mg),
benzylamine (7) (65 µL, 64 mg, 0.60 mmol), and acetone (6) (75
µL, 59 mg, 1.0 mmol). Aliquots (200 µL) were taken 2, 5, and 24
h after the addition of acetone, filtered, evaporated to dryness, and
1
analyzed by H NMR (CDCl3).
General Procedure 3: Synthesis of Isocyanides (4g-j). Unless
stated otherwise, SOCl2 (18.0 mL, 29.4 g, 245 mmol) was added
dropwise at 0 °C to a stirred solution of the corresponding amino
acid 8g-j (or amino acid‚HCl salt) (100 mmol) in methanol (190
mL). The reaction mixture was heated for 3 h at reflux temperature
followed by evaporation of all volatiles under reduced pressure to
produce the methyl ester‚HCl salt as a colorless solid in quantitative
yield. Semisaturated Na2CO3 (aq) (100 mL) was added, and the
mixture was extracted with DCM (4 × 100 mL). The organic layers
were combined and dried over MgSO4. Removal of the solvent
under reduced pressure allowed isolation of the corresponding
methyl ester 9g-j (46-100%).
Acetic formic anhydride (prepared by stirring 1 equiv of acetic
anhydride and 1.1 equiv of formic acid for 2 h at 55 °C; 15 mL,
16.8 g, 110 mmol) was added dropwise at 0 °C to a stirred solution
of the appropriate methyl ester 9g-j (50 mmol) in DCM (135 mL),
and the mixture was stirred for 2 h at room temperature. All volatiles
were evaporated under reduced pressure, and the corresponding
formamide 10g-j was isolated in quantitative yield.
A solution of POCl3 (2.9 mL, 4.8 g, 31 mmol) in THF (60 mL,
dried over KOH) was added dropwise to a solution of a formamide
10g-j (25 mmol) in Et3N (17 mL) and THF (60 mL, dried over
KOH) at -78 °C. The reaction mixture was stirred for 2 h at 0 °C,
and the resulting red mixture was added to cold H2O (60 mL) and
extracted with Et2O (3 × 60 mL). The organic layers were
combined, washed with H2O (2 × 50 mL), dried (MgSO4), filtered,
and concentrated in vacuo to yield the desired (racemic) isonitrile
4g-j (65-91%), which was sufficiently pure for follow-up
chemistry.
Conclusions
Depending on the isocyanide used, optimal yields for the
three-component synthesis of 2H-2-imidazolines are observed
in different solvents. Although a wide range of solvents can be
used efficiently as the reaction medium, in general, MeOH
proved to be a good to excellent solvent for the MCR. AgOAc
is an efficient catalyst for this reaction; however, most of the
reactions performed very well without this catalyst. In this MCR
the solvents can be used as purchased, and in situ preformation
of the imine is not necessary. With MeOH as the solvent, it
was possible to considerably expand the range of compatible
isocyanides toward less R-acidic isocyanides. Further process
simplification was achieved by performing the reaction at higher
concentrations and avoiding purification by column chroma-
tography, resulting in a fast, easy to perform, and resource-
efficient protocol for this 3-CR. The high conversions, absence
of side products, and large range of compatible reaction media
makes in situ follow-up chemistry for this MCR feasible.
(()-Methyl 2-Isocyanopropanoate (4g).33 General procedure
3 was followed using DL-alanine (8g) (8.91 g, 100.0 mmol) to give
1
(()-4g (1.74 g, 15.4 mmol, 62%) as a red oil. H NMR (250.13
3
MHz, CDCl3) δ (ppm) 4.34 (q, J ) 7.2 Hz, 1H), 3.83 (s, 3H),
1.66 (d, 3J ) 7.2 Hz, 3H). 13C{1H} NMR (100.62 MHz, CDCl3) δ
(ppm) 167.5 (C), 159.6 (C), 53.3 (CH3), 51.5 (CH), 19.3 (CH3);
IR (KBr) 2588 (s), 2145 (s), 1755 (s), 1455 (m), 1216 (m) cm-1
;
MS (EI, 70 eV) m/z (%) 86 (100) [M - CNH]+, 72 (20) [C3H4O2]+,
58 (25) [C2H2O2]+.
(()-Methyl 2-Isocyanobutanoate (4h). General procedure 3 was
followed starting from dl-R-aminobutyrate hydrochloride (9h‚HCl)
(5.0 g, 32.5 mmol). The dehydration step was performed at 23.6
mmol scale, furnishing (()-4h (2.31 g, 18.2 mmol, 77%) as a red
1
3
oil. H NMR (250.13 MHz, CDCl3) δ (ppm) 4.24 (dd, J ) 5.4
Hz, 3J ) 7.4 Hz, 1H), 3.82 (s, 3H), 2.03-1.93 (m, 2H), 1.09 (t, 3J
) 7.4 Hz, 3H); 13C{1H} NMR (100.62 MHz, CDCl3) δ (ppm) 167.1
Experimental Section
For the general experimental section, see the Supporting Infor-
mation.
General Procedure 1: Reaction of 4d, 6, and 7 in Different
Solvents. One milliliter of either stock solution 1 (4d (0.50 M)
(33) (a) Maeda, I.; Togo, K.; Yoshida, R. Bull. Chem. Soc. Jpn. 1971,
44, 1407-1410. (b) Uban, R.; Marquarding, D.; Seidel, P.; Ugi, I.; Weinelt,
A. Chem. Ber. 1977, 110, 2012-2015.
6140 J. Org. Chem., Vol. 72, No. 16, 2007

Three-Component Synthesis of 2-Imidazolines
(C), 160.1 (C), 57.7 (CH), 53.2 (CH3), 26.3 (CH2), 9.6 (CH3); IR
(KBr) 2980 (s), 2149 (s), 1757 (s), 1439 (m), 1212 (m) cm-1; MS
(EI, 70 eV) m/z (%) 100 (58) [M - CHN]+, 86 (80) [M - C2H3N]+,
72 (6) [C3H4O2]+, 58 (100) [C2H2O2]+.
9H), 1.32 (s, 3H), 1.15 (s, 3H); 13C{1H} NMR (62.90 MHz, CDCl3)
δ (ppm) 170.0 (C), 156.4 (CH), 138.1 (C), 128.7 (2 CH), 127.6 (2
CH), 127.6 (CH), 81.2 (C), 79.3 (CH), 64.5 (C), 45.9 (CH2), 28.1
(3 CH3), 27.2 (CH3), 20.0 (CH3); IR (KBr) 2977 (m), 2840 (w),
1744 (s), 1589 (s), 1152 (s) cm-1; MS (EI, 70 eV) m/z (%) 288 (2)
[M]+, 187 (100) [M - C5H9O2]+, 91 (65) [C7H7]+; HR-MS (EI,
70 eV) calcd for C17H24N2O2 (M+) 288.18378, found 288.18346.
Methyl 1-Benzyl-4,5,5-trimethyl-4,5-dihydro-1H-imidazole-
4-carboxylate (5g). General procedure 4 was followed using 4g
(226 mg, 2.0 mmol). Twenty-two hour reaction time followed by
column chromatography (Al2O3, EtOAc, Rf 0.30) furnished 5g (417
mg, 1.6 mmol, 80%) as a yellow oil.
(()-Methyl 2-Isocyano-3-phenylpropanoate (4i).33b,34 General
procedure 3 was followed using L-phenylalanine (8i) (16.5 g, 100.0
mmol) to give (()-4i (3.56 g, 18.8 mmol, 75%) as a colorless solid.
1
Mp: 43-45 °C; H NMR (250.13 MHz, CDCl3) δ (ppm) 7.35-
3
3
7.23 (m, 5H), 4.47 (dd, J ) 5.0 Hz, J ) 8.2 Hz, 1H), 3.78 (s,
3H), 3.30-3.03 (m, 2H); 13C{1H} NMR (100.62 MHz, CDCl3) δ
(ppm) 166.5 (C), 161.1 (C), 134.3 (C), 129.2 (2 CH), 128.8 (2 CH),
127.8 (CH), 58.0 (CH), 53.4 (CH3), 38.9 (CH2); IR (KBr) 3296
1H NMR (250.13 MHz, CDCl3) δ (ppm) 7.37-7.29 (m, 5H),
(br, s), 2950 (m), 2155 (s), 1755 (s), 1444 (m), 1221 (m) cm-1
;
2
2
MS (EI, 70 eV) m/z (%) 162 (5) [M - CHN]+, 157 (10) [M -
CH4O]+, 130 (48) [M - C2H3O2]+, 91 (100) [C7H7]+, 77 (16)
[C6H5]+.
6.81 (s, 1H), 4.19 (d, J ) 15.2 Hz, 1H), 4.13 (d, J ) 15.2 Hz,
1H), 3.75 (s, 3H), 1.36 (s, 3H), 1.25 (s, 3H), 1.05 (s, 3H); 13C{1H}
NMR (62.90 MHz, CDCl3) δ (ppm) 174.0 (C), 154.9 (CH), 138.2
(C), 128.7 (2 CH), 127.6 (CH), 127.5 (2 CH), 78.9 (C), 66.3 (C),
51.9 (CH3), 45.8 (CH2), 21.0 (CH3), 20.9 (CH3), 20.5 (CH3); IR
(KBr) 3016 (m), 2840 (s), 1959 (w), 1731 (s), 1600 (s) cm-1; MS
(EI, 70 eV) m/z (%) 260 (2) [M]+, 201 (100) [M - C2H3O2]+, 169
(6) [M - C7H7]+, 91 (48) [C7H7]+; HR-MS (EI, 70 eV) calcd for
C15H20N2O2 (M+) 260.15248, found 260.15237.
(()-Methyl 2-Isocyano-4-methylpentanoate (4j).33b,35 General
procedure 3 was followed using DL-leucine (8j) (13.1 g, 100.0
1
mmol) to give (()-4j (3.53 g, 22.7 mmol, 91%) as a red oil. H
NMR (250.13 MHz, CDCl3) δ (ppm) 4.28 (dd, 3J ) 4.7 Hz, 3J )
9.6 Hz, 1H), 3.82 (s, 3H), 1.94-1.80 (m, 2H), 1.72 (m, 1H), 0.98
(m, 6H); 13C{1H} NMR (100.62 MHz, CDCl3) δ (ppm) 167.6 (C),
160.1 (C), 55.1 (CH), 53.2 (CH3), 41.3 (CH2), 24.8, 22.5, and 20.9
(2 CH3 and CH); IR (KBr) 3337 (w), 2956 (s), 2148 (s), 1756 (s),
1469 (m), 1273 (m) cm-1; MS (EI, 70 eV) m/z (%) 128 (80) [M -
CHN]+, 114 (10) [M - C2H3N]+, 99 (14) [M - C4H8]+, 86 (100)
[M - C4H7N]+.
Alternatively, 4g (226 mg, 2.0 mmol), benzylamine (7) (220 µL,
214 mg, 2.0 mmol), acetone (6) (150 µL, 116 mg, 2.0 mmol), and
MgSO4 (100 mg) were stirred in methanol (1 mL) for 8 h at room
temperature. Water (15 mL) was added, and the resulting mixture
was extracted with DCM (3 × 10 mL). The organic layers were
combined, dried (MgSO4), filtered, and concentrated to yield pure
4g (464 mg, 1.78 mmol, 89%).
General Procedure 4: Synthesis of 2-Imidazolines 5a,f-k.
An isocyanide 4a,f-k (2.0 mmol), benzylamine (7) (330 µL, 321
mg, 3.0 mmol, 1.5 equiv), acetone (6) (300 µL, 232 mg, 4.0 mmol,
2.0 equiv), and MgSO4 (200 mg) were stirred in methanol (10 mL)
Methyl 1-Benzyl-4-ethyl-5,5-dimethyl-4,5-dihydro-1H-imida-
zole-4-carboxylate (5h). General procedure 4 was followed using
4h (250 mg, 2.0 mmol). Forty-eight hour reaction time followed
by column chromatography (Al2O3, EtOAc/pentane (5%), Rf 0.63)
furnished 5h (399 mg, 1.5 mmol, 73%) as a pale yellow oil.
1H NMR (250.13 MHz, CDCl3) δ (ppm) 7.37-7.28 (m, 5H),
1
until complete consumption of 4 (monitored by H NMR). Water
(15 mL) was added, and the resulting mixture was extracted with
DCM (3 × 10 mL). The organic layers were combined, dried
(MgSO4), filtered, and concentrated, and the resulting 2-imidazoline
was purified by column chromatography (Al2O3, EtOAc/MeOH
gradient, unless stated otherwise).
2
2
6.81 (s, 1H), 4.20 (d, J ) 15.2 Hz, 1H), 4.11 (d, J ) 15.2 Hz,
1H), 3.76 (s, 3H), 1.94-1.86 (m, 1H), 1.63-1.55 (m, 1H), 1.25
(s, 3H), 1.04 (s, 3H), 0.96 (t, J ) 7.4 Hz, 3H); 13C{1H} NMR
3
Methyl 1-Benzyl-5,5-dimethyl-4,5-dihydro-1H-imidazole-4-
carboxylate (5a).22a General procedure 4 was followed using 4a
(198 mg, 2.0 mmol). Five-hour reaction time followed by column
chromatography (SiO2, 5% MeOH in EtOAc containing 0.33%
Et3N, Rf 0.16) furnished 5a (440 mg, 1.8 mmol, 89%) as a yellow
oil.
(62.90 MHz, CDCl3) δ (ppm) 173.5 (C), 154.9 (CH), 138.3 (C),
128.7 (2 CH), 127.6 (CH), 127.6 (2 CH), 82.8 (C), 66.7 (C), 51.7
(CH3), 45.8 (CH2), 28.1 (CH2), 21.2 (CH3), 20.4 (CH3), 9.2 (CH3);
IR (KBr) 3205 (w), 2877 (m), 1951 (w), 1747 (s), 1598 (s), 1456
(m), 1253 (m) cm-1; MS (EI, 70 eV) m/z (%) 274 (2) [M]+, 245
(2) [M - C2H5]+, 215 (100) [M - C2H3O2]+, 183 (6) [M - C7H7]+,
91 (58) [C7H7]+; HR-MS (EI, 70 eV) calcd for C16H22N2O2 (M+)
274.16813, found 274.16719.
1H NMR (250.13 MHz, CDCl3) δ (ppm) 7.37-7.29 (m, 5H),
6.88 (d, 4J ) 1.3 Hz, 1H), 4.44 (d, 4J ) 1.3 Hz, 1H), 4.23 (d, 2J )
2
15.1 Hz, 1H), 4.18 (d, J ) 15.1 Hz, 1H), 3.76 (s, 3H), 1.35 (s,
Methyl 1,4-Dibenzyl-5,5-dimethyl-4,5-dihydro-1H-imidazole-
4-carboxylate (5i). General procedure 4 was followed using 4i (378
mg, 2.0 mmol). Forty-eight hour reaction time followed by column
chromatography (Al2O3, EtOAc/pentane (10%), Rf 0.44) furnished
5i (706 mg, quantitative) as a pale yellow oil.
3H), 1.10 (s, 3H); 13C{1H} NMR (62.90 MHz, CDCl3) δ (ppm)
171.5 (C), 156.7 (CH), 137.8 (C), 128.7 (2 CH), 127.7 (2 CH),
127.7 (CH), 79.0 (CH), 64.7 (C), 51.9 (CH3), 46.0 (CH2), 27.2
(CH3), 20.1 (CH3); IR (KBr) 3010 (m), 2854 (s), 1957 (w), 1747
(s), 1598 (s) cm-1; MS (EI, 70 eV) m/z (%) 246 (12) [M]+, 231
(4) [M - CH3]+, 187 (98) [M - C2H3O2]+, 155 (4) [M - C7H7]+,
91 (100) [C7H7]+; HR-MS (EI, 70 eV) calcd for C14H18N2O2 (M+)
246.13683, found 246.13682.
1H NMR (250.13 MHz, CDCl3) δ (ppm) 7.37-7.18 (m, 10H),
2
2
6.87 (s, 1H), 4.24 (d, J ) 15.1 Hz, 1H), 4.14 (d, J ) 15.1 Hz,
2
2
1H), 3.59 (s, 3H), 3.15 (d, J ) 12.8 Hz, 1H), 2.87 (d, J ) 12.8
Hz, 1H), 1.41 (s, 3H), 1.08 (s, 3H); 13C{1H} NMR (62.90 MHz,
CDCl3) δ (ppm) 172.7 (C), 154.7 (CH), 138.3 (C), 137.0 (C), 130.5
(2 CH), 128.7 (2 CH), 127.7 (2 CH), 127.6 (CH), 127.6 (2 CH),
126.3 (CH), 82.9 (C), 67.3 (C), 51.5 (CH3), 45.8 (CH2), 40.7 (CH2),
20.9 (CH3), 20.5 (CH3); IR (KBr) 3029 (m), 2971 (m), 2947 (m),
1950 (w), 1877 (w), 1750 (s), 1718 (s), 1598 (s), 1495 (m), 1215
(br, s) cm-1; MS (EI, 70 eV) m/z (%) 366 (1) [M]+, 277 (16) [M
- C2H3O2]+, 245 (100) [M - C7H7]+, 91 (70) [C7H7]+; HR-MS
(EI, 70 eV) calcd for C21H24N2O2 (M+) 366.18378, found 366.18473.
Methyl 1-Benzyl-4-isobutyl-5,5-dimethyl-4,5-dihydro-1H-imi-
dazole-4-carboxylate (5j). General procedure 4 was followed using
4j (310 mg, 2.0 mmol). After 48 h reaction time, 5j (466 mg, 1.54
mmol, 77%) could be isolated as a pale yellow oil.
tert-Butyl 1-Benzyl-5,5-dimethyl-4,5-dihydro-1H-imidazole-
4-carboxylate (5f). General procedure 4 was followed using 4f
(282 mg, 2.0 mmol). After 22 h reaction time, 5f (567 mg, 1.9
mmol, 98%) could be isolated as a colorless solid.
Mp: 87-90 °C; 1H NMR (250.13 MHz, CDCl3) δ (ppm) 7.33-
7.27 (m, 5H), 6.87 (d, 4J ) 1.2 Hz, 1H), 4.29 (d, 4J ) 1.2 Hz, 1H),
2
2
4.21 (d, J ) 15.2 Hz, 1H), 4.17 (d, J ) 15.2 Hz, 1H), 1.49 (s,
(34) (a) Failli, A.; Nelson, V.; Immer, H.; Gotz, M. Can. J. Chem. 1973,
51, 2769-2772. (b) Seebach, D.; Adam, G.; Gees, T.; Schiess, M.; Weigand,
W. Chem. Ber. 1988, 121, 507-518. (c) Takiguchi, K.; Yamada, K.; Suzuki,
M.; Nunami, K. I.; Hayashi, K.; Matsumoto, K. Agric. Biol. Chem. 1989,
53, 77-82.
(35) Owens, T. D.; Araldi, G.-L.; Nutt, R. F.; Semple, J. E. Tetrahedron
Lett. 2001, 42, 6271-6274.
1H NMR (250.13 MHz, CDCl3) δ (ppm) 7.38-7.29 (m, 5H),
2
2
6.78 (s, 1H), 4.18 (d, J ) 15.2 Hz, 1H), 4.09 (d, J ) 15.2 Hz,
J. Org. Chem, Vol. 72, No. 16, 2007 6141

Elders et al.
2
3
1H), 3.75 (s, 3H), 1.88 (m, 1H), 1.71 (dd, J ) 12.9 Hz, J ) 6.8
1747 (s), 1598 (m), 1454 (m), 1043 (m) cm-1; MS (EI, 70 eV) m/z
(%) 288 (4) [M]+, 245 (100) [M - C3H7]+, 229 (69) [M -
C2H3O2]+, 197 (6) [M - C7H7]+, 187 (19) [M - C5H9O2]+, 91
(78) [C7H7]+; HR-MS (EI, 70 eV) calcd for C17H24O2N2 (M+)
288.18378, found 288.18354.
Alternatively, 4k (282 mg, 2.0 mmol), benzylamine (7) (220 µL,
214 mg, 2.0 mmol), acetone (6) (150 µL, 116 mg, 2.0 mmol),
AgOAc (33.3 mg, 0.2 mmol, 10 mol %), and MgSO4 (100 mg)
were stirred in methanol (1 mL) for 2 weeks at room temperature.
Water (15 mL) was added, and the resulting mixture was extracted
with DCM (3 × 10 mL). The organic layers were combined, dried
(MgSO4), filtered, and concentrated to yield pure 5k (578 mg, 2.0
mmol, quantitative).
2
3
Hz, 1H), 1.59 (dd, J ) 12.9 Hz, J ) 6.8 Hz, 1H), 1.23 (s, 3H),
1.00 (s, 3H), 0.94 (d, 3J ) 6.6 Hz, 3H), 0.85 (d, 3J ) 6.6 Hz, 3H);
13C{1H} NMR (62.90 MHz, CDCl3) δ (ppm) 174.1 (C), 154.6 (CH),
138.4 (C), 128.7 (2 CH), 127.6 (2 CH), 127.6 (CH), 81.4 (C), 67.5
(C), 51.6 (CH3), 45.8 (CH2), 42.7 (CH2), 25.1 (CH3), 24.5 (CH),
22.6 (CH3), 20.6 (CH3), 20.0 (CH3); IR (KBr) 3160 (w), 2950 (w),
2867 (w), 1747 (s), 1598 (s), 1454 (m), 1035 (s) cm-1; MS (EI, 70
eV) m/z (%) 302 (2) [M]+, 287 (22) [M - CH3]+, 243 (68) [M -
C2H3O2]+, 231 (18) [M - C5H11]+, 211 (10) [M - C7H7]+, 187
(20) [M - C6H11O2]+, 91 (100) [C7H7]+; HR-MS (EI, 70 eV) calcd
for C18H26N2O2 (M+) 302.19943, found 302.19953.
Methyl 1-Benzyl-4-isopropyl-5,5-dimethyl-4,5-dihydro-1H-
imidazole-4-carboxylate (5k). General procedure 4 was followed
using 4k (282 mg, 2.0 mmol) and AgOAc (6.6 mg, 0.04 mmol, 2
mol %). After 4 weeks reaction time, 5k (328 mg, 1.1 mmol, 57%)
could be isolated as a yellow oil.
Acknowledgment. This work was performed with financial
support from the Dutch Science Foundation (NWO, VICI
Grant). Dr. M. T. Smoluch (Vrije Universiteit Amsterdam) is
kindly acknowledged for conducting HRMS measurements.
1H NMR (250.13 MHz, CDCl3) δ (ppm) 7.37-7.28 (m, 5H),
2
2
6.86 (s, 1H), 4.14 (d, J ) 14.6 Hz, 1H), 4.08 (d, J ) 14.6 Hz,
3
1H), 3.75 (s, 3H), 2.29 (hp, J ) 6.6 Hz, 1H), 1.35 (s, 3H), 1.04
Supporting Information Available: General experimental
methods and spectral data (1H NMR and 13C NMR) for all new
compounds. This material is available free of charge via the Internet
at http://pubs.acs.org.
3
3
(s, 3H), 0.96 (d, J ) 6.6 Hz, 3H), 0.89 (d, J ) 6.6 Hz, 3H);
13C{1H} NMR (62.90 MHz, CDCl3) δ (ppm) 174.0 (C), 155.2 (CH),
137.8 (C), 128.7 (2 CH), 128.1 (2 CH), 127.7 (CH), 85.5 (C), 66.3
(C), 51.4 (CH3), 46.2 (CH2), 32.8 (CH), 22.4 (CH3), 19.3 (CH3),
19.2 (CH3), 17.3 (CH3); IR (KBr) 3019 (w), 2821 (s), 1956 (w),
JO070840X
6142 J. Org. Chem., Vol. 72, No. 16, 2007