Synthesis of 1,5-Ring-Fused Imidazoles from Cyclic Imines and TosMIC – Identification of in situ Generated N -Methyleneformamide as a Catalyst in the van Leusen Imidazole Synthesis

: Imidazoles fused with a cyclic system in 1,5-position were synthesized via the van Leusen imidazole synthesis employing saturated aliphatic tricycles including an imine function in the base catalyzed cycloaddition reaction with p -toluene-sulfonyl-methyl isocyanide (TosMIC). Thereby, N -(tosyl-methyl)formamide, a decomposition product of TosMIC, was found to act as a promoter of this reaction leading to considera-bly reduced reaction times and improved yields. Mechanistic studies revealed that N -(tosylmethyl)formamide is transformed


Introduction
Imidazole rings are a common structural motif present in many natural products, medicinal drugs, and chemical compounds. [1] Thus, imidazole rings are found for example in numerous anticancer, antibacterial, antiparasitic, antihistaminic, antihypertensive, antineuropathic, and antifungal drugs. [2] Crop protection agents containing an imidazole heterocycle, for instance Prochloraz (1) or Imazalil (2) (Figure 1), are widely applied to maintain crop quality and quantity. [1a,3] Since the first imidazole syntheses by Debus and Radziszewski in the 19 th century, a multitude of synthetic methods for the preparation of imidazoles has evolved. [4] A common approach for the preparation of imidazoles is the van Leusen imidazole synthesis which is based on the 1,3-cycloaddition of tosylmethyl isocyanide (TosMIC) with imines under basic conditions. [4c,5] By this method, a large variety of either 1,5-di-, or into N-methyleneformamide acting as a catalyst in this reaction under the applied basic conditions. Being a Michael acceptor, the employed imines add to this compound, thus being transformed into iminium ions. The so formed intermediates facilitate the first step of the van Leusen imidazole synthesis, which is the addition of deprotonated TosMIC to the iminium subunit. N-methyleneformamide is finally reformed during the overall reaction and can thus be considered as an organocatalyst of the studied cycloaddition reaction. 1,4,5-tri-substituted imidazoles employing acyclic imines as starting materials has been synthesized. [5,6] In contrast, examples in which the van Leusen imidazole synthesis has been applied to the construction of imidazoles displaying a fused ring system originating from 1,5-position are less common which is likely due to the fact that cyclic imines are less abundant than their acyclic counterparts.
Exhibiting an imine subunit, pyrazine-2(1H)one derivatives have been employed in cycloaddition reactions with TosMIC yielding the corresponding ring fused systems that served as intermediates for the development of anticancer agents. [7] Further examples for the construction of 1,5-ring-fused imidazoles by means of TosMIC are found in syntheses of imidazobenzodiazepine and imidazo -carboline derivatives. [8][9][10] Furthermore, also nitrogen containing heteroaromatic compounds like quinolone, isoquinoline, and quinoxaline formally displaying a C=N subunit have successfully been employed in the synthesis of the corresponding N-fused imidazo heterocycles employing TosMIC ( Figure 2). [11] Figure 2. Structures of 1,5-ring-fused imidazoles synthesized from TosMIC and pyrazine-2(1H)ones (4); [7] benzodiazepines (5); [9] -carboline derivatives (6) [10] and nitrogen containing heteroaromatics (7). [11] Though, N-fused imidazoles with a saturated aliphatic cycle in 1,5-position are of great interest as for example Fadrozole (3), a non-steroidal aromatase inhibitor used for the treatment of breast cancer, [12] cycloaddition reactions of basic cyclic imines devoid of any additional functionalities have not been explored in the van Leusen imidazole synthesis, except for a cycloaddition reaction with 4-azahomoadamant-4-ene. [13] It is likely to be attributed to the limited availability of appropriate cyclic imines which are devoid of any additional unsaturation that cycloaddition reactions of this type of compounds with TosMIC for the preparation of the respective N-fused imidazoles have hardly been explored so far. We have repeatedly reported on the synthesis of this kind of alicyclic imines by acid catalyzed intramolecular cycloaddition reactions of 4,4-disubstituted 1,4-dihydropyridines (1,4-DHPs) with one of the 4-substituents serving as dienophile. [14] The tricyclic imines resulting from these reactions exhibiting a highly defined geometry are to be considered as valuable building blocks for the construction of drug like compounds, as they represent scaffolds of high Table 1. Synthesis of symmetric tricyclic imines 13a-f.
[a] The yield of 11 and 12 in the crude product and the product ratio were determined using 1 H NMR spectroscopy with 2,4,6-collidine as internal standard. Isol. yields surpassing the NMR-yield are within error deviations. [16] [b] Not determinable due to low signal intensity.
[c] Not determined. rigidity encompassing well defined trajectories for individual substituents. To further improve the versatility of these building blocks, we now intended to utilize the imine function for the anellation of an imidazole ring by the van Leusen imidazole synthesis to introduce a polar subdomain in this otherwise apolar compounds.

Results and Discussion
As starting material for the anellation of an imidazole ring, we intended to use tricyclic imines which are symmetric, possess substituents R at bridge heads of different size (CH 3 , C 6 H 5 ), and vary with regard of the length of the "upper bridge" (n = 0-2). Therefore, compounds 13a-13f should be employed for this purpose. For the synthesis of these compounds, 13a-13f, the synthetic procedure developed for the construction of related, but non-symmetrically substituted tricyclic imines should be followed. [14a] Accordingly, in the first step appropriately 4,4disubstituted 1,4-dihydropyridines should be prepared via reaction of N-silylpyridinium ions with bisorganomagnesium compounds. An acid catalyzed intramolecular hetero-Diels-Alderreaction of these 4,4-disubstituted 1,4-dihydropyridines -with one 4-substituent exhibiting a double bond serving as dienophile -should finally furnish the respective tricyclic imines.
Hence, for the synthesis of the required 1,4-DHPs 11a-11f, following a published procedure, 4-methylpyridine 8a or 4-phenylpyridine 8b were treated with TIPSOTf (1.1 equiv., in CH 2 Cl 2 at 20°C for 15 min) to generate the corresponding pyridinium ions 9a-9b which were then trapped by addition of the respective bisorganomagnesium species 10a-10f (-30°C). However, for economic reasons here only 0.55 equivalents instead of 1.1 equiv. of the organometallic reagents were used in contrast to the literature procedure. [14a] As in related cases, [14,15] these reactions resulted in mixtures of the regioisomeric 1,2-and 1,4-addition products, i.e. of 11a-11f and 12a-12f. In these mixtures according to 1 H NMR quantification based on the use of an internal standard, the desired 1,4-addition products 11a-11e clearly prevailed in each case over the respective 1,2-addition products 12a-12e. Thus, the 1 H NMR yields for 11a-11e amounted to 26-66 % whereas for 12a-12e, they ranged from values partly too low for an accurate determination (<1 %) to up to 20 %. In line with these results, 11a-11e could finally be isolated in yields from 19-55 %. Dihydropyridine 11f, for which the crude product had not been analyzed by 1 H NMR, was isolated in a yield of 55 %, indicating that also this addition reaction had proceeded in favor of the 1,4-addition product.
Next, we focused on the anellation of an imidazole ring to the imine function of the synthesized tricyclic imines 13a-13f to generate the desired condensation products, imidazole derivatives 14. This we intended to perform as already mentioned afore according to the so called van Leusen imidazole synthesis, in which imines are reacted with TosMIC in the presence of a base to give the corresponding imidazole derivative. [5] When imine 13c, chosen as a model compound, was treated with TosMIC (1.5 equiv.) in MeOH and subsequently with tBuNH 2 (2.0 equiv., 20°C) and stirred for 14 h at 50°C ( that an increased amount of deprotonated TosMIC might raise the reaction rate thus reducing the required reaction time, in a next attempt 6 equivalents of the base were employed under otherwise identical reaction conditions (50°C, 14 h). However, the amount of formed product 14c dropped to 19 % (Table 2, entry 3) indicating that a higher concentration of the base had an adverse effect. Therefore, the original ratio of TosMIC to tBuNH 2 of 1.5:2 was restored and the amount of TosMIC and tBuNH 2 relative to imine 13c was doubled ( Table 2, entry 4). This led to an improved, but still mediocre yield of 37 % ( Table 2, entry 4). To our surprise, when the reaction was carried out with another batch of TosMIC under the initial reaction conditions (1.5 equiv. TosMIC, 2 equiv. tBuNH 2 , 14 h), the yield improved from 29 % to 40 % ( Table 2, compare entries 5 and 1). Careful analysis of the batch of TosMIC employed in this reaction revealed that about 2/3 of the reagent had undergone conversion into N-(tosylmethyl)formamide (15) by addition of water and only 1/3 of the reagent had remained unchanged. This result suggested that N-(tosylmethyl)formamide (15) has a positive effect on the imidazole formation given the fact that the actual quantity of TosMIC utilized was only about 1/3 of the calculated 1.5 equiv. whereas the yield of imidazole 14c was still higher than that for the reaction with pure TosMIC ( Table 2, compare entries 5 and 1). Accordingly, at next an experiment was performed which was identical with the first reaction (  Table 2, compare entries 5 and 6), the yield remained roughly unchanged. Hence, it seemed reasonable that the effect mediated by N-(tosylmethyl)formamide (15) might also depend on the amount of the base present. Therefore, the last reaction ( Table 2, entry 6) was repeated with 6 instead of 3 equivalents of tBuNH 2 with the other reaction conditions remaining unchanged. In that case (1.5 equiv. TosMIC, 3 equiv. formamide 15, 6 equiv. tBuNH 2 ), imidazole 14c was isolated in an excellent yield of 91 %, suggesting that for the positive effect of formamide 15 on the imidazole formation indeed a sufficient amount of the base is required. Thus, in this reaction, the base tBuNH 2 might not only be required for the deprotonation of the cycloaddition reagent TosMIC, but also for a so far unknown activation of formamide 15.
To verify whether other bases also might be suitable for this reaction, tBuNH 2 was substituted by n-butylamine or by 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU) ( Table 2, entries 8-9). With nBuNH 2 , the yield significantly decreased to only 48 %, whereas DBU proofed to be a suitable base as well and a very good yield (84 %) was achieved. However, as it is known that TosMIC does not decompose in the presence of tBuNH 2 [5] and the best yield in our experiments was obtained with this base, tBuNH 2 was chosen as base for all future experiments. Next, for the so far developed reaction conditions, 1 H NMR experiments were performed in the presence of 1,3,5-trimethoxybenzene as internal standard over a period of 20.5 h (Figure 3, solid line) to get an estimate in what quantity the starting material 13c is consumed and the product 14c is formed. Because of the need of ( 2 H 4 )CH 3 OH as a deuterated solvent, these 1 H NMR experiments, however, did not reflect the signals of TosMIC, but of its deuterated analogue [ 2 H 2 ]-TosMIC (exchange of protons of CH 2 group) and finally also those of the double deuterated form of the final product, [ 2 H 2 ]-14c. In case of the reaction of 13c with TosMIC in the presence of N-(tosylmethyl)formamide (15), the percentage of the product [ 2 H 2 ]-14c was fast-growing. An amount of 47 % and 76 % had been reached after 0.5 h and 1.5 h, respectively thereafter it took 19 h to further raise to 88 % (after 20.5 h). Interestingly, the share of remaining imine 13c had dropped within 0.5 h to a value as low as 11 %. Thereafter, it lowered to 4 % within a reaction time of 2.5 h from whereon no further significant change could be observed. Due to the fact that a good 1 H NMR yield for imidazole [ 2 H 2 ]-14c could already be observed after a reaction time of 1.5 h, this reaction time was considered sufficient for any further reaction to be performed.
In contrast, the reaction of imine 13c with [ 2 H 2 ]-TosMIC to give imidazole [ 2 H 2 ]-14c performed in the absence of formamide 15 (Figure 3, dashed line) proceeded much slower. After 1.5 h, just 4 % of imidazole [ 2 H 2 ]-14c had formed. This amount rose slowly to 51 % within 48 h, which equals the quantity that had been reached within only 0.5 h in the prior experiment with formamide 15, clearly demonstrating the promoting effect of this compound (15). Intriguingly, in case of the cycloaddition reaction of 14c with TosMIC executed in the presence of formamide 15, a large gap between the amount of remaining starting material 13c and formed product [ 2 H 2 ]-14c exists, the sum of the share of both compounds being distinctly below 100 %. This phenomenon was most pronounced at the beginning of the reaction and became continuously less with increasing reaction time. In the absence of formamide 15, no such discrepancy could be observed (see Figure 3). This clearly points to the formation of some intermediate during the reaction performed in the presence of N-(tosylmethyl)formamide (15), though at this point due to the complexity of the 1 H NMR spectra no such compound could be identified.
Next, the reaction conditions established for the cycloaddition of 13c with TosMIC in the presence of N-(tosylmethyl)formamide (15) were applied to the tricyclic imines 13a-13b and 13d-13f. In order to get insight in the promoting effect of N-(tosylmethyl)formamide (15), these reactions were also performed in the absence of N-(tosylmethyl)formamide (15).
In both cases, the consumption of imine and formation of imidazole was quantified directly by 1 H NMR at the time point given. For this reason, the reactions were carried out in ( 2 H 4 )CH 3 OH again. When imine 13a was treated with TosMIC (1.5 equiv.) in the presence of formamide 15 (3 equiv.) and tBuNH 2 (6 equiv.) for 1.5 h at 50°C, the desired imidazole [ 2 H 2 ]-14a was formed to 51 % with no imine 13a remaining (Table 3, entry 1). When in the same reaction formamide 15 was omitted, the 1 H NMR yield of imidazole [ 2 H 2 ]-14a dropped to 25 %, and 45 % of the starting material 13a was found to be still present. The results obtained for the reactions of imines 13b-13d with TosMIC leading to [ 2 H 2 ]-14b-14d (for the sake of completeness data of the formation of [ 2 H 2 ]-14c described above have been included here, too) highlight the positive effect of N-(tosylmethyl)formamide (15) even better. Thus, the yields for imidazoles [ 2 H 2 ]-14b-14d amounted to 46-76 % when formamide 15 was present, whereas only negligible amounts were identified when 15 was absent and large amounts of starting materials, Table 3. Synthesis of various imidazoles.
[a] The amount of 13 and 14 in the crude reaction mixture was determined using 1 H NMR spectroscopy with 1,3,5-trimethoxybenzene as internal standard.
[b] Isolated yield after purification (given in parentheses). The experiment was carried out in non-deuterated methanol leading to a non-deuterated imidazole.
[c] Identical to data given in Figure 3; isolated yield identical to data given in Table 2.
[d] Yield determined after aqueous workup (addition of 1,3,5-trimethoxybenzene as internal standard to the crude reaction mixture, evaporation of ( 2 H 4 )CH 3 OH, redissolving in CH 2 Cl 2 and twofold washing with brine) using 1 Figure 3). Similar to this transformation described in Figure 3, also the sum of the quantities of unreacted imine and formed imidazole was distinctly lower than 100 %, in particular for the transformations of imines 13a-13b into imidazoles [ 2 H 2 ]-14a-14b. Remarkably, when the synthesis of imidazoles 14a-14d was carried out in non-deuterated methanol (in the presence of 15), the yields achieved after purification for the, in consequence non-deuterated imidazoles 14a-14d were higher (56-91 % vs. 46-76 %; see Table 3  . X-ray crystal structures of imidazole 14d and tricyclic imines 13b, 13d and 13f. [17] Eur. J. Org. Chem. 2020, 3599-3612 www.eurjoc.org product rose from 48 % to 59 %, now being in good accord with the isolated yield of 56 % (Table 3, entry 4). By crystallization and subsequent X-ray crystallography of the non-deuterated imidazole 14d the unique structure of these imidazoles was corroborated (Figure 4). In contrast to the results described above, the yields obtained in the syntheses of imidazoles [ 2 H 2 ]-14e-f from imines 13e-13f were quite disappointing. Monitoring the reactions by TLC revealed that within 1.5 h no detectable amount of product had formed independent of the absence or presence of formamide 15. When the reaction time was extended to 6 d for the formation without N-(tosylmethyl)formamide (15), still only minute amounts of imidazole derivatives [ 2 H 2 ]-14e-14f could be detected (ca. 2 %, Table 3, entries 5-6). In contrast, the yield for these compounds was distinctly higher when formamide 15 was present in the reaction mixture, though still low with values of 14 % and 12 % for [ 2 H 2 ]-14e and [ 2 H 2 ]-14f, respectively. Hence, despite the poor outcome of these reactions, the positive effect of formamide 15 was still clearly evident.
The poor yields obtained for the cycloaddition reaction performed with the cyclic imines 13e-13f appear quite astonishing, considering the close structural similarity of these compounds with the imines 13a-13d, for which the yields for the cycloaddition products, the imidazole derivatives [ 2 H 2 ]-14a-14d had been quite satisfying. Clearly, this phenomenon must be associated with the continuous enlargement of the "upper bridge", from a CH 2 , to a CH 2 CH 2 , and finally a CH 2 CH 2 CH 2 unit upon the transition from 13a-13b to 13c-13d and finally to 13e-13f. As a result of the increasing size of this bridge, the adjacent bridgehead substituents should be pushed towards the imine function, thus increasing the shielding and associated with that reducing the reactivity of the latter. The assumed change of the orientation of the aforementioned bridgehead substituents could be verified by X-ray structures obtained for the phenyl-substituted imines 13b, 13d, and 13f. These clearly show that with the increasing size of the "upper bridge" the bridgehead substituents are getting closer to the imine function.
Finally, the effect of N-(tosylmethyl)formamide (15) on the cycloaddition reaction of imines 13a-13f with TosMIC should exemplarily also be studied for some imines structurally different from 13a-13f. As such 2,3,4,5-tetrahydropyridine (13g) and 3,4-dihydroisoquinoline (13h) were selected. In case of the reaction with imine 13g, the starting material was fully consumed within 1.5 h, independent of whether formamide 15 was present or not. However, this time the yield of the cycloaddition product [ 2 H 2 ]-14g was higher when 15 was absent (41 %) than when it was present (21 %). Possibly, formamide 15 mediates decomposition reactions in this case as a multitude of side products was detected by 1 H NMR, which might be associated with the dynamic character of imine 13g existing in mono-and trimeric form. [18] However, the positive effect of N-(tosylmethyl)formamide (15) in the cycloaddition reaction with Tos-MIC became again evident when 3,4-dihydroisoquinoline (13h) was used as starting material. Employing the standard conditions, the 1 H NMR yield for the product [ 2 H 2 ]-14h amounted to 83 % when formamide 15 was present and to 66 % when it was absent. Thereby, according to the 1 H NMR data in the first case the starting material had been completely consumed (0 %, 13h) and in the latter 25 % remained unchanged (reaction time 1.5 h). The positive effect of N-(tosylmethyl)formamide (15) became even more apparent, when the conversion of imine 13h into [ 2 H 2 ]-14h was performed at a reduced temperature of 25°C instead of 50°C. Then, after the same reaction time (1.5 h) only 23 % of the imine 13h had been transformed into product [ 2 H 2 ]-14h when 15 was absent, but 86 % in its presence ( 1 H NMR yields, Table 3, entry 8).
Next, to shed some light on the fate and possibly on the function of N-(tosylmethyl)formamide 15 in the above described cycloaddition reaction, a series of control experiments was performed. First, formamide 15 dissolved in ( 2 H 4 )CH 3 OH was kept for 1.5 h at 50°C in the absence of any additive and further in the presence of TosMIC (0.5 equiv.), tricylic imine 13c (0.33 equiv.), or tBuNH 2 (2.0 equiv.) ( Table 4, entries 1-4). According to the subsequently performed 1 H NMR analysis of the respective reactive mixtures, formamide 15 remained completely unchanged when no additive or TosMIC was present, or was accompanied with minute amounts of the decomposition product 16 (ca. 1 %; 16 was identified in a subsequent reaction) when tricyclic imine 13c was present. However, when tert-butylamine was added (Table 4, entry 4) only minor amounts of 15 (4 %) remained unchanged after 1.5 h and new species had formed. One of these could be identified as p-toluenesulfinic acid 16, the share of which amounted to 96 %. Thereby, the base-induced decomposition of formamide 15 proceeds rather fast, as about 35 % of this compound had been converted into p-toluenesulfinic acid 16 even at the lower temperature of 25°C within 7 min (Table 4, entry 5). To check whether TosMIC or imine 13c might influence the tBuNH 2 induced decomposition of formamide 15, control experiments were performed, in which in addition to tBuNH 2 either TosMIC or imine 13c was present (Table 4, entries 6-7). The decay of formamide 15 turned out to be largely independent from these additives. However, new signals appeared in the 1 H NMR spectra (as compared to the reactions without these additives) indicating that from 15 derived decomposition products might have reacted with TosMIC and tricyclic imine 13c, respectively. Yet, attempts to identify the newly formed species remained unsuccessful due to the high complexity of the 1 H NMR spectra and the low amounts of the respective compounds present.
According to Xia et al., [19] N-(tosylmethyl)formamide (15) upon treatment with Cs 2 CO 3 (in toluene, at 70°C) undergoes a decomposition reaction yielding p-toluenesulfinate 16 and N-methyleneformamide (17). Thereby the formation of the latter had only become evident from a by-product that had formed via its participation in a Michael addition reaction. Hence, it seemed reasonable to assume that also upon treatment of formamide 15 with tBuNH 2 (as it is e.g. the case in the reaction listed in Table 4, entry 4) besides p-toluenesulfinate (16) also N-methyleneformamide (17) is generated, though also as a rather short-lived intermediate.
A first hint that N-methyleneformamide 17 may also have formed under the reaction conditions used for the cycloaddition of imines 13 with TosMIC, i.e. when tBuNH 2 in ( 2 H 4 )CH 3 OH is applied as a base, came from an MS analysis (ESI-HRMS, see SI). A reaction product obtained by treatment of imine 13c with formamide 15 and tBuNH 2 (Table 4, entry 7) showed a MS signal attributable to an adduct consisting of imine 13c and N-methyleneformamide 17.
Next, tBuNH 2 should be substituted by Cs 2 CO 3 in the cycloaddition reactions of imine 13c with TosMIC. That way, so our hope, consecutive reactions of N-methyleneformamide (17) might be shifted towards intermediates important for the cycloaddition reaction with TosMIC, as no competing reactions with tBuNH 2 as nucleophile could take place.
A control experiment performed in this context, in which N-(tosylmethyl)formamide 15 was treated with Cs 2 CO 3 in ( 2 H 4 )CH 3 OH at 25°C, revealed that also under these reaction conditions and within 20 min, 15 is almost quantitatively transformed in p-toluenesulfinic acid salt 16 (Table 4, entry 8). Though still no evidence for the formation of N-methyleneformamide (17) was found. However, when the decomposition experiment of N-(tosylmethyl)formamide 15 by Cs 2 CO 3 in ( 2 H 4 )CH 3 OH at 25°C was performed in the presence of imine 13c (Scheme 1), a new compound could be detected and isolated. This compound could be identified as the dimer 18 [20] the structure of which comprising a unique 1,3,5,7-tetrazoctane ring could be unequivocally established by X-ray crystallography ( Figure 5). As can be seen from the structure of dimer 18, this compound is the result of the combination of two molecules of the tricyclic imine 13c with two molecules of N-methyleneformamide 17. Accordingly, upon decomposition of formamide 15 besides p-toluenesulfinic acid 16 (compare to Table 4, entry 8), N-methyleneformamide 17 must have formed. Still, the existence of N-methyleneformamide 17 itself could not be corroborated, which might indicate that it is prone to rapid consecutive reactions under the reaction conditions given.
Interestingly, later on dimer 18 (and what is thought to be its racemic diastereomer rac-18a) could also be identified in the 1 H NMR spectra of experiments performed before (see support-Scheme 1. Cs 2 CO 3 -induced decomposition of N-(tosylmethyl)formamide 15 in presence of imine 13c. Figure 5. X-ray crystal structure of dimer 18. [17] Eur. J. Org. Chem. 2020, 3599-3612 www.eurjoc.org ing information). In particular, these were the control experiment when the decomposition of formamide 15 by tBuNH 2 had been studied in presence of imine 13c (Table 4, entry 7) as well as the experiments in which the reactions time course under the original reaction conditions had been monitored by 1 H NMR ( Figure 3, reaction with N-(tosylmethyl)formamide 15; NMR taken after 0.5 h). Obviously also tBuNH 2 similar to Cs 2 CO 3 appears to lead to the formation of N-methyleneformamide 17 upon fragmentation of N-(tosylmethyl)formamide (15). Based on the above described results, the following mechanism for the catalytic effect of N-(tosylmethyl)formamide 15 on the synthesis of imidazoles seems plausible (Scheme 2). In the first step, N-(tosylmethyl)formamide (15) is cleaved by tert-butylamine to give p-toluenesulfinic acid 16 besides N-methyleneformamide 17. By acting as a Michael acceptor methyleneformamide 17 reacts with imine 13c to the iminium ion 19, which exists in a reversible equilibrium with the isolated dimer 18 (and rac-18a) which has been isolated. Then TosMIC adds to this derivative, the thus activated intermediate iminium ion 19 -which possibly exists in an equilibrium with a cyclic oxadiazene species -to give the addition product 20. Retro-Michael addition releases N-methyleneformamide 17 which is now available for a new reaction cycle. The nitrogen centered anion 21 that has been liberated by the retro-Michael addition should then successively react to imidazole 14c, as it has been proposed by van Leusen et al. for the formation of imidazoles from imines and TosMIC, where a species analogous to 21 has been postulated as primary addition product. [5] According to this rationale, N-methyleneformamide 17 acts as a catalyst for the activation of the imine function thus accelerating the imidazole synthesis. Finally, to ensure the promoting effect for the imidazole syntheses arises from N-methyleneformamide 17 and not from another decomposition product of N-(tosylmethyl)formamide 15, p-toluenesulfinic acid 16 and the most obvious hydrolysation products of N-methyleneformamide (17), i.e. formaldehyde and formamide, were studied for their effects on the formation of imidazole 14c under the standard conditions (Table 5, entries 1-3). None of the tested compounds led to a reasonable effect and the starting imine 13c remained largely unchanged. Interestingly, also the attempt to mimic the function of N-methyleneformamide 17 with acrolein in the course of the imidazole synthesis proved to be unsuccessful (Table 5, entry 4). As it seems, acrolein, due to its high reactivity, is prone to extensive side reactions leading to consumption of starting material 13c and of TosMIC, that way interfering with the formation of the desired imidazole 14c. This highlights nicely the unique function of N-methyleneformamide 17 as a catalyst that activates the imine function in the van Leusen imidazole synthesis. Table 5. Control experiments to affirm N-methyleneformamide (17) as catalyst.
[a] The amount of 13c and [ 2 H 2 ]-14c in the crude reaction mixture was determined using 1H NMR spectroscopy with 1,3,5-trimethoxybenzene as internal standard.

Conclusion
In summary, a small set of imidazoles fused with a cyclic system in 1-and 5-position, starting from saturated aliphatic tricycles incorporating an imine functional group and TosMIC has been synthesized. By serendipity, N-(tosylmethyl)formamide was identified as a pre-catalyst for the imidazole synthesis, leading to significantly increased yields and shortened reaction times. Mechanistic studies suggest that by a tert-butylamine induced decomposition of N-(tosylmethyl)formamide, N-methyleneformamide is generated. Being a Michael acceptor, N-methyleneformamide (17) acts as an organocatalyst of these reactions by reacting with the imines, thus forming the corresponding iminium ions 19, that are activated for the nucleophilic attack by TosMIC. This appears to be the first time an activation of imines for imidazole synthesis via cycloaddition with TosMIC is described which is likely to possess great potential for the employment of less reactive imines for the construction of 1,5-disubstituted imidazoles via the van Leusen imidazole synthesis. Accordingly, further studies exploring the scope of this method, the use of methyleneformamide (17) as an organocatalyst on an expanded set of acyclic and cyclic imines in the van Leusen imidazole synthesis can be expected to become a rewarding endeavor.

Experimental Section
Anhydrous reactions were performed under an argon atmosphere in vacuo-dried glassware. All solvents were distilled prior to use and dry THF, Et 2 O, 1,4-dioxane and CH 2 Cl 2 were prepared under a nitrogen atmosphere according to standard procedures. [21] All purchased chemicals were used without further purification.  [22] prior to use were employed. Melting points were determined with a BÜCHI 510 melting point apparatus. All melting points are uncorrected. Infrared spectra were recorded with a Perkin Elmer Paragon 1000 and a Jasco FT/IR-410. Solid substances were measured as KBr pellets and oils as film on NaCl. HRMS were obtained with a Finnigan MAT 95 (EI) and a Finnigan LTQ FT (ESI). 1 H and 13 C NMR spectra were acquired with a Avance III HD Bruker BioSpin (400 or 500 MHz), referenced to the solvent residual peak as internal standard and analyzed with MestReNova (Version 12.0.0-20080; Mestrelab Research S.L.; released 26.09.2017). [23] 2,3,4,5-Tetrahydropyridine 13g [24] and N-(tosylmethyl)formamide 15 [19] were synthesized according to the literature.

Synthesis of 4,4-disubstituted N-triisopropylsilyl-1,4-dihydropyridines (general procedure/ GP1)
The 4-substituted pyridine derivatives were dissolved in CH 2 Cl 2 (0.86 mL/mmol) and TIPSOTf (1.1 equiv.) was added. Prior to cooling to -30°C and subsequent dropwise addition of the R 2 Mg solution (0.55 equiv.) the solution was stirred at r.t. for 15 min. After the time given the reaction was quenched by addition of water (10 mL/ mmol) followed by extraction of the aqueous layer with CH 2 Cl 2 (3 × 10 mL/mmol). The combined organic layers were dried with MgSO 4 and the solvent was removed under vacuum. Quantitative determination of the dihydropyridines in the crude product was achieved by 1 H NMR spectroscopy using 2,4,6-collidine as internal standard. The oxidation of side products was realized by stirring of the crude product under air for the specified period of time, followed by purification by FC.

Synthesis of symmetric tricyclic imines (general procedure / GP2)
The symmetric tricyclic imines were prepared in analogy to the literature. [14a] TFA (15 equiv.) was added to a solution of the 4,4-disubstituted Ntriisopropylsilyl-1,4-dihydropyridine (1.0 equiv.) in pentane (10 mL/ mmol) in one portion and the resulting mixture was stirred for 15 min at 20°C. The reaction was quenched by the addition of K 2 CO 3 (8 equiv.) and a 1:1 mixture of 2 M HCl aq. and EtOH (40 mL/ mmol) was added. The solution was washed with pentane (6 × 20 mL/mmol) and adjusted to pH = 9 with K 2 CO 3 . The aqueous layer was extracted with CH 2 Cl 2 (4 × 20 mL/mmol), the organic layers were combined, dried with Na 2 SO 4 , and the solvent was removed under vacuum. The crude product was purified by FC.

Synthesis of symmetric tricyclic imidazoles (general procedure / GP3)
To a solution of TosMIC (1.5 equiv.) in methanol (6.7 mL/mmol) the imine (1.0 equiv.) and subsequently N-(tosylmethyl)formamide (3 equiv.) was added at 20°C. The resulting mixture was treated with tBuNH 2 (6 equiv.), stirred for 1.5 h at 50°C and then allowed to reach 20°C. The solvent was removed under vacuum, the residue was dissolved in CH 2 Cl 2 (20 mL/mmol) and washed with saturated aqueous NaCl solution (20 mL/mmol) twice. The organic layer was dried with MgSO 4 , the solvent removed under vacuum and the crude product was purified by FC.

NMR experiments
The 1 H NMR experiments to study the formation of the imidazoles ( Figure 3; Table 3, Table 5) and to explore the function of N-(tosylmethyl)formamide 15 (Table 4; Scheme 1) were carried out on the basis of GP3 in ( 2 H 4 )CH 3 OH. The concentrations of the reagents used were identical to those described in GP3 and as follows: Imines 13a-13h (0.1 mmol/mL), TosMIC (0.15 mmol/mL), N-(tosyl-methyl)formamide 15 (0.3 mmol/mL), tBuNH 2 (0.6 mmol/mL). After the reaction time indicated the crude reaction mixtures were cooled to 20°C and analyzed by 1 H NMR spectroscopy. Quantification of the imines 13a-13h and the imidazoles 14a-14h in the crude reaction mixture was achieved by 1 H NMR spectroscopy with 1,3,5-trimethoxybenzene as internal standard. Assignment of the imine and imidazole protons was accomplished by means of reference spectra given in this publication or in literature.
Magnesium turnings (1.5 equiv.) were covered with THF (0.13 mL/ mmol) and a solution of the organic halide (1.0 equiv.) in THF (0.8 mL/mmol) was added dropwise to keep the reaction mixture boiling mildly. After complete addition stirring was continued for 1 h at 20°C followed by addition of 1,4-dioxane (1.1 equiv.) and further stirring for 1 h at 20°C. The resulting suspension was centrifuged (30 min, 3000 g), the supernatant was separated and the remaining slurry was suspended in Et 2 O to retrieve the same volume as before. Centrifugation was repeated (30 min, 3000 g) and the supernatants were combined. The concentrations of the bis-(organo)magnesium solutions were determined according to a procedure of Chong et al. [31] Deviating from this, bis(2-methylallyl)magnesium 10a and bis(2phenylallyl)magnesium 10b were synthesized as reported below.

Bis(2-methylallyl)magnesium 10a
3-Bromo-2-methylpropene (1.0 equiv., 2 M in THF) was added to magnesium powder (1.2 equiv., 3 M in THF) over a period of 2 h at 0°C. The reaction mixture was kept at 0°C for 2 h, subsequently stirred at 20°C for 12 h followed by addition of 1,4-dioxane (1.1 equiv.) and further stirring for 1 h at 20°C. The resulting suspension was centrifuged (30 min, 3000 g), the supernatant was separated and the remaining slurry was suspended in Et 2 O to retrieve the same volume as before. Centrifugation was repeated (30 min, 3000 g) and the supernatants were combined.