Article pubs.acs.org/joc
Diastereoselective One-Pot Synthesis of Tetrafunctionalized 2‑Imidazolines Guido V. Janssen,† Paul Slobbe,† Maurice Mooijman,† Art Kruithof,† Andreas W. Ehlers,† Célia Fonseca Guerra,‡ F. Matthias Bickelhaupt,‡,§ J. Chris Slootweg,† Eelco Ruijter,† Koop Lammertsma,*,† and Romano V. A. Orru*,† †
Department of Chemistry and Pharmaceutical Sciences, Amsterdam Institute for Molecules, Medicines & Systems (AIMMS), VU University Amsterdam, De Boelelaan 1083, NL-1081 HV Amsterdam, The Netherlands ‡ Department of Theoretical Chemistry, Amsterdam Center for Multiscale Modeling (ACMM), VU University Amsterdam, De Boelelaan 1083, NL-1081 HV Amsterdam, The Netherlands § Institute of Molecules and Materials, Radboud University Nijmegen, Heyendaalseweg 135, NL-6525 AJ Nijmegen, The Netherlands S Supporting Information *
ABSTRACT: A convenient trans-selective one-pot synthesis of tetrafunctionalized 2-imidazolines is described. Our approach to these valuable heterocyclic scaffolds involves a formal 1,3-dipolar cycloaddition between nitrile ylides or nitrilium triflates and imines. A detailed experimental study in combination with a high-level computational exploration of reaction routes reveals a plausible reaction pathway that accounts for the observed diastereoselectivity.
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have been associated with antitumor activities.6 Furthermore, 2imidazolines are also frequently used as chiral organocatalysts (e.g., 2),7 as chiral P,N-ligands in asymmetric transition-metal catalysis (e.g., 3),7a,8 and as precursors for N-heterocyclic carbenes (e.g., 4).9 Several multistep approaches are known to synthesize highly functionalized 2-imidazolines.7a,10 However, functionalization at the C2-position proves to be challenging. Currently, four direct methods are available as summarized in Scheme 1. One approach involves the Ugi-deprotection−cyclization strategy (A),11 whereas a Pd-catalyzed carbonylative coupling procedure (B) toward tetrasubstituted 2-imidazolines has also been reported.12 Alternatively, the Ritter reaction (C)13 has been employed, and finally, a TMSCl mediated cycloaddition (D) has been effective.14 However, all four approaches suffer from various limitations including the lack of relative stereocontrol. We envisioned an alternative synthetic protocol based on a recently developed silver(I) acetate catalyzed three-component reaction. Starting from α-acidic isocyanides (6) and imines, generated in situ from aldehydes or ketones and amines (Scheme 2), trisubstituted 2-imidazolines (9a) are synthesized efficiently.15 In this reaction, the silver ion coordinates to the isocyanide terminal carbon, thereby lowering the pKa of the αproton. After deprotonation of 6, the resulting iminium ion (7) and the Ag(I)-dipole (8) undergo a subsequent rapid stepwise cyclocondensation to the desired 2-imidazolines (9a).
INTRODUCTION
2-Imidazolines are valuable heterocyclic compounds with a variety of applications in both catalysis and biology. Indeed, antihypertensive,1 antihyperglycemic,2 antidepressive,3 antihypercholesterolemic,4 and anti-inflammatory5 activities have been reported. Important examples of C2-functionalized 2imidazolines are the so-called nutlins (e.g., 1, Figure 1), which
Figure 1. Tetrasubstituted 2-imidazolines as an antitumor compound (1), as chiral ligands for asymmetric catalysis (2 and 3), and as an NHC complex (4). © XXXX American Chemical Society
Received: April 8, 2014
A
dx.doi.org/10.1021/jo500790n | J. Org. Chem. XXXX, XXX, XXX−XXX
The Journal of Organic Chemistry
Article
diastereomeric ratio (17:83) according to 1H NMR analysis of the crude mixture (Table 1, entry 2). The major isomer was assigned as the trans configuration based on comparison of the measured 1H NMR spectra with the calculated spectra (see ref 20 for details) and the observed lower oxidation rate of this isomer toward the corresponding imidazole.20 We then investigated the efficiency of several bases for the synthesis of 16a (Table 1). Using 2,6-lutidine as the base gave 16a in a comparable yield of 18% (entry 4). When the stronger base DBU was used, only decomposition of the starting materials was observed (entry 5). Although using tert-butoxides seems to result in faster formation of 16a, the overall yield did not improve significantly (11−33%, entries 6−9), but especially with lithium and sodium tert-butoxide in CH 2 Cl 2 (entries 6 and 7), excellent diastereoselectivities were obtained (cis/trans =
Diastereoselective One-Pot Synthesis of Tetrafunctionalized 2‑Imidazolines Guido V. Janssen,† Paul Slobbe,† Maurice Mooijman,† Art Kruithof,† Andreas W. Ehlers,† Célia Fonseca Guerra,‡ F. Matthias Bickelhaupt,‡,§ J. Chris Slootweg,† Eelco Ruijter,† Koop Lammertsma,*,† and Romano V. A. Orru*,† †
Department of Chemistry and Pharmaceutical Sciences, Amsterdam Institute for Molecules, Medicines & Systems (AIMMS), VU University Amsterdam, De Boelelaan 1083, NL-1081 HV Amsterdam, The Netherlands ‡ Department of Theoretical Chemistry, Amsterdam Center for Multiscale Modeling (ACMM), VU University Amsterdam, De Boelelaan 1083, NL-1081 HV Amsterdam, The Netherlands § Institute of Molecules and Materials, Radboud University Nijmegen, Heyendaalseweg 135, NL-6525 AJ Nijmegen, The Netherlands S Supporting Information *
ABSTRACT: A convenient trans-selective one-pot synthesis of tetrafunctionalized 2-imidazolines is described. Our approach to these valuable heterocyclic scaffolds involves a formal 1,3-dipolar cycloaddition between nitrile ylides or nitrilium triflates and imines. A detailed experimental study in combination with a high-level computational exploration of reaction routes reveals a plausible reaction pathway that accounts for the observed diastereoselectivity.
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have been associated with antitumor activities.6 Furthermore, 2imidazolines are also frequently used as chiral organocatalysts (e.g., 2),7 as chiral P,N-ligands in asymmetric transition-metal catalysis (e.g., 3),7a,8 and as precursors for N-heterocyclic carbenes (e.g., 4).9 Several multistep approaches are known to synthesize highly functionalized 2-imidazolines.7a,10 However, functionalization at the C2-position proves to be challenging. Currently, four direct methods are available as summarized in Scheme 1. One approach involves the Ugi-deprotection−cyclization strategy (A),11 whereas a Pd-catalyzed carbonylative coupling procedure (B) toward tetrasubstituted 2-imidazolines has also been reported.12 Alternatively, the Ritter reaction (C)13 has been employed, and finally, a TMSCl mediated cycloaddition (D) has been effective.14 However, all four approaches suffer from various limitations including the lack of relative stereocontrol. We envisioned an alternative synthetic protocol based on a recently developed silver(I) acetate catalyzed three-component reaction. Starting from α-acidic isocyanides (6) and imines, generated in situ from aldehydes or ketones and amines (Scheme 2), trisubstituted 2-imidazolines (9a) are synthesized efficiently.15 In this reaction, the silver ion coordinates to the isocyanide terminal carbon, thereby lowering the pKa of the αproton. After deprotonation of 6, the resulting iminium ion (7) and the Ag(I)-dipole (8) undergo a subsequent rapid stepwise cyclocondensation to the desired 2-imidazolines (9a).
INTRODUCTION
2-Imidazolines are valuable heterocyclic compounds with a variety of applications in both catalysis and biology. Indeed, antihypertensive,1 antihyperglycemic,2 antidepressive,3 antihypercholesterolemic,4 and anti-inflammatory5 activities have been reported. Important examples of C2-functionalized 2imidazolines are the so-called nutlins (e.g., 1, Figure 1), which
Figure 1. Tetrasubstituted 2-imidazolines as an antitumor compound (1), as chiral ligands for asymmetric catalysis (2 and 3), and as an NHC complex (4). © XXXX American Chemical Society
Received: April 8, 2014
A
dx.doi.org/10.1021/jo500790n | J. Org. Chem. XXXX, XXX, XXX−XXX
The Journal of Organic Chemistry
Article
diastereomeric ratio (17:83) according to 1H NMR analysis of the crude mixture (Table 1, entry 2). The major isomer was assigned as the trans configuration based on comparison of the measured 1H NMR spectra with the calculated spectra (see ref 20 for details) and the observed lower oxidation rate of this isomer toward the corresponding imidazole.20 We then investigated the efficiency of several bases for the synthesis of 16a (Table 1). Using 2,6-lutidine as the base gave 16a in a comparable yield of 18% (entry 4). When the stronger base DBU was used, only decomposition of the starting materials was observed (entry 5). Although using tert-butoxides seems to result in faster formation of 16a, the overall yield did not improve significantly (11−33%, entries 6−9), but especially with lithium and sodium tert-butoxide in CH 2 Cl 2 (entries 6 and 7), excellent diastereoselectivities were obtained (cis/trans =
