Toluenesulphonylmethyl isocyanide (TOSMIC) and the van Leusen MCR
The Chemistry of TOSMIC
The chemistry of TOSMIC has been extensively elaborated by the Dutch chemist Prof. van Leusen and his school. It constitutes by far the most versatile synthon derived from methyl isocyanide and exhibits a multifaceted chemistry that is of great utility in organic synthesis. TOSMIC constitutes a densely functionalized building block with three crucial groups contributing to a multitude of reactions (Fig. 1): the isocyano function undergoes typical α-addition reactions, the acidic α-carbon atom, and the sulphonyl group in the α-position that serves two functions, acting both as a sulphinyl leaving group and further enhancing the acidity of the α-carbon. The geminal isocyano and tosyl groups in TOSMIC can be regarded as a specialized type of N,S-acetal, and reacts accordingly.
Figure 1 TOSMIC is a densely functionalized isocyanide, involving an isocyano group, an acidic α-carbon atom and a sulphonyl group. This compact collection of functionality is a crucial factor in the rich chemistry of TOSMIC.
TOSMIC is a multipurpose synthetic reagent (Fig. 2). It performs reductive cyanations of ketones and aldehydes, and easily undergoes Knoevenagel-type condensations with aldehydes and ketones. The reagent is a connective C1 synthon and can be dialkylated as well. Moreover, as a heteroacetal derivative, it is useful for the synthesis of ketones by alkylation and subsequent hydrolysis. This process constitutes an Umpolung of the formaldehyde reactivity.
In the synthesis of heterocycles, it provides a versatile synthesis of oxazolidinones and oxazoles, thiazoles, imidazoles, indoles, triazoles and pyrroles (Fig. 2).
Today, many other α-substituted TOSMIC derivatives in addition to the parent compound are commercially available, thus facilitating its use in applied and combinatorial chemistry. The chemistry of TOSMIC has recently been authoritatively reviewed in Organic Reactions (D. van Leusen, A. M. van Leusen, Org. React. 2003, 57, 419).
This small review aims to highlight some recent applications of the TOSMIC-based MCRs.
Figure 2 TOSMIC is a versatile building block, undergoing many useful reactions. The red parts show the portions of the product originating from the TOSMIC starting material. A (Selective reductive cyanation of ketones): TOSMIC, t-BuOK; B (oxazole ring formation): 1. TOSMIC condensation with cyclohexanone, 2. cinnamic aldehyde, 2 eq. n-BuLi (-70 to 0 °C, 2 h); C (4-alkoxy-2-oxazoline formation): 1. acetophenone, TOSMIC, EtOH; 2. H3O+; D (formation of substituted α,β-unsaturated ketones): 1. TOSMIC condensation with cyclohexanone, 2. benzyl bromide, t-BuOK, DME; 3. H3O+; E (TOSMIC as connective reagent, reduction): 1. alkyl iodide, TOSMIC, PTC, 2. Li, NH3(liq.); F (TOSMIC as connective reagent, hydrolysis): 1. TOSMIC, dialkylation 2. H2SO4 (50%), sulpholane, 20 to 100 °C, 2 h; G (pyrroles from Michael acceptors): benzyl-substituted TOSMIC, NaH, acrylonitrile; H (triazole formation): diazonium salt, TOSMIC, K2CO3, DMSO, MeOH, H2O,-10 °C.
1,4,5-trisubstituted Imidazoles by vL-3CR
Besides the classical Passerini and Ugi reactions, the van Leusen chemistry of TOSMIC and its derivatives constitutes the most important application of isocyanides in multicomponent reactions (IMCR). In 1977, van Leusen described the reaction of aldehydes, primary amines and TOSMIC, thus yielding 1,4,5-trisubstituted imidazoles (vL-3CR) which are otherwise not easily accessible (A. M. van Leusen, J. Wildeman, O. H. Oldenziel, J. Org. Chem. 1977, 42, 1153. A. M. van Leusen, Heterocycl. Chem. 1980, 5, S-111). The mechanism involves cycloaddition of TOSMIC to a Schiff base carbon-nitrogen double bond, a base-induced cyclisation and proton rearrangement towards an imidazoline, which upon loss of tosylsulphinic acid aromatises to yield the imidazole. The reaction runs in protic or unprotic polar solvents (EtOAc, THF, MeCN, DMF, DCM, MeOH), from room temperature to reflux, most often under anhydrous conditions. n-BuLi, t-BuOK and NaH have been described as the required base; but the reaction was also found to require mild base to promote the cycloaddition (piperazine, morpholine, K2CO3). The choice of reaction conditions is influenced by the solubility of the aldehyde and amine as well the product isolation. The combination of DMF/K2CO3 is described as the best choice for ensuring successful TOSMIC/imine cycloadditions. However, other solvent/base combinations can be equally effective and can help to avoid the difficulties associated with removing DMF from the product.
Figure 3 Generally assumed reaction mechanism of the vL-3CR of imidazoles
Most of the examples published until recently have used imines which are devoid of any additional functionality. Only recently has the usefulness of this reaction been dramatically enlarged by the introduction and investigation of α-substituted TOSMICs and of a variety of functional groups in the starting materials. Sisko et al. from Glaxo-Smith-Kline investigated in-depth scope and limitations of this imidazole synthesis (J. Org. Chem. 2000, 65, 1516. ).
Thus it was found that the reaction works quite well with aldehydes bearing other O-functional groups in different oxidation states, such as glyoxal that yields a free aldehyde group in the product 11, hydroxyacetaldehyde that yields a free primary hydroxyl group in the product 12, α-ketoaldehydes that yield free keto groups in the products 10 and 16 or esters 13. Moreover, free phenolic groups 15 or indole 14, imidazole and pyridine heterocycles are well tolerated, as in 13 and 16 respectively.
Figure 4 Various van Leusen imidazoles showing multiple functional group tolerance.
Dialdehydes and diamines have also been used successfully in this multicomponent reaction to generate dimeric bis-imidazoles. Glutaric dialdehyde, as a 50% aqueous solution, readily reacts with an amine to form the bis-imidazole 17. Moreover, the hydrogenolytically sensitive cysteamine reacts nicely to yield the corresponding bis-imidazole 18 in excellent yield.
Figure 5 Dialdehydes and diamines readily undergo the vL-3CR.Another family of attractive target molecules for the vL-3CR methodology are 2-imidazol-1-yl alkanoic acids. It has been demonstrated that unprotected α- and β-aminoacids are good substrates in this reaction. Moreover chiral α-amino acids yield the optically pure products 19 - 21.
Figure 6 Unprotected chiral amino acids yield optically active products.
Glyoxylic acid can be used advantageously as a substitute for formaldehyde, and yields the 1,4-disubstituted imidazoles 23 - 25 in high yields. It is assumed that upon addition of the base and TOSMIC, the Schiff base decarboxylates. The corresponding 4,5-disubstituted imidazoles are also accessible by using vL-3CR. Thus, simply treating an aldehyde with excess NH4OH (30% aqueous) in THF followed by addition of an isonitrile generates imidazoles 26 - 29 in a single operation.
Figure 7 The 1,4- and 4,5-substitution pattern of imidazoles is as readily accessible via vL-3CR.
Out of the class of 1,4,5-trisubstituted imidazoles, a potent and selective p38 kinase inhibitor 37 has been discovered (J. Sisko, M. Mellinger, P. W. Sheldrake, N. H. Baine., Tetrahedron Lett. 1996, 37, 8113. ). This compound has possible implications in the treatment of rheumatoid arthritis and development was subsequently promoted to phase III clinical trials. Thus, a technical preparation of multi-kilogram amounts was developed (J. Sisko, M. Mellinger, Pure Appl. Chem. 2002, 74, 1349.). The synthesis of the TOSMIC derivative on the scale of several hundred kilograms was accomplished as shown in Figure 8. The corresponding TOSMIC precursor, the formamide 33, was synthesized by employing another multicomponent reaction, an α-amino alkylation of p-fluorobenzaldehyde (30), formamide (31) and p-methylphenylsulphinic acid (32) in the presence of TMSCl in toluene. The dehydration is simple to perform, experimentally involving the addition of excess Et3N to a suspension of formamide in THF containing two equivalents of POCl3 (Ugi method). Once isolated, the TOSMIC derivative is a stable crystalline, easily-handled material. This synthesis has been used to produce in excess of 500 kg 34 safely.
Figure 8 Large scale synthesis of a TOSMIC derivative.The scale-up technical synthesis of the final inhibitor 37 is shown in Figure 9. The vL-3CR and subsequent protecting group transformations led to clean formation of the imidazole product 37 in 60–65 % isolated yield, even on a 200-gallon scale.
Figure 9 Technical synthesis of the GSK p38 kinase inhibitor by a vL-3CR.
Solid Phase TOSMICsPolymer bound reagents are quite useful to leverage the advantages of solid phase organic chemistry (SPOC). Polymeric TOSMIC analogues have been prepared in high yields by free-radical polymerization of (4-ethenylphenyl)sulphonylmethyl isocyanide (H. Kamogawa, H. Maeda, Polym. Sci., J. Polym. Chem. Ed. 1984, 22, 1393). The polymeric TosMIC analogues have been used for the reductive cyanation of ketones and for the synthesis of imidazoles. The eliminated (polymeric) sulphinic acids can be reused.
Moreover Ganessan et al. described an alternative approach for solid-bound TOSMIC, and its use in SPOC of oxazoles (Tetrahedron Lett. 1999, 40, 5633. ). They used Tentagel-SH (Rapp polymer) as a starting material, yielding the target PS-TOSMIC after 3 steps. The authors synthesized 10 different oxazoles in reasonable to good yields.
Figure 10 Solid phase TOSMICs. 1.) KtOBu, p-Me-C6H4-SO2CH2NHCHO, DMSO/THF, 0°C to 20°C, 18h; 2.) m-CPBA, DCM; 3.) PPh3, CCl4, NEt3, DCM, 20°C, 16h.
Recent publications and patents of diverse biologically active vL-3CR products underline the potential and usefulness of this emerging isocyanide-based MCR. A highly potent class of tubulin inhibitors was described by Abbott chemists (J. Med. Chem. 2002, 45, 1697. ). The lead compounds, e.g. 38, showed potent antitumor activity in various mouse models of cancer. Moreover the pharmacokinetic profile of several compounds was excellent, making them good candidates for oral bioavailability. Besides the abovementioned GSK p38 inhibitor 37, Pfizer recently disclosed two classes of kinase inhibitors 39 and 40, based upon TOSMIC chemistry (M. A. Dombroski, M. A. Letavic, K. F. McClure, Preparation of 5-(phenylheteroaryl)-1,3-dihydro-2-benzimidazolone MAP kinase inhibitors as anti-inflammatory agents. 2002, WO 2002072576; M. A. Dombroski, M. A. Letavic, K. F. McClure, U.S. Pat. Appl. Publ. (2004)). Finally Morphochem workers disclosed potent and selective glucose-6-phosphate translocase (G6PT) inhibitors 41 with potential application in diabetis-type-2, based upon a van Leusen imidazole core (J. Comb. Chem. 2005, 7, 218. ).
Figure 11 Biologically relevant, active TOSMIC products.
In summary, apart from the general utility of TOSMIC in organic chemistry, the vL-3CR is a highly efficient method for preparing a variety of imidazoles compounds in a one-pot, multicomponent reaction sequence. Yields are mostly high, reaction conditions are quite mild, and the transformations are experimentally simple. In addition, functional group compatibility is excellent, and introduction of asymmetric centres from chiral amines or aldehydes can easily be accomplished. Clearly the general and broad availability of the three staring material classes, as well as the above mentioned features, make the vL-3CR ideally suited for combinatorial chemistry.