Novel multicomponent reaction for the combinatorial synthesis of 2-imidazolines

Article abstract of DOI:10.1021/ol035521g

(Matrix presented) The three-component condensation between an amine, an aldehyde, and an α-acidic isocyanide efficiently provides substituted 2-imidazolines in a one-pot reaction under mild conditions.

Full text of DOI:10.1021/ol035521g

ORGANIC
LETTERS
2003
Vol. 5, No. 20
3759-3762
Novel Multicomponent Reaction for the
Combinatorial Synthesis of
2-Imidazolines
Robin S. Bon, Chongen Hong, Marinus J. Bouma, Rob F. Schmitz,
Frans J. J. de Kanter, Martin Lutz,† Anthony L. Spek,† and Romano V. A. Orru*
Department of Chemistry, Vrije UniVerstiteit Amsterdam, De Boelelaan 1083,
1081 HV, Amsterdam, The Netherlands
orru@few.Vu.nl
Received August 12, 2003
ABSTRACT
The three-component condensation between an amine, an aldehyde, and an
in a one-pot reaction under mild conditions.
r-acidic isocyanide efficiently provides substituted 2-imidazolines
Despite recent advances in molecular biology and the
progress in combinatorial synthetic methodology, the rate
of introduction of new medicines has decreased markedly
over the past two decades.1a Structural diversity in a focused
collection of potential therapeutics is believed to increase
the positive hit rate. Most medicines in use are still small
synthetic organic molecules that often contain a heterocyclic
ring.1a-c However, the range of easily accessible and suitably
functionalized heterocyclic building blocks for the synthesis
of structurally diverse libraries is rather limited. The
development of new, rapid, and clean synthetic routes toward
focused libraries of such compounds is therefore of great
importance to both medicinal and synthetic chemists.1
Undoubtedly, the most efficient strategies involve multi-
component reactions (MCRs), which have manifested as a
powerful tool for the rapid introduction of molecular
diversity.2 Consequently, the design and development of
(new) MCRs for the generation of heterocycles receives
growing interest.2a
The 2-imidazoline scaffold is one such interesting hetero-
cycle. Besides being widely encountered in natural products,3
2-imidazolines are also convenient building blocks for the
synthesis of pharmaceutically relevant molecules such as
azapenams, dioxocyclams, and diazapinones.4 Imidazoline
derivatives have been studied as R2-adrenoceptor or estrogen
receptor modulators.5 Their interaction with specific imida-
zoline binding sites results in a multiplicity of biological
functions.6 Also, suitably functionalized 2-imidazolines are
easily converted to 2,3-diamino acids, which are incorporated
(2) (a) Orru, R. V. A.; de Greef, M. Synthesis 2003, 1471-1499. (b)
Do¨mling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168-3210. (c)
Bienayme´, H.; Hulme, C.; Oddon, G.; Schmitt, P. Chem. Eur. J. 2000, 6,
3321-3329.
(3) For example, see: Hassner, A.; Fischer, B. Heterocycles 1993, 35,
1441-1465.
(4) (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, 3586-3591.
(5) (a) Scha¨fer, U.; Burgdorf, C.; Engelhardt, A.; Kurz, T.; Richardt, G.
J. Pharmacol. Exp. Ther. 2002, 303, 1163-1170. (b) Rondu, F.; le Bihan,
G.; Wang, X.; Lamouri, A.; Touboul, E.; Dive, G.; Bellahsene, T.; Pfeiffer,
B.; Renard, P.; Guardiola-Lemaitre, B.; Manechez, D.; Penicaud, L.; Ktorza,
A.; Godfroid, J.-J. J. Med. Chem. 1997, 40, 3793-3803. (c) Gust, R.; Keilitz,
R.; Schmidt, K. J. Med. Chem. 2001, 44, 1963-1970. (d) Gust, R.; Keilitz,
R.; Schmidt, K.; Von Rauch, M. J. Med Chem. 2002, 45, 3356-3365.
† Bijvoet Center for Biomolecular Research, Crystal and Structural
Chemistry, Utrecht University, Padualaan 8, 3584 CH, Utrecht, The
Netherlands.
(1) (a) Newton, R. sp2 2002, NoVember, 16-18 (see: http://www.
sp2.uk.com). (b) Teague, S. J.; Davis, A. M.; Leeson, P. D.; Oprea, T.
Angew. Chem., Int. Ed. 1999, 38, 3743-3748. (c) Armstrong, R. W.; Combs,
A. P.; Tempest, P. A.; Brown, S. D.; Keating, T. A. Acc. Chem. Res. 1996,
29, 123-131. (d) Schreiber, S. L. Science 2000, 287, 1964-1969.
10.1021/ol035521g CCC: $25.00
© 2003 American Chemical Society
Published on Web 09/09/2003

in a wide range of antibiotics and other biologically active
compounds.7 Furthermore, chiral 2-imidazolines have at-
tracted considerable interest as templates for asymmetric
synthesis8 and as chiral ligands for asymmetric catalysis9,10
and have found wide application as potent N-heterocyclic
carbene ligands in organometallic catalysis.10 Thus, the
2-imidazoline scaffold is considered an attractive synthetic
target.
Scheme 1
Typical synthetic procedures toward 2-imidazoline deriva-
tives include ring closure of 1,2-diamines11 and base-
promoted aldol reaction.12 The latter method was developed
by the groups of Scho¨llkopf12a and Van Leusen12b simulta-
neously in the 1970s. Scho¨llkopf’s procedure involves the
reaction of isocyanoacetates or R-lithiated isocyanides with
imines. Van Leusen used TosMIC and its derivatives as
R-acidic isocyanides to synthesize imidazoles13 via 4-tosyl-
2-imidazolines. Recently, imidazoline chemistry regained
attention and some catalytic diastereo- and enantioselective
routes toward 2-imidazolines have been reported.14 However,
most syntheses were performed in a stepwise fashion and
were not set up as MCR.15 They are therefore not suited for
the combinatorial synthesis of small focused libraries of
2-imidazolines. Our main objective was the translation of
the aldol synthesis of 2-imidazolines to an elegant and
flexible MCR and to determine its scope with respect to the
input components. In this communication, preliminary results
are presented.
From previous work in this area, it seemed reasonable to
use isocyanoacetate 6. However, the initial results for the
MCR combining 6 with benzylamine 7 and benzaldehyde 8
were disappointing (Table 1). Even after prolonged stirring
Table 1. Initial MCR for the Synthesis of 2-Imidazolines
Using 6
We envisioned a MCR toward 2-imidazolines of type 5
to proceed through in situ formation of imines 3 from amines
1 and aldehydes 2, followed by attack of the R-acidic
isocyanide 4 and subsequent ring closure (Scheme 1). Traces
of amine present in the reaction mixture may act as a basic
catalyst to promote R-addition to generate the tentative
intermediate A.12a
entry
conditions
scale (mmol)
yielda (%)
1
2
3
MeOH, rt, 3 days
MeOH, rt, 18 h
DCM, rt, 3 days
1
5
1
<5b
34b
0
a Isolated yields. b Only the anti diastereomer (1H NMR) of 9 was found.
(6) Gentili, F.; Bousquet, P.; Brasili, L.; Dontenwill, M.; Feldman, J.;
Ghelfi, F.; Gianella, M.; Piergentili, A.; Quaglia, W.; Pigini, M. J. Med.
Chem. 2003, 46, 2169-2176.
in MeOH, only traces of 2-imidazoline 9 were formed (entry
1). Also, in our hands, reaction times between 6 and the
preformed imine of 7 and 8 proved to be significantly longer
than those reported earlier.16 However, when the reaction
was performed at a larger scale (entry 2), a reasonable
amount of 9 could be isolated. On the other hand, stirring
the same components in DCM gave no detectable 2-imida-
zoline 9.
(7) (a) Dunn, P. J.; Haner, R.; Rapoport, H. J. Org. Chem. 1990, 55,
5017-5025 and references therein. (b) Han, H.; Yoon, J.; Janda, K. D. J.
Org. Chem. 1998, 63, 2045-2048.
(8) (a) Jones, R. C. F.; Howard, K. J.; Snaith, J. S. Tetrahedron Lett.
1996, 37, 1707-1710. (b) Jones, R. C. F.; Howard, K. J.; Snaith, J. S.
Tetrahedron Lett. 1996, 37, 1711-1714. (c) Dalko, P. I.; Langlois, Y. Chem.
Commun. 1998, 331-332.
(9) Menges, F.; Neuburger, M.; Pfaltz, A. Org. Lett. 2002, 4, 4713-
4716.
(10) Herrmann, W. A. Angew. Chem., Int. Ed. 2002, 41, 1290-1309
and references therein.
(11) (a) Riebsomer, J. L. J. Am. Chem. Soc. 1948, 70, 1629-1631. (b)
Jones, R. C. F.; Howard, K. J.; Snaith, J. S. Tetrahedron Lett. 1996, 37,
1707-1710.
Interesting in this respect is that isocyanoacetate 6 can be
easily applied in Ugi four-component condensations (Ugi-
4CC).17 A reaction between 6, isopropylamine 10, isobu-
tyraldehyde 11, and propionic acid 12 provides the bisamide
13 in 81% yield (Scheme 2).
(12) (a) Meyer, R.; Scho¨llkopf, U.; Bo¨hme, P. Liebigs Ann. Chem. 1977,
1183-1193. (b) van Leusen, A. M.; Wildeman, J.; Oldenziel, O. H. J. Org.
Chem. 1977, 42, 1153-1159.
(13) Recently, a multicomponent synthesis of imidazoles using van
Leusen’s TosMIC chemistry was published: Sisko, J.; Kassick, A. J.;
Mellinger, M.; Filan, J. J.; Allen, A.; Olsen, M. A. J. Org. Chem. 2000,
65, 1516-1524.
2-Phenylisocyanoacetate 16 has a more acidic R-H com-
pared to 6 and should serve as a more appropriate isocyanide
(14) (a) Hayashi, T.; Kishi, E.; Soloshonok, V. A.; Uozumi, Y.
Tetrahedron Lett. 1996, 37, 4969-4972. (b) Lin, Y.-R.; Zhou, X.-T.; Dai,
L.-X.; Sun, J. J. Org. Chem. 1997, 62, 1799-1803. (c) Zhou, X.-T.; Lin,
Y.-R.; Dai, L.-X.; Sun, J.; Xia, L.-J.; Tang, M.-H. J. Org. Chem. 1999, 64,
1331-1334.
(15) Notable exception is the highly diastereoselective multicomponent
synthesis of imidazolines employing oxazolones in 1,3-dipolar cycloaddition
reactions reported by: Peddibhotla, S.; Jayakumar, S.; Tepe, J. J. Org. Lett.
2002, 4, 3533-3535.
(16) Scho¨llkopf reported that reactions between the isocyanoacetate 6
and imines at 10 mmol scale in methanol were usually complete after 3 h.
See also ref 12a.
(17) (a) Lehnhoff, S.; Goebel, M.; Karl, R. M.; Klo¨sel, R.; Ugi, I. Angew.
Chem. 1995, 107, 1208-1211. (b) Cheng, J.-F.; Chen, M.; Arrhenius, T.;
Nadzan, A. Tetrahedron Lett. 2002, 43, 6293-6296. (c) Bradley, H.;
Fitzpatrick, G.; Glass, W. K.; Kunz, H.; Murphy, P. V. Org. Lett. 2001, 3,
2629-2632.
3760
Org. Lett., Vol. 5, No. 20, 2003

Ugi-4CC product was not formed. Apparently, the carboxylic
acid does not participate in this MCR.
Scheme 2
Formation of the anti diastereomer 17a is favored over
formation of the syn diastereomer 17b and is independent
of the solvent used (Table 2). X-ray data of 17a unambigu-
ously proved the anti relationship between the methyl ester
at C(4) and isopropyl substituent at C(5) (Figure 1).19a
component in the MCR of Scheme 1. Racemic 16 was
synthesized from D-phenylglycine methyl ester 14 via the
N-formamide 15 in 55% yield (Scheme 3).18
Scheme 3
Figure 1. Displacement ellipsoid plot of 17a. Drawn at the 50%
probability level. H-atoms are omitted for clarity.
The MCR using 16 together with 10 and 11 afforded the
desired 2-imidazolines 17 in reasonable yields depending on
the solvent used (Table 2). In MeOH, DCM, and toluene,
The scope of this MCR was further elaborated. One-pot
combination of 16 with functionalized aliphatic, aromatic,
or benzylic amines and aliphatic, (hetero)aromatic, or R,â-
unsaturated aldehydes provides a range of imidazolines
(Figure 2; 18-26). Except for the reaction with sterically
demanding benzhydrylamine (formation of 18),20 all reactions
went smoothly and the products were obtained in fair to good
yields (47-91%).21
Table 2. MCR for the Synthesis of 2-Imidazolines Employing
16
In analogy with 17a, whose relative configuration was
confirmed by X-ray crystal structure determination (vide
supra), 1H NMR data were used to assign the relative
configuration at C(4) and C(5) of 18-26.19 Without excep-
tion, the anti products were formed predominantly. Interest-
ingly, Spartan semiempirical PM3 calculations show that,
in general, the syn diastereomers are energetically favored
over the anti isomers. However, the calculations suggest that
formation of the anti diastereomers proceeds via favored
intermediates A and is easier than formation of the syn
diastereomers.
entry
solvent
yielda (%)
ratio of 17a:17bb,c
1
2
3
4
MeOH
DCM
toluene
THF
67
74
62
10
75:25
75:25
75:25
75:25
a Isolated yields. b Diastereomeric ratios were calculated from 1H NMR
spectra. c Relative stereochemistry of 17a was determined using X-ray
diffraction.
Besides isocyanoacetates, other isocyanides with acidic
R-protons, e.g., 9-isocyanofluorene 29 (becomes aromatic
upon deprotonation), react in a similar fashion with in situ-
comparable yields were obtained (entries 1-3), whereas in
THF, almost no formation of 17 was observed (entry 4). It
is important to note that the use of carboxylic acid 12,
together with 10, 11, and 16, in a procedure similar to that
described above for 6 (Scheme 2) only gave 17. The expected
(19) (a) For X-ray details, including the CIF file, see Supporting
Information. (b) Analysis of all 1H NMR spectra revealed for H(5) a
characteristic ∆δ(anti-syn) ) 0.6 ( 0.05. The upfield shift of H(5) in the
spectra of the syn diastereomers can be explained by a shielding effect of
the Ph-group at C(4). This is confirmed by NOE measurements.
(20) Considerable amounts of imine are isolated in this case, and 16
presumably decomposes before the reaction is complete. That 2-imidazoline
formation with sterically demanding amines proceeds relatively slow is
supported by the observation that combination of benzhydrylamine, 11, 12,
and 16 only gave (within 18 h) the corresponding Ugi-4CC product in 60%
yield.
(18) (a) Cristau, P.; Vors, J.-P.; Zhu, J. Org. Lett. 2001, 3, 4079-4082.
(b) Isocyanoacetate 16 turned out to be somewhat unstable toward silica
column chromatography and possesses an unpleasant odor. Other reagents
for the dehydration of N-formamide 15 were tested, like Burgess' reagent,
TsCl/pyridine, and triphosgene/NMM. Unfortunately, no optically active
isocyanide could be obtained.
(21) Reactions all proceed at room temperature and only require the
addition of Na2SO4 to remove water, which is formed during initial imine
formation. See Supporting Information for details.
Org. Lett., Vol. 5, No. 20, 2003
3761

Figure 2. Series of 2-imidazolines synthesized from 16. Ratios
refer to anti:syn; only the major diastereomer is depicted.
generated imines. The stable, crystalline, almost odorless 29
can be prepared from 27 in 88% using the procedure
described for 16 (Scheme 4).
Figure 3. Series of spiro-2-imidazolines synthesized from 29.
Scheme 4
combinatorial application. Both 2-phenylisocyanoacetate 16
and 9-isocyanofluorene 29 were shown to be appropriate
isocyanide components in this reaction. The results indicate
that the MCR is compatible with a large range of amine and
aldehyde components. However, the use of sterically de-
manding amines results in lower yields. Currently, other
isocyanides with acidic R-protons are under investigation.
Further, we are exploring one-pot methods to prepare highly
complex polycyclic structures using the MCR described here.
Condensation of 29 with a variety of functionalized amines
(aliphatic, benzylic, or furfuryl) and aldehydes (aliphatic,
(hetero)aromatic, or R,â-unsaturated) provides spiro-2-imi-
dazolines 30-39 (Figure 3). The yields were generally good
(up to 91%), but once more, application of benzhydrylamine
resulted in an unsatisfying yield (30, 20%).22 Steric con-
straints in the amine component seem to determine the
limitations of this MCR.
Acknowledgment. Dr. M. Posthumus (Agricultural Uni-
versity Wageningen) is kindly acknowledged for conducting
HRMS measurements.
Supporting Information Available: Experimental pro-
cedures and characterization data for all new compounds and
X-ray crystallographic details of 17a (CIF file; atomic
coordinates, displacement parameters, bond lengths and
angles, and torsion angles). This material is available free
of charge via the Internet at http://pubs.acs.org.
In summary, the stepwise aldol synthesis of 2-imidazolines
was successfully translated to a flexible MCR suited for
(22) When 29 is combined with 10, 11, and propionic acid 12, the same
trend as for 16 can be recognized. Formation of 2-imidazoline 31 was
exclusive (70%) and no Ugi-4CC product was observed. However, a similar
reaction, but now with benzhydrylamine instead of isopropylamine (10) as
amine input, gave no 2-imidazoline. The bisamide, resulting from an Ugi-
4CC, was isolated as the only reaction product in 67%.
OL035521G
3762
Org. Lett., Vol. 5, No. 20, 2003